Isoindoline compositions and methods for treating neurodegenerative disease

Abstract

Presented herein are methods for reducing clinical measures of cognitive decline and Alzheimer's disease in a subject, wherein clinical measures are correlated with changes in biomarker expression, biological pathways, and biological processes after treatment with sigma-2 receptor modulators. The present disclosure is directed to methods of treating Alzheimer's disease. Also disclosed are methods of determining the Alzheimer's disease status of a subject.

Description

ISOINDOLINE COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims priority to U.S. Provisional Application No. 63 / 490,878 filed March 17, 2023, U.S. Provisional Application No. 63 / 542,973 filed October 6, 2023, U.S. Provisional Application No. 63 / 547,819 filed November 8, 2023, and U.S. Provisional Application No. 63 / 549,054 filed February 2, 2024, which are incorporated herein by reference in their entirety.FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under AG057553 and AG058660 awarded by the National Institutes of Health. The government has certain rights in the invention.SUMMARY OF THE INVENTION

[0003] Embodiments described herein are directed to a method of reducing or maintaining an Alzheimer's Disease Assessment Scale- Cognitive (ADAS-Cog) score in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to Formula I:

[0004] wherein:

[0005] Ri and R2 are each independently selected from H, C1-C6alkyl, or CH2OR1; where R1= H orC1-C6alkyl;

[0006] R3, R4, R5, and R6are each independently selected from H, C1-C6alkyl, OH,OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O( C1-C6alkyl), OCF3, OCH2CH2OH, O( C1- C6alkyl)OH, O( C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4alkyl)2, NH(C3-7 cycloalkyl),NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(0) (CI-4 alkyl), and C(0)NH(C1-4 alkyl); where n= 0, 1, or 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-6haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1 -yl, piperidin- 1 -yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4 alkyl), or NH(C1-4alkyl)2, wherein optionally substituted group is selected from C1-C6 alkyl or C2-C? acyl;

[0007] or R3and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2methylene-O- group;

[0008] or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a -O-C1-2methylene-O- group;

[0009] R7, R8, R9, R10, and R11are each independently selected from H, C1-6alkylOH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-6alk yl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4 alkyl), N(C1-4alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(C1-4allcyl); where n= 0, 1, or 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, haClo1a-Clk6yl, aryl, alkylaryl, piperazin- 1 -yl, piperidin- 1 -yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1- 4 alkyl), or NH(C 1-4 alkyl)2;

[0010] or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R? and Rs are linked together to form a -O-C1-2 methylene-O- group;

[0011] or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group,

[0012] wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

[0013] with the proviso that the following compounds are excluded:

[0014] Embodiments described herein are directed to a method of reducing levels of a-synuclein (aSyn) in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0015] Embodiments described herein are directed to a method of reducing levels of Ap in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0016] Embodiments described herein are directed to a method of restoring synaptic function in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0017] Embodiments described herein are directed to a method of slowing neurodegeneration in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0018] Embodiments described herein are directed to a method of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein; wherein the administration of the compound according to Formula I results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the at least one biomarker with increased expression is selected from the group comprising IGHG1, IGHV3- 64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof; and wherein the at least one biomarker with decreased expression is selected from the group comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF1 1, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof.

[0019] Embodiments described herein are directed to a method of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein; wherein the administration of the compound according to Formula I results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the at least one biomarker with increased expression is selected from the group comprising IGHG1, IGHV3- 64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof; and wherein the at least one biomarker with decreased expression is selected from the group comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF1 1, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5,ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, 0LFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof.BRIEF DESCRIPTION OF DRAWINGS

[0020] FIG. 1 is a set of graphs illustrating the correlation between SYT1 abundance and qSYTl (upper left), the correlation between NRGN abundance and qNrgn (upper right), the correlation between NEFL abundance and qNfL (lower left) and between the abundance of MAPT and qTau (lower right).

[0021] FIG. 2A is a graph illustrating abundances of AD-related genes compared between healthy control, the Emory AD population, and the SHINE-A baseline CSF proteomes. Abundances were plotted (Log2 abundance) to determine how SHINE-A CSF compares to CSF of either healthy or AD known populations. Data is presented as mean abundance (line within box) + / - SEM (box height) and + / - SD (error bars).

[0022] FIG. 2B is a graph illustrating abundances of AD-related genes compared between healthy control, the Emory AD population, and the SHINE-A baseline CSF proteomes. Abundances were plotted (Log2 abundance) to determine how SHINE-A CSF compares to CSF of either healthy or AD known populations. Data is presented as mean abundance (line within box) + / - SEM (box height) and + / - SD (error bars).

[0023] FIG. 2C is a graph illustrating abundances of AD-related genes compared between healthy control, the Emory AD population, and the SHINE-A baseline CSF proteomes. Abundances were plotted (Log2 abundance) to determine how SHINE-A CSF compares to CSF of either healthy or AD known populations. Data is presented as mean abundance (line within box) + / - SEM (box height) and + / - SD (error bars).

[0024] FIG. 3 A is a forest plot of proteins found to be normalized by CT1812 towards healthy control levels, moving in the opposition of that in AD disease state (p < 0.05), by functional category of protein.

[0025] Fig. 3B is a graph illustrating abundance of clusterin in the healthy control, the pooled AD cohort, and the SHINE baseline subjects (left), and abundance of clusterin in the difference between the reference AD and control, the placebo change from baseline (CFB), and the treated CFB CT- 1812 group (right). Data is presented as mean (line within box) log abundance + / - SEM (box height) and + / - SD (error bars).

[0026] FIG. 3C is a graph illustrating abundance of HLA-DRB1 (HLA class II histocompatibility antigen, DRB 1 beta chain) abundance in the healthy control, the pooled AD cohort, and the SHINE baseline subjects (left), and abundance of HLA-DRB1 in the difference between the reference AD and control, the placebo CFB, and the treated CFB CT- 1812 group (right). Data is presented as mean (line within box) log abundance + / - SEM (box height) and + / - SD (error bars).

[0027] FIG. 4 is a set of graphs illustrating correlations between Ab42 CFB and TMT-MS CFB levels for select proteins. Each dot is a value from an individual participant.

[0028] FIG. 5 is a set of graphs illustrating correlations between A [342 / 40 CFB and TMT-MS CFB levels for select proteins. Each dot is a value from an individual participant.

[0029] FIG. 6 is a graph illustrating the CFB ADAS-Cogl l scores by treatment group over course of 6 months are plotted with all 24 patients (intent to treat).

[0030] FIG. 7 is a set of scatter plots showing relationship between individual patient LTBP1 log2 abundance CFB CSF values and CFBADAS-Cogl 1 values for placebo treated patients only (left) and CT1812-treated only (right).

[0031] FIG. 8 (Left) is a graph illustrating the correlation of CSF LTBP1 CFBwith ADAS-Cogl l CFB in individual CT1812-treated patients (left; each dot is CFB value from individual participant). Right: differential log2 abundance of CFB LTBP1 in AD vs control CSF, and in SHINE placebo- or CT1812-treated CSF at 6 months. CFB = change from baseline).

[0032] FIG. 9 is a scatter plot of individual patient values for the core AD biomarker qNfL, measured using quantitative assay, and TMT-MS-detected NEFM; (r=0.88, p=1.95e- 12).

[0033] FIG. 10 is a set of graphs illustrating modules of proteins with similar coexpression patterns which are significantly correlated with treatment effects.

[0034] FIG. 11A and FIG. 1 IB are graphs illustrating the seven out of 20 modules that were significantly associated with treatment (CT1812 vs placebo).

[0035] FIG. 12 is a graph illustrating change in aSyn from baseline values for individual patients treated with either placebo or CT1812 and show a significant treatment effect.DETAILED DESCRIPTION OF THE INVENTION

[0036] Before compounds, compositions and methods are described in detail, it is to be understood that this disclosure is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the disclosure, the preferred methods, devices, and materials are now described.

[0037] It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0038] Definitions

[0039] The singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a “cell” is a reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.

[0040] The term “about” as used herein, means plus or minus 10 % of a given value. For example, “about 50 %” means in the range of 45 % - 55 %.

[0041] The term “amyloid beta peptide”, “Ap,” or “Abeta” as used herein, refers to extracellular amyloid beta protein that is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by p- and y-secretases. Alzheimer’s disease (AD) is defined histologically by the presence of Ap in the brain.

[0042] The term "agonist" as used herein, refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.

[0043] The term "partial agonist" as used herein, refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.

[0044] The term "antagonist" as used herein, refers to an entity, e.g., a compound, antibody or fragment, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor. As used herein, the term “sigma- 2 receptor antagonist” is used to describe a compound that acts as a “functional antagonist” at the sigma-2 receptor in that it blocks Abeta effects, for example, Abeta oligomer-induced synaptic dysfunction, for example, as seen in an in vitro assay, such as a membrane trafficking assay, or a synapse loss assay, or Abeta oligomer mediated sigma-2 receptor activation of caspase-3, or in a behavioral assay, or in a patient in need thereof. The functional antagonist may act directly by inhibiting binding of, for example, an Abeta oligomer to a sigma-2 receptor, or indirectly, by interfering with downstream signaling resultant from Abeta oligomer binding the sigma-2 receptor.

[0045] The term “modulator” as used herein, refers to an entity, e.g., a compound, antibody, or fragment, a substance, endogenous or exogenous, that binds to and regulates the activity of a substrate such as a receptor. A modulator can be a mixed agonist-antagonist. A modulator can be an antagonist. A modulator can be an agonist.

[0046] The term “biomarker” as used herein, shall mean an organic biomolecule which is differentially present in a sample taken from a subject of one phenotypic status (e.g., having a disease) as compared with another phenotypic status (e.g., not having the disease). A biomarker is differentially present between different phenotypic statuses if the mean or median expression level of the biomarker in the different groups is calculated to be statistically significant. “Increased expression” as used herein refers to an increased amount of a biomarker in one group compared to another, in this case the biomarker may be present at “elevated levels.” “Decreased expression” as used herein refers to a decreased amount of a biomarker in one group compared to another; in this case the biomarker may be present in at “decreased levels.” Common tests for statistical significance include, but are not limited to, t-test, ANOVA, Kruskal-Wallis, Wilcoxon, Mann- Whitney and odds ratio. Biomarkers, alone or in combination, provide measures of relative risk that a subject belongs to one phenotypic status or another. As such, they are useful as markers for disease, therapeutic effectiveness of a drug, or drug candidate and of drug toxicity. In some embodiments, the biomarker is a protein. In some embodiments, the biomarker is ribonucleic acid (RNA).

[0047] The term “Alzheimer’s disease Assessment Scale- Cognitive Subscale” or “ADAS-Cog” as used herein refers to the neuropsychological assessment used to assess the severity of cognitive symptoms of dementia. It is one of the most widely used cognitive scalesin clinical trials and is considered to be the “gold standard” for assessing antidementia treatments. The ADAS-Cog is one half of the Alzheimer's Disease Assessment Scale (ADAS), which also contains a non-cognitive subscale (ADAS-Noncog), which includes 10 tasks which assess mood and behavioral changes which may occur in Alzheimer's disease and other forms of dementia. The ADAS-Cog consists of 11 tasks: Word Recall Task, Word Recall Task, Word Recall Task, Word Recall Task, Word Recall Task, Word Recall Task, Word Recall Task, Word Recall Task, Word Recall Task, Word Recall Task, and Word Recall Task. Multiple variations of the ADAS-Cog test exist, including ADAS-Cog-IRT, ADAS-Cog Plus, and VADAS-Cog. Any ADAS-Cog test known in the art can be used with the methods described herein.

[0048] The term “Alzheimer’s disease priority biomarkers” as used herein refers to biomarkers significantly correlated with Alzheimer’s disease. Priority biomarkers are selected from CLU, APP, SPON1, COL6A1, DDAH1, YWHAB, APOE, OLFML3, PTPR21, SPP1, GLOD4, or any combination thereof.

[0049] The term “eigengene” as used herein refers to the first principal component of a module derived from Weighted Correlation Network Analysis (WGCNA). It can be considered a representative of the gene / protein expression profiles in a module. An “eigengene value” refers to the x samples matrix that tabulates, e.g., the mRNA or gene expression of the genes across the samples. An “eigengene value” also refers the strength of “relative expression or signal” of each sample / subject in the eigengene of the module or network. An “eigenprotein” as used herein refers to protein products.

[0050] The term “sigma-2 receptor antagonist” as used herein, refers to a molecule that binds to a sigma-2 receptor in a measurable amount and acts as a functional antagonist with respect to Abeta effects oligomer induced synaptic dysfunction resultant from sigma-2 receptor binding.

[0051] The term “sigma-2 receptor modulator” as used herein, refers to a molecule that binds to a sigma-2 receptor in a measurable amount and acts to modulate the function of the sigma-2 receptor.

[0052] The term “sigma-2 ligand” as used herein, refers to a compound that binds to a sigma-2 receptor and includes agonists, antagonists, partial agonists, inverse agonists and simply competitors for other ligands of this receptor or protein.

[0053] The term “selectivity” or “selective” as used herein, refers to a difference in the binding affinity of a compound (Ki) for a sigma receptor, for example, a sigma-2 receptor, compared to a non-sigma receptor. The sigma-2 modulators possess high selectivity for a sigmareceptor in synaptic neurons. The Ki for a sigma-2 receptor or both a sigma-2 and a sigma- 1 receptor is compared to the Ki for a non-sigma receptor. In some embodiments, the selective sigma-2 receptor modulator, or sigma- 1 receptor ligand, has at least 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 100-fold, or 500-fold higher affinity, or more, for binding to a sigma receptor compared to a non-sigma receptor as assessed by a comparison of binding dissociation constant Ki values, or IC50 values, or binding constant, at different receptors. Any known assay protocol can be used to assess the Ki or IC50 values at different receptors, for example, by monitoring the competitive displacement from receptors of a radiolabeled compound with a known dissociation constant, for example, by the method of Cheng and Prusoff (1973) (Biochem. Pharmacol. 22, 3099-3108), or specifically as provided herein. In some embodiments, the sigma-2 modulator compound is an antibody, or active binding fragment thereof, specific for binding to a sigma-2 receptor compared to a non-sigma receptor. In the case of an antibody, or fragment, binding constants at a sigma-2 receptor, or fragment, can be calculated and compared to binding constants at a non-sigma receptor by any means known in the art, for example, by the method of Beatty et al., 1987, J Immunol Meth, 100(1-2): 173-179, or the method of Chaiquest, 1988, J. Clin. Microbiol. 26(12): 2561-2563. The non-sigma receptor is, for example, selected from a muscarinic M1-M4 receptor, serotonin (5-HT) receptor, alpha adrenergic receptor, beta adrenergic receptor, opioid receptor, serotonin transporter, dopamine transporter, adrenergic transporter, dopamine receptor, or NMDA receptor.

[0054] The term "high affinity" as used herein, is intended to mean a compound which exhibits a Ki value of less than 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, less than 150 nM, less than 100 nM, less than 80 nM, less than 60 nM, or preferably less than 50 nM in a sigma receptor binding assay, for example against [3H]-DTG, as disclosed by Weber et al., Proc. Natl. Acad. Sci (USA) 83: 8784-8788 (1986), incorporated herein by reference, which measures the binding affinity of compounds toward both the sigma- 1 and sigma-2 receptor sites. Especially preferred sigma ligands exhibit Ki values of less than about 150 nM, preferably less than 100 nM, less than about 60 nM, less than about 10 nM, or less than about 1 nM against [3H]-DTG.

[0055] The term “therapeutic profile” as used herein, refers to a compound that meets the therapeutic phenotype, and also has good brain penetrability (the ability to cross the blood brain barrier), good plasma stability and good metabolic stability.

[0056] The term “drug-like properties” as used herein, refers to the pharmacokinetic and stability characteristics of the sigma-2 receptor ligands upon administration, including brain penetrability, metabolic stability and / or plasma stability.

[0057] The term “administering,” when used in conjunction with the compounds of the disclosure, means to administer a compound directly into or onto a target tissue or to administer a compound systemically or locally to a patient or other subject.

[0058] The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, experimental, domestic and farm animals and pets.

[0059] The terms “subject,” “individual,” and “patient,” as used herein are interchangeable and refer to any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, non-human primates, humans, and the like. In some embodiments the term subject refers to a mammalian cell.

[0060] The term “contacting” as used herein, refers to the bringing together or combining of molecules (or of a molecule with a higher order structure such as a cell or cell membrane) such that they are within a distance that allows for intermolecular interactions such as the non-covalent interaction between two peptides or one protein and another protein or other molecule, such as a small molecule. In some embodiments, contacting occurs in a solution in which the combined or contacted molecules are mixed in a common solvent and are allowed to freely associate. In some embodiments, the contacting can occur at or otherwise within a cell or in a cell-free environment. In some embodiments, the cell-free environment is the lysate produced from a cell. In some embodiments, a cell lysate may be a whole-cell lysate, nuclear lysate, cytoplasm lysate, and combinations thereof. In some embodiments, the cell-free lysate is lysate obtained from a nuclear extraction and isolation wherein the nuclei of a cell population are removed from the cells and then lysed. In some embodiments, the nuclei are not lysed, but are still considered to be a cell-free environment. The molecules can be brought together by mixing such as vortexing, shaking, and the like.

[0061] The term “improves” as used herein, conveys that the disclosure changes either the characteristics and / or the physical attributes of the tissue to which it is being provided, applied or administered. The term “improves” may also be used in conjunction with a disease state such that when a disease state is “improved” the symptoms or physical characteristics associated with the disease state are diminished, reduced, eliminated, delayed or averted.

[0062] The term “inhibiting” as used herein, includes the blockade, aversion of a certain result or process, or the restoration of the converse result or process. In terms of prophylaxis or treatment by administration of a compound of the disclosure, “inhibiting” includes protecting against (partially or wholly) or delaying the onset of symptoms, alleviating symptoms, or protecting against, diminishing or eliminating a disease, condition or disorder.

[0063] The term “log P” as used herein, refers to the partition coefficient of a compound. The partition coefficient is the ratio of concentrations of un-ionized compound in each of two solution phases, for example, octanol and water. To measure the partition coefficient of ionizable solute compounds, the pH of the aqueous phase is adjusted such that the predominant form of the compound is un-ionized. The logarithm of the ratio of concentrations of the un-ionized solute compound in the solvents is called log P. The log P is a measure of lipophilicity. For example,

[0064]

[0065] At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that embodiments of the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose e.g. methyl (Ci alkyl), ethyl (C2 alkyl), C3 alkyl, C4 alkyl, C5 alkyl, and C6alkyl as well as, e.g. C1-C2 allcyl, C1-C3 alkyl, C1-C4 allcyl, C2-C3 allcyl, C2-C4 allcyl, C3-C6allcyl, C4-C5 alkyl, and C5-C6 alkyl.

[0066] For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, then the two R groups can represent different moieties selected from the Markush group defined for R.

[0067] The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.

[0068] The term “hydrogen bond acceptor group” as used herein, refers to a group capable of accepting a hydrogen bond. Examples of hydrogen bond acceptor groups are known and include, but are not limited to, alkoxy groups, oxazolidin-2-one groups, -O-C(O)-N-; - C(O)-N-; -O-; the hetero atom (e.g. oxygen) in a cycloheteroalkyl; -N-SO2- and the like. The groups can be bound in either direction and can be connected to another carbon or heteroatom. A hydrogen bond acceptor group can also be present in or near a hydrophobic aliphatic group. For example, a tetrahydro furan group comprises both a hydrogen bond acceptor group and a hydrophobic aliphatic group. The oxygen present in the tetrahydrofiiran ring acts as a hydrogen bond acceptor and the carbons in the tetrahydrofuran ring act as the hydrophobic aliphatic group.

[0069] The term “hydrophobic aliphatic group” as used herein, refers to a carbon chain or carbon ring. The carbon chain can be present in a cycloheteroalkyl, but the hydrophobic aliphatic group does not include the heteroatom. The tetrahydrofuran example provided above is one such example, but there are many others. In some embodiments, the hydrophobic aliphatic group is an optionally substituted C1- C6 alkyl, cycloalkyl, or C1- C6 carbons of a heterocycloalkyl. A “hydrophobic aliphatic group” is not a hydrophobic aromatic group.

[0070] The term “positive ionizable group” as used herein, refers to an atom or a group of atoms present in a structure that can be positively charged under certain conditions such as biological conditions present in solution or in a cell. In some embodiments, the positive ionizable group is a nitrogen. In some embodiments, the positive ionizable group is a nitrogen present in a cycloheteroalkyl ring. For example, in a piperazine group, the two nitrogens would be considered two positive ionizable groups. However, in some embodiments, the carbons linked to a positive ionizable group are not considered a hydrophobic aliphatic group. In some embodiments, the positive ionizable group is a nitrogen containing ring. Examples of nitrogen containing rings include, but are not limited to, piperazine, piperadine, triazinane, tetrazinane, and the like. In some embodiments with respect to the positive ionizable group, a nitrogen containing ring comprises 1, 2, 3, or 4 nitrogens. In some embodiments, the positive ionizable group is not the nitrogen present in a -N-SO2- group

[0071] In some embodiments, a group comprises both a hydrogen bond acceptor and a positive ionizable group. For example, a morpholine group comprises both a hydrogen bond acceptor in the oxygen group and a positive ionizable group in the nitrogen.

[0072] The term “hydrogen bond donor” as used herein, refers to a group that is capable of donating a hydrogen bond. Examples of a hydrogen bond donor group include, but are not limited to, -OH, and the like.

[0073] The term “alkyl” as used herein, refers to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t- butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. The term “alkylene” refers to a divalent alkyl linking group. An example of alkylene is methylene (CH2).

[0074] The term “alkenyl” as used herein, refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include, but are not limited to,ethenyl, propenyl, cyclohexenyl, and the like. The term “alkenylenyl” refers to a divalent linking alkenyl group.

[0075] The term, “alkynyl” as used herein, refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like. The term “alkynylenyl” refers to a divalent linking alkynyl group.

[0076] The term “haloalkyl” as used herein, refers to an alkyl group having one or more halogen substituents selected from F, Cl, Br, and / or I. Example haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CCh, CHCh, C2CI5, CH2CF3, and the like.

[0077] The term “aryl” as used herein, refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms.

[0078] The term “cycloalkyl” as used herein, refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ringforming carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. A cycloalkyl group can contain from 3 to about 15, from 3 to about 10, from 3 to about 8, from 3 to about 6, from 4 to about 6, from 3 to about 5, or from 5 to about 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Example of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3 -dihydro- IH-indene-l-yl, or lH-inden-2(3H)-one-l-yl). Preferably, “cycloalkyl” refers to cyclized alkyl groups that contain up to 20 ring-forming carbon atoms. Examples of cycloalkyl preferably include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0079] The term “heteroaryl” or “heteroaryl groups” as used herein, refer to an aromatic heterocycle having up to 20 ring-forming atoms and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms eachindependently selected from sulfur, oxygen, and nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazo lyl, indazolyl, 1,2,4- thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, carbon atoms as ring-forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0080] The term “heterocycloalkyl” as used herein, refers to non-aromatic heterocycles having up to 20 ring-forming atoms including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can be mono or polycyclic (e.g., both fused and spiro systems). Example “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3 -dihydrobenzofuryl, 1,3 -benzodioxole, benzo- 1 ,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. For example, a ring-forming S atom can be substituted by 1 or 2 oxo [i.e., form a S(O) or S(O)2]. For another example, a ring-forming C atom can be substituted by oxo (i.e., form carbonyl). Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indoline, isoindoline, isoindolin-l-one-3-yl, 4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, and 3,4-dihydroisoquinolin-l(2H)-one-3yl groups. Ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

[0081] The term “halo” or “halogen” as used herein, includes fluoro, chloro, bromo, and iodo.

[0082] The term “alkoxy” as used herein, refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0083] The term “haloalkoxy” as used herein, refers to an -O-haloalkyl group. An example haloalkoxy group is OCF3. As used herein, “trihalomethoxy” refers to a methoxy group having three halogen substituents. Examples of trihalomethoxy groups include, but are not limited to, -OCF3, -OCCIF2, -OCCI3, and the like.

[0084] The term “arylalkyl” as used herein, refers to a C 1-6 alkyl substituted by aryl and “cycloalkylalkyl” refers to C1-6alkyl substituted by cycloalkyl.

[0085] The term “heteroarylalkyl” as used herein, refers to a C1-6alkyl group substituted by a heteroaryl group, and “heterocycloalkylalkyl” refers to a C1-6alkyl substituted by heterocycloalkyl.

[0086] The term “amino” as used herein, refers to NH2.

[0087] The term “alkylamino” as used herein, refers to an amino group substituted by an alkyl group.

[0088] The term “dialkylamino” as used herein, refers to an amino group substituted by two alkyl groups.

[0089] The term “C(O)” as used herein, refers to C(=O).

[0090] The term “optionally substituted” as used herein, means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valence of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH3) is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups, in indicated.

[0091] The term “salts” as used herein, includes acid addition salts or addition salts of free bases. Preferably, the salts are pharmaceutically acceptable. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from nontoxic inorganic acids such as nitric, phosphoric, sulfuric, or hydrobromic, hydroiodic, hydrofluoric, phosphorous, as well as salts derived from nontoxicorganic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic, maleic, succinic, or citric acids. Non-limiting examples of such salts include napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, et al. “Pharmaceutical Salts,” J. Pharma. Sci. 1977;66: 1).

[0092] The term “pharmaceutically acceptable” as used herein, refers to molecular entities and compositions that are generally regarded as safe and nontoxic. In particular, pharmaceutically acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of this disclosure are physiologically tolerable, compatible with other ingredients, and do not typically produce an allergic or similar untoward reaction (for example, gastric upset, dizziness and the like) when administered to a patient. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The phrase "pharmaceutically acceptable salt(s)", as used herein, includes those salts of compounds of the disclosure that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the disclosure or in compounds identified pursuant to the methods of the disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p- toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the disclosure can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron and diethanolamine salts. Pharmaceuticallyacceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0093] The term “therapeutic” as used herein, means an agent utilized to treat, combat, ameliorate, protect against or improve an unwanted condition or disease of a subject.

[0094] The term “active ingredient” as used herein, refers to a compound of any of the formulae defined herein.

[0095] The term “metabolite” as used herein, refers to a derivative of a compound which is formed when the compound is metabolized. The term “active metabolite” as used herein, refers to a biologically active derivative of a compound which is formed when the compound is metabolized. The term “metabolized” as used herein, refers to the sum of the processes by which a particular substance is changed in the living body. In brief, all compounds present in the body are manipulated by enzymes within the body in order to derive energy and / or to remove them from the body. Specific enzymes produce specific structural alterations to the compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996), pages 11-17. Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art.

[0096] The term “effective amount” as used herein, refers to an amount that results in measurable inhibition of at least one symptom or parameter of a specific disorder or pathological process. For example, an amount of a sigma-2 ligand of the disclosure that provides a measurably lower synapse reduction in the presence of Abeta oligomer qualifies as an effective amount because it reduces a pathological process even if no clinical symptoms of amyloid pathology are altered, at least immediately.

[0097] The terms “therapeutically effective amount” or “effective amount” of a compound or composition of the disclosure as used herein, refers to a predetermined amount which confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect orphysician observes a change). An effective amount of a compound of the disclosure may broadly range from about 0.01 mg / Kg to about 500 mg / Kg, about 0.1 mg / Kg to about 400 mg / Kg, about 1 mg / Kg to about 300 mg / Kg, about 0.05 to about 20 mg / Kg, about 0.1 mg / Kg to about 10 mg / Kg, or about 10 mg / Kg to about 100 mg / Kg. The effect contemplated herein includes both medical therapeutic and / or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this disclosure to obtain therapeutic and / or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the co-administration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed and the duration of the treatment;. The effective amount administered will be determined by the physician in the light of the foregoing relevant circumstances and the exercise of sound medical judgment. A therapeutically effective amount of a compound of this disclosure is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue. The total daily dose of the compounds of this disclosure administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 mg / Kg to about 500 mg / Kg, about 0.1 mg / Kg to about 400 mg / Kg, about 1 mg / Kg to about 300 mg / Kg, about 10 mg / Kg to about 100 mg / Kg, or more usually from 0.1 to 25 mg / kg body weight per day. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the disclosure comprise administration to a patient in need of such treatment will usually include from about 1 mg to about 5000 mg, 10 mg to about 2000 mg of the compound(s), 20 to 1000 mg, preferably 20 to 500 mg and most preferably about 50 mg or 100 mg or 300 mg of a compound according to Formula I, Formula II, and / or Formula III or a pharmaceutically acceptable salt thereof, per day in single or multiple doses. In some embodiments, a compound or pharmaceutical composition according to any embodiment disclosed herein is administered daily for about 6 months. In some embodiments, a compound or pharmaceutical composition according to any embodiment disclosed herein is administered daily for at least about 6 months.

[0098] The terms “treat”, “treated”, or “treating” as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to protect against (partially or wholly) or slow down (e.g., lessen or postpone the onset of) anundesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results such as partial or total restoration or inhibition in decline of a parameter, value, function or result that had or would become abnormal. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent or vigor or rate of development of the condition, disorder or disease; stabilization ( / .<?. , not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether or not it translates to immediate lessening of actual clinical symptoms, or enhancement or improvement of the condition, disorder or disease. Treatment seeks to elicit a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0099] The term “tissue” as used herein, generally refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.

[0100] The term “cognitive decline” as used herein, refers to any negative change in an animal’s cognitive function. For example, cognitive decline, includes but is not limited to, memory loss (e.g. behavioral memory loss), failure to acquire new memories, confusion, impaired judgment, personality changes, disorientation, or any combination thereof. A compound that is effective to treat cognitive decline can be thus effective by restoring long term neuronal potentiation (LTP) or long term neuronal depression (LTD) or a balance of synaptic plasticity measured electrophysiologically; inhibiting, treating, and / or abatement of neurodegeneration; inhibiting, treating, and / or abatement of general amyloidosis; inhibiting, treating, abatement of one or more of amyloid production, amyloid assembly, amyloid aggregation, and amyloid oligomer binding; inhibiting, treating, and / or abatement of a nonlethal effect of one or more of Abeta species on a neuron cell (such as synapse loss or dysfunction and abnormal membrane trafficking); and any combination thereof. Additionally, that compound can also be effective in treating Abeta related neurodegenerative diseases and disorders including, but not limited to dementia, including but not limited to Alzheimer’s Disease (AD) including mild Alzheimer’s disease, Down’s syndrome, vascular dementia (cerebral amyloid angiopathy and stroke), dementia with Lewy bodies, HIV dementia, Mild Cognitive Impairment (MCI); Age-Associated Memory Impairment (AAMI); Age-Related Cognitive Decline (ARCD), preclinical Alzheimer’s Disease (PC AD); and Cognitive Impairment No Dementia (CIND).

[0101] The term “Alzheimer’s disease” as used herein refers to a type of dementia. Patients with Alzheimer’s disease (AD) progress through a continuum of stages, starting with asymptomatic followed by mild cognitive impairment (MCI), mild dementia, moderate dementia, and severe dementia.

[0102] The term “brain penetrability” as used herein, refers to the ability of a drug, antibody or fragment, to cross the blood-brain barrier. In some embodiments, an animal pharmacokinetic (pK) study, for example, a mouse pharmacokinetic / blood-brain barrier study can be used to determine or predict brain penetrability. In some embodiments various concentrations of drug can be administered, for example at 3, 10 and 30 mg / kg, for example p.o. for 5 days and various pK properties are measured, e.g., in an animal model. In some embodiments, dose related plasma and brain levels are determined. In some embodiments, brain Cmax > 100, 300, 600, 1000, 1300, 1600, or 1900 ng / mL. In some embodiments good brain penetrability is defined as a brain / plasma ratio of > 0.1, > 0.3, > 0.5, > 0.7, > 0.8, >0.9, preferably > 1, and more preferably > 2, > 5, or > 10. In other embodiments, good brain penetrability is defined as greater than about 0.1%, 1%, 5%, greater than about 10%, and preferably greater than about 15% of an administered dose crossing the BBB after a predetermined period of time. In certain embodiments, the dose is administered orally (p.o.). In other embodiments, the dose is administered intravenously (i.v.), prior to measuring pK properties.

[0103] The term “plasma stability” as used herein, refers to the degradation of compounds in plasma, for example, by enzymes such as hydrolases and esterases. Any of a variety of in vitro assays can be employed. Drugs are incubated in plasma over various time periods. The percent parent compound (analyte) remaining at each time point reflects plasma stability. Poor stability characteristics can tend to have low bioavailability. Good plasma stability can be defined as greater than 50% analyte remaining after 30 min, greater than 50% analyte remaining after 45 minutes, and preferably greater than 50% analyte remaining after 60 minutes.

[0104] The term “metabolic stability” as used herein, refers to the ability of the compound to survive first-pass metabolism (intestinal and hepatic degradation or conjugation of a drug administered orally). This can be assessed, for example, in vitro by exposure of the compounds to mouse or human hepatic microsomes. In some embodiments, good metabolic stability refers to a ti / 2 > 5 min, > 10 min, > 15 minutes, > 20 minutes, and preferably > 30 min upon exposure of a compound to mouse or human hepatic microsomes. In some embodiments,good metabolic stability refers to an Intrinsic Clearance Rate (Clint) of < 300 uL / min / mg, preferably < 200 uL / min / mg, and more preferably < 100 uL / min / mg.

[0105] COMPOUNDSAND PHARMACEUTICAL COMPOSITIONS

[0106] Embodiments disclosed herein are directed to methods of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to Formula I:

[0108] wherein: Ri and R2 are each independently selected from H, C a1l-kCy6l, or CH2OR1; where R1= H or C1a-Clk6yl; R3, R4, Rs, and Re are each independently selected from H, C1-C6alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy Ci -ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4 alkyl), N(C1-4alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR, S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(C1-4alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, hCal1o-aClk6yl; or optionally substituted aryl, alkylaryl, piperazin- 1 -yl, piperidin- 1 -yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(CI-4 alkyl), or NH(CI-4 alkyl)2, wherein optionally substituted group is selected from C1-C6alkyl or C2-C7 acyl; or R3 and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2 methylene-O- group; or R4 and Rs, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a-O-C1-2methylene-O- group; R7, Rs, R9, Rio, and Rn are each independently selected from H, C1-C6alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(CI-4 alkyl), N(C1-4alkyl)2, NH(C3.7cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(C1-4alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-Ce alkyl, C1-Ce haloalkyl, aryl, alkylaryl, piperazin- 1 -yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(CI-4 alkyl), or NH(CI-4 alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R7 and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C1-6haloalkyl, C1- 6 alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group, wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:

[0109]

[0112] In some embodiments, excluded are certain compounds of the prior art. In some embodiments, the compounds described in Table 1 are disclosed in WO2013 / 029057 and / or WO2013 / 029060, each of which is incorporated by reference herein, and are disclaimed with respect to compositions or methods provided herein.TABLE 1. Disclaimed Compounds.

[0113] In some embodiments, the compound may comprise a racemic mixture or an enantiomer of compound of Formula I, wherein Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, Rio, and Rn are as described above.

[0114] In some embodiments, the compounds for use in the methods described herein may be a compound of Formula I:(Formula I);

[0116] or a pharmaceutically acceptable salt thereof, wherein Ri, FC, R3, R4, R5, Re, R7, Rs, R9, Rio, and Rn are as defined herein, with the proviso that when Ri, R3, FC, R?, Rio and Rn are each H; R2is CH3; Rs is OCH3or Cl; and R9is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF3.

[0117] In other embodiments, the compounds for use in the methods described herein may be a compound of Formula I:

[0118] (Formula I);

[0119] or a pharmaceutically acceptable salt thereof, wherein Ri, R2, R3, R4, R5, Re,R7, Rs, R9, Rio, and Rn are as defined herein, with the proviso that a compound according to Formula I wherein Ri, R3, R6, R?, Rio and Rn are each H; R2is CH3; R8is OCH3or Cl; and R9is OH or Cl; R4 is Cl or CF3, and R5 is Cl or CF3, is not a preferred compound.

[0120] In another embodiment, a pharmaceutical composition is provided for use in the methods described herein according to Formula I:

[0121] (Formula I);

[0122] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Ri, R2, R3, R4, R5, Re, R7, Rs, R9, Rio, and Rn are as defined herein, with the proviso that when Ri, R3, R(„ R7, Rio and Ru are each H; R2is CH3; Rs is OCH3or Cl; and R9is OH or Cl; then R4 is not Cl or CF3, and R5 is not Cl or CF3.

[0123] In some embodiments, the compounds for use in the methods described herein may be a compound of Formula II:

[0124]

[0125] wherein R3, R4, R5, Re, Rs, and R9 are as described herein.

[0126] In some embodiments, the compounds for use in the methods described herein may be a compound of Formula III, wherein R3, R4, R5, Re, R7, Rs, R9, Rio and Rn are as provided herein and wherein - are each independently selected from a single, double or triple bond.

[0128] In some aspects, a compound according to Formula III is selected from:

[0130] or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the the compounds for use in the methods described herein may comprise a racemic mixture or an enantiomer of a compound of Formula I, wherein R3, R4, R5, Re, Rs, and R9 are as described herein.

[0132] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Rs and R9 are independently selected from OH, C1-6alkoxy, and hydroxy C1-6alkoxy.

[0133] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Rs and R9 are independently selected from OH and NH(C1-4 alkyl).

[0134] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Rs and R9 are independently selected from H, halo, C1-6haloalkyl, and C1-6haloalkoxy.

[0135] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Rs and R9 are each independently selected from OH, halo, C1-6alkoxy and C1-6haloalkoxy and Ri and R2 are each independently C1-6alkyl.

[0136] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Ri and R2 are each methyl.

[0137] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein one of Ri and R2 is methyl and the other is H.

[0138] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Rs and R9 are each independently selected from OH and C1-6alkoxy and Ri and R2 are each independently methyl.

[0139] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Rs and R9 are independently selected from H, halo, and C1-6haloalkyl, and Ri and R2 are each methyl.

[0140] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein Rs and R9 are each independently selected from H, halo and C1- 6 haloalkyl.

[0141] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R7 and Rn are each H.

[0142] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R3, R4, R5, and Re are each independently selected from H, halo, C1-6alkyl, C1-6haloalkyl and C1-6alkoxy.

[0143] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R3, R4 and R5 are each independently selected from H, halo, C 1- 6 alkyl, C1- 6 haloalkyl and C 1-6 alkoxy.

[0144] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R3, R4, R . and Re are each independently selected from H, halo, S(O)nR', C(O)OR’, C(O)N(R’)2, and C(O)R’; where n= 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, haloCal1k-Cyl6, or optionally C1-C6alkyl or C2-C7 acyl substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocycloalkyl, and heteroaryl.

[0145] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R3, R4 and R5 are each independently selected from H, halo, S(O)nR', and C(O)R’; where n= 2; R' are each independently CH3, CH2CH3, C3-C6alkyl, aryl, piperazin- 1 -yl, piperidin- 1 -yl, and morpholinyl-4-yl.

[0146] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R3, R4 and R5 are each independently selected from H, halo, S(O)nR', and C(O)R’; where n= 2; R' are each independently CH3, CH2CH3, C3-C6alkyl, aryl, piperazin- 1 -yl, piperidin- 1 -yl, and morpholinyl-4-yl; Rs and R9 are each independently selected from OH, halo, C 1-6 alkoxy and C1-6haloalkoxy; and Ri and R2 are each methyl.

[0147] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R3 and R4 or R4 and R5 together with the C atom to which they are attached form a 6-membered cycloalkyl, or a heterocycloalkyl, aryl or heteroaryl ring.

[0148] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R3 and R4 or R4 and R5 are O, and are linked together to form a -O-C1-2methylene-O- group.

[0149] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R2 and R3 are independently selected from H, OH, halo, C1-6alkoxy and C1-6haloalkyl.

[0150] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula II, wherein R3 and R4 are independently selected from H, Cl, F, -OMe, -CF3, S(O)nR', and C(O)R’; where n= 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, aryl, piperazin- 1 -yl, piperidin- 1 -yl, and morpholinyl-4-yl; Rs and R9 are each independently selected from OH and C 1-6 alkoxy.

[0151] In some embodiments, the compounds for use in the methods described herein may be a compound or a pharmaceutically acceptable salt of Formula I, wherein R2 and R3 are independently selected from H, OH, Cl, F, -OMe, and -CF3, wherein R7and R8are each independently selected from H and C 1-6 alkyl, wherein R9is H, and wherein R5and R6are each independently selected from H and C 1-6 haloalkyl.

[0152] Preferred salts for use in the disclosure include the hydrochloride and fumarate salts of the above compounds.

[0153] These have been synthesized in accordance with general methods provided herein and specific synthetic examples with any additional steps being well within the skill in the art. Several of these compounds have been tested in various assays as detailed herein and have been found active. Tested compounds also display increased bioavailability by reference to compounds disclosed in WO 2010 / 110855.

[0154] In some embodiments, each of the general formulae above may contain a proviso to remove one or more of the following compounds:

[0158] Compounds according to Formula I, Formula II, and / or Formula III have been synthesized in accordance with general methods provided in WO 2015 / 116923, incorporated herein by reference, Several of these compounds have been tested in various assays as detailed herein and have been found active. Tested compounds also display increased bioavailability by reference to compounds disclosed in WO 2010 / 110855, incorporated herein by reference.

[0159] In some embodiments, the compound of Formula I is

[0161] or a pharmaceutically acceptable salt thereof. This compound is also known as CT1812 and is refered to by this name in the examples. In some embodiments, the pharmaceutically acceptable salt is the fumarate salt.

[0162] In some embodiments, the therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1500 mg, about 0.0001 mg to about 1200 mg, about 0.0001 mg to about 1000 mg, about 0.0001 mg to about 800 mg, about 0.0001 mg to about 500 mg, about 0.0001 mg to about 250 mg, about 0.0001 mg to about 200 mg, or about 0.0001 mg to about 100 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I is about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg, about 90 mg, about 180 mg, about 280mg, about 450 mg, about 560 mg, about 840 mg, about 1120 mg, about 1500 mg, about 2000 mg.

[0163] Salts, solvates, stereoisomers, derivatives, prodrugs and active metabolites of the compounds for use in the methods described herein.

[0164] The disclosure further encompasses salts, solvates, stereoisomers, prodrugs and active metabolites of the compounds of any of the formulae above.

[0165] The acid addition salts of the compounds of any of the formulae above may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the disclosure.

[0166] Also included are both total and partial salts, that is to say salts with 1, 2 or 3, preferably 2, equivalents of base per mole of acid of a, e.g., Formula I compound or salt, with 1, 2 or 3 equivalents, preferably 1 equivalent, of acid per mole of base of a any of the formulae above compound.

[0167] For the purposes of isolation or purification it is also possible to use pharmaceutically unacceptable salts. However, only the pharmaceutically acceptable, nontoxic salts are used therapeutically and they are therefore preferred.

[0168] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N’ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0169] The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.

[0170] Compounds of the disclosure may have both a basic and an acidic center and may therefore be in the form of zwitterions or internal salts.

[0171] Typically, a pharmaceutically acceptable salt of a compound of any of the formulae above may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered byevaporation of the solvent. For example, an aqueous solution of an acid such as hydrochloric acid may be added to an aqueous suspension of a compound of any of the formulae above and the resulting mixture evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid. Alternatively, a compound of any of the formulae above may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent. The resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.

[0172] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of the compound of the disclosure are within the scope of the disclosure. The salts of the compound of any of the formulae above may form solvates (e.g., hydrates) and the disclosure also includes all such solvates. The meaning of the word "solvates" is well known to those skilled in the art as a compound formed by interaction of a solvent and a solute (i.e., solvation). Techniques for the preparation of solvates are well established in the art (see, for example, Brittain. Polymorphism in Pharmaceutical solids. Marcel Decker, New York, 1999.).

[0173] The disclosure also encompasses N-oxides of the compounds of formulas I. The term "N-oxide" means that for heterocycles containing an otherwise unsubstituted sp2N atom, the N atom may bear a covalently bound O atom, i.e., -N->0. Examples of such N-oxide substituted heterocycles include pyridyl N-oxides, pyrimidyl N-oxides, pyrazinyl N-oxides and pyrazolyl N-oxides.

[0174] Compounds of any of the formulae above may have one or more chiral centers and, depending on the nature of individual substituents, they can also have geometrical isomers. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has a chiral center, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R— and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomer respectively). A chiral compound can exist as either an individual enantiomer or as a mixture of enantiomers. A mixture containing equal proportions of theenantiomers is called a “racemic mixture”. A mixture containing unequal portions of the enantiomers is described as having an “enantiomeric excess” (ee) of either the R or S compound. The excess of one enantiomer in a mixture is often described with a % enantiomeric excess (% ee) value determined by the formula:

[0175] % ee = (R) - (S) / (R) + (S)

[0176] The ratio of enantiomers can also be defined by “optical purity” wherein the degree at which the mixture of enantiomers rotates plane polarized light is compared to the individual optically pure R and S compounds. Optical purity can be determined using the following formula:

[0177] Optical purity = enant.ma / or / (enant.„M / or+ enant.m!„or)

[0178] Compounds of any of the formulae above can be a substantially pure (+) or(-) enantiomer of the compounds described herein. In some embodiments, a composition comprising a substantially pure enantiomer comprises at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of one enantiomer. In some embodiments, a composition comprising a substantially pure enantiomer is at least 99.5% one enantiomer. In some embodiments, the composition comprises only one enantiomer of a compound described herein.

[0179] The disclosure encompasses all individual isomers of the compounds of any of the formulae above. The description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Methods for the determination of stereochemistry and the resolution or stereotactic synthesis of stereoisomers are well-known in the art. Specifically, there is a chiral center shown in the compounds of any of the formulae above which gives rise to one set of enantiomers. Additional chiral centers may be present depending on the substituents.

[0180] For many applications, it is preferred to carry out stereoselective syntheses and / or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions. Those of skill in the art will further recognize that disclosure compounds may exist in polymorphic forms wherein a compound is capable of crystallizing in different forms. Suitable methods for identifying and separating polymorphisms are known in the art.

[0181] Diastereomers differ in both physical properties and chemical reactivity. A mixture of diastereomers can be separated into enantiomeric pairs based on solubility,fractional crystallization or chromatographic properties, e.g., thin layer chromatography, column chromatography or HPLC.

[0182] Purification of complex mixtures of diastereomers into enantiomers typically requires two steps. In a first step, the mixture of diastereomers is resolved into enantiomeric pairs, as described above. In a second step, enantiomeric pairs are further purified into compositions enriched for one or the other enantiomer or, more preferably resolved into compositions comprising pure enantiomers. Resolution of enantiomers typically requires reaction or molecular interaction with a chiral agent, e.g., solvent or column matrix. Resolution may be achieved, for example, by converting the mixture of enantiomers, e.g., a racemic mixture, into a mixture of diastereomers by reaction with a pure enantiomer of a second agent, i.e., a resolving agent. The two resulting diastereomeric products can then be separated. The separated diastereomers are then reconverted to the pure enantiomers by reversing the initial chemical transformation.

[0183] Resolution of enantiomers can also be accomplished by differences in their non-covalent binding to a chiral substance, e.g., by chromatography on homochiral adsorbants. The noncovalent binding between enantiomers and the chromatographic adsorbant establishes diastereomeric complexes, leading to differential partitioning in the mobile and bound states in the chromatographic system. The two enantiomers therefore move through the chromatographic system, e.g., column, at different rates, allowing for their separation.

[0184] Chiral resolving columns are well known in the art and are commercially available (e.g., from MetaChem Technologies Inc., a division of ANSYS Technologies, Inc., Lake Forest, CA). Enantiomers can be analyzed and purified using, for example, chiral stationary phases (CSPs) for HPLC. Chiral HPLC columns typically contain one form of an enantiomeric compound immobilized to the surface of a silica packing material.

[0185] D-phenylglycine and L-leucine are examples of Type I CSPs and use combinations of n- n interactions, hydrogen bonds, dipole-dipole interactions, and steric interactions to achieve chiral recognition. To be resolved on a Type I column, analyte enantiomers must contain functionality complementary to that of the CSP so that the analyte undergoes essential interactions with the CSP. The sample should preferably contain one of the following functional groups: it -acid or it -base, hydrogen bond donor and / or acceptor, or an amide dipole. Derivatization is sometimes used to add the interactive sites to those compounds lacking them. The most common derivatives involve the formation of amides from amines and carboxylic acids.

[0186] The MetaChiral ODM™ is an example of a type II CSP. The primary mechanisms for the formation of solute-CSP complexes is through attractive interactions, but inclusion complexes also play an important role. Hydrogen bonding, n - n interactions, and dipole stacking are important for chiral resolution on the MetaChiral™ ODM. Derivatization maybe necessary when the solute molecule does not contain the groups required for solutecolumn interactions. Derivatization, usually to benzylamides, may be required for some strongly polar molecules like amines and carboxylic acids, which would otherwise interact strongly with the stationary phase through non-specific-stereo interactions.

[0187] Where applicable, compounds of any of the formulae above can be separated into diastereomeric pairs by, for example, separation by column chromatography or TLC on silica gel. These diastereomeric pairs are referred to herein as diastereomer with upper TLC Rf; and diastereomer with lower TLC Rf. The diastereomers can further be enriched for a particular enantiomer or resolved into a single enantiomer using methods well known in the art, such as those described herein.

[0188] The relative configuration of the diastereomeric pairs can be deduced by the application of theoretical models or rules (e.g. Cram’s rule, the Felkin-Ahn model) or using more reliable three-dimensional models generated by computational chemistry programs. In many instances, these methods are able to predict which diastereomer is the energetically favored product of a chemical transformation. As an alternative, the relative configuration of the diastereomeric pairs can be indirectly determined by discovering the absolute configurations of a single enantiomer in one (or both) of the diastereomeric pair(s).

[0189] The absolute configuration of the stereocenters can be determined by very well known method to those skilled in the art (e.g. X-Ray diffraction, circular dichroism). Determination of the absolute configuration can be useful also to confirm the predictability of theoretical models and can be helpful to extend the use of these models to similar molecules prepared by reactions with analogous mechanisms (e.g. ketone reductions and reductive amination of ketones by hydrides).

[0190] The disclosure may also encompass stereoisomers of the Z-E type, and mixtures thereof due to R2-R3 substituents to the double bond not directly linked to the ring. Additional Z-E stereoisomers are encountered when m is not 1 and m and n are different. The Cahn-Ingold-Prelog priority rules are applied to determine whether the stereoisomers due to the respective position in the plane of the double bond of the doubly bonded substituents are Z or E. The stereoisomer is designated as Z (zusammen = together) if the 2 groups of highestpriority lie on the same side of a reference plane passing through the C=C bond. The other stereoisomer is designated as E (entgegen = opposite).

[0191] Mixture of stereoisomers of E-Z type can be separated (and / or characterized) in their components using classical method of purification that are based on the different chemico-physical properties of these compounds. Included in these method are fractional crystallization, chromatography carried out by low, medium or high pressure techniques, fractional distillation and any other method very well known to those skilled in the art.

[0192] The disclosure also encompasses prodrugs of the compounds of any of the formulae above, i.e., compounds which release an active drug according to any of the formulae above in vivo when administered to a mammalian subject. A prodrug is a pharmacologically active or more typically an inactive compound that is converted into a pharmacologically active agent by a metabolic transformation. Prodrugs of a compound of any of the formulae above are prepared by modifying functional groups present in the compound of any of the formulae above in such a way that the modifications may be cleaved in vivo to release the parent compound. In vivo, a prodrug readily undergoes chemical changes under physiological conditions ( e.g. , are hydrolyzed or acted on by naturally occurring enzyme(s)) resulting in liberation of the pharmacologically active agent. Prodrugs include compounds of any of the formulae above wherein a hydroxy, amino, or carboxy group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino or carboxy group, respectively. Examples of prodrugs include, but are not limited to esters (e.g. , acetate, formate, and benzoate derivatives) of compounds of any of the formulae above or any other derivative which upon being brought to the physiological pH or through enzyme action is converted to the active parent drug. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the art (see, for example, Bundgaard. Design of Prodrugs. Elsevier, 1985).

[0193] Prodrugs may be administered in the same manner as the active ingredient to which they convert or they may be delivered in a reservoir form, e.g. , a transdermal patch or other reservoir which is adapted to permit (by provision of an enzyme or other appropriate reagent) conversion of a prodrug to the active ingredient slowly over time, and delivery of the active ingredient to the patient.

[0194] The disclosure also encompasses metabolites.

[0195] Sigma-2 Receptor Ligands for Selection as Sigma-2 Receptor Modulators

[0196] The isoindoline compounds provided herein act as high affinity, selective sigma-2 functional modulators or selective sigma-2 functional antagonists having thetherapeutic phenotype, and good drug-like properties, and thus can be used to treat Abeta oligomer-induced synaptic dysfunction.

[0197] In certain embodiments, the compositions are provided comprising isoindoline compounds of Formula I, Formula II, or Formula III as selective sigma-2 functional modulators that have high binding affinity to the sigma receptors. In some embodiments, the sigma receptors include both the sigma- 1 and sigma-2 subtypes. See Hellewell, S. B. and Bowen, W. D., Brain Res. 527: 224-253 (1990); and Wu, X.-Z. et al., J. Pharmacol. Exp. Ther. 257: 351-359 (1991). A sigma receptor binding assay which quantitates the binding affinity of a putative ligand for both sigma sites (against3H-DTG, which labels both sites with about equal affinity) is disclosed by Weber et al., Proc. Natl. Acad. Sci (USA) 83: 8784-8788 (1986). Alternatively, [3H]pentozocine may be used to selectively label the sigma- 1 binding site in a binding assay. A mixture of [3H]DTG and unlabeled (+)pentazocine is used to selectively label the sigma-2 site in a binding assay. The disclosure is also directed to compositions comprising certain ligands which are selective for the sigma- 1 and sigma-2 receptors and act as sigma-2 functional modulators or sigma-2 functional antagonists as well as use of these compositions to treat Abeta oligomer-induced synaptic dysfunction. The discovery of such ligands which are selective for one of the two sigma receptor subtypes may be an important factor in identifying compounds which are efficacious in treating central nervous system disorders with minimal side effects.

[0198] In some embodiments, isoindoline compounds of Formula I, Formula II, or Formula III exhibit sigma-2 antagonist activity, high affinity for the sigma-2 receptor, and the ability to block soluble Abeta oligomer binding or Abeta oligomer-induced synaptic dysfunction.

[0199] In some embodiments, the sigma-2 modulators, are designed to enhance their ability to cross the blood-brain barrier.

[0200] In some embodiments, the specific sigma-2 receptor modulator compound blocks binding between soluble Abeta oligomers and a sigma-2 receptor.

[0201] In some embodiments, the sigma-2 modulator compound exhibits high affinity for the sigma-2 receptor.

[0202] In some embodiments, sigma-2 receptor modulators for use in the present disclosure are selected from among sigma-2 receptor ligand compounds that also meet additional selection criteria. Additional criteria are used to select sigma-2 receptor modulators for use in the present disclosure from among sigma-2 receptor ligands. Additional selection criteria include: acting as a functional antagonist in a neuronal cell with respect to inhibitingsoluble Abeta oligomer induced synapse loss, and inhibiting soluble Abeta oligomer induced deficits in a membrane trafficking assay; having high selectivity for one or more sigma receptors compared to any other non-sigma receptor; exhibiting high affinity at a sigma-2 receptor; and exhibiting good drug-like properties including good brain penetrability, good metabolic stability and good plasma stability. In some embodiments, the sigma-2 receptor modulator is further selected on the basis of exhibiting one or more of the additional following properties: does not affect trafficking or synapse number in the absence of Abeta oligomer; does not induce caspase-3 activity in a neuronal cell; inhibits induction of caspase-3 activity by a sigma-2 receptor agonist; and / or decreases or protects against neuronal toxicity in a neuronal cell caused by a sigma-2 receptor agonist.

[0203] In some embodiments, certain sigma-2 receptor ligand compounds subject to further selection criteria are selected from compounds described herein and can be synthesized according to the methods described herein or in WO 2011 / 014880 (Application No. PCT / US2010 / 044136), WO 2010 / 118055 (Application No. PCT / US2010 / 030130), WO 2011 / 0106785 (Application No. PCT / US2011 / 026530), WO 2012 / 106426 (Application No. PCT / US2012 / 023483), WO 2013 / 029057 (Application No. PCT / US2012 / 052572), and WO 2013 / 029060 (Application No. PCT / US2012 / 052578), each of which is incorporated herein by reference in its entirety.

[0204] In some embodiments, the compounds for use in the methods described herein have an IC50 value of less than lOOpM, 50 pM, 20 pM, 15 pM, 10 pM, 5 pM, 1 pM, 500 nM, 100 nM, 50 nM, or 10 nM with respect to inhibition of one or more of the effect of Abeta oligomers on neurons (such as neurons in the brain), amyloid assembly or disruption thereof, and amyloid (including amyloid oligomer) binding, and amyloid deposition. In some embodiments, the compound has an IC50 value of less than lOOpM, 50 pM, 20 pM, 15 pM, 10 pM, 5 pM, 1 pM, 500 nM, 100 nM, 50 nM, or 10 nM with respect to inhibition of the activity / effect of Abeta species such as oligomers on neurons (such as central nervous system neurons).

[0205] In some embodiments, percentage inhibition by the compounds for use in the methods described herein of one or more of the effects of Abeta species such as oligomers on neurons (such as neurons in the brain), such as amyloid (including amyloid oligomer) binding to synapses, and abnormalities in membrane trafficking mediated by Abeta oligomer was measured at a concentration of from 10 nM to 10 pM. In some embodiments, the percentage inhibition measured is about 1% to about 20%, about 20% to about 50%, about 1% to about 50%, or about 1 % to about 80%. Inhibition can be assessed for example by quantifyingsynapse number of a neuron prior to and after exposure to an amyloid beta species or quantifying the number of synapses in the presence of both of a sigma-2 modulator and the Abeta species wherein the sigma-2 modulator is simultaneous with, or precedes or follows, Abeta species exposure. As another example, inhibition can be assessed by determining membrane trafficking and comparing one or more parameters that measure exocytosis rate and extent, endocytosis rate and extent, or other indicators of cell metabolism in the presence and absence of an Abeta species and in the presence and absence of a sigma-2 modulator according to the disclosure. The present inventors have adduced biochemical assay evidence that compounds of the disclosure also inhibit amyloid aggregation (data not shown).

[0206] In some embodiments, the compounds for use in the methods described herein bind specifically to a sigma-2 receptor. A compound that binds specifically to a specific receptor refers to a compound that has a preference for one receptor over another. For example, although a compound may be capable of binding both sigma- 1 and sigma-2 receptor, a compound can be said to be specific for a sigma-2 receptor when it binds with a binding affinity that is at least 10% greater than to the sigma- 1 receptor. In some embodiments, the specificity is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, or 1000% greater for one binding partner (e.g. receptor) than a second binding partner.

[0207] In determining whether a compound of any of the formulae above and other compounds described as sigma-2 modulators above is effective in treating the various conditions described herein, in vitro assays can be used. The in vitro assays have been correlated with an in vivo effect. For example, in the in vitro assays described herein, it can also be used in vivo to treat or ameliorate the conditions described herein including inhibiting or restoring synapse loss, modulating a membrane trafficking change in neuronal cells, protecting against or restoring memory loss, and treating cognitive decline conditions, diseases and disorders such as MCI and Alzheimer’s disease. The assays are based, in part, on the amyloid beta oligomers and their function in binding to neurons at the synapses and the effect that amyloid beta oligomers have on neurons in vitro. In some embodiments, an Abeta oligomer receptor in neurons which the present inventors believe includes a sigma-2 protein is contacted with an amyloid beta assembly as described herein and a compound according to Formula I, II, or III that binds to the sigma-2 protein will inhibit the binding of the amyloid beta assembly to the receptor. In competitive radioligand binding assays the present inventors have shown that the present compounds are specific for the sigma-2 receptor. The inventors have also shown that the compounds of the disclosure inhibit binding of Abeta oligomers to their heretofore unidentified receptor on the surface of neurons. In some embodiments, methods areprovided to determine a compound of any above formula’s sigma-2 ligand efficacy in neuronal signaling. In some embodiments, the method comprises contacting a cell, such as but not limited to, a primary neuron, with a sigma-2 ligand and measuring neuronal function. In some embodiments, the cell is contacted in vitro. In some embodiments the cell is contacted in vivo. The neuronal activity can be signaling activity, electrical activity, the production or release of synaptic proteins, and the like. A sigma-2 modulator that enhances or restores the signaling is identified as a compound that is effective in modulating neuronal activity. In some embodiments, the cell is derived from a pathological sample. In some embodiments, the cell is derived from a subject having a neurodegenerative disease. In some embodiments, the neurodegenerative disease is MCI or Alzheimer’s Disease, especially mild Alzheimer’s disease.

[0208] Pharmaceutical Compositions Comprising a Sigma-2 Receptor Modulator

[0209] The compounds provided herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0210] Thus, another embodiment of the disclosure comprises pharmaceutical compositions for use in the methods described herein comprising a pharmaceutically acceptable excipient or diluent and a therapeutically effective amount of a compound of the disclosure, including an enantiomer, diastereomer, N-oxide or pharmaceutically acceptable salt thereof.

[0211] While it is possible that a compound may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, e.g. , wherein the active agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

[0212] Accordingly, in one aspect, the disclosure provides a pharmaceutical composition comprising at least one compound, antibody or fragment, of any of the formulae above and other compounds described as sigma-2 receptor modulators above described above or a pharmaceutically acceptable derivative (e.g., a salt or solvate) thereof, and, optionally, a pharmaceutically acceptable carrier. In particular, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any of the formulae above or a pharmaceutically acceptable derivative thereof, and, optionally, a pharmaceutically acceptable carrier.

[0213] Combinations

[0214] For the compositions and methods of the disclosure, a compound of any of the formulae above and other compounds described as sigma-2 receptor modulators above described above may be used in combination with other therapies and / or active agents.

[0215] In some embodiments, the compounds for use in the methods described herein can be combined with one or more of a cholinesterase inhibitor, an N-methyl-D- aspartate (NMDA) glutamate receptor antagonist, a beta-amyloid specific antibody, a beta- secretase 1 (BACE1, beta-site amyloid precursor protein cleaving enzyme 1) inhibitor, a tumor necrosis factor alpha (TNF alpha) modulator, an intravenous immunoglobulin (IVIG), or a prion protein antagonist. In some embodiments the sigma-2 receptor modulator is combined with a cholinesterase inhibitor selected from tacrine (COGNEX®; Sciele), donepezil (ARICEPT®; Pfizer), rivastigmine (EXELON®; Novartis), or galantamine (RAZADYNE®; Ortho-McNeil-Janssen). In some embodiments, the sigma-2 receptor modulator is combined with a TNFalpha modulator that is perispinal etanercept (ENBREL®, Amgen / Pfizer). In some embodiments, the sigma-2 receptor modulator is combined with a beta-amyloid specific antibody selected from bapineuzumab (Pfizer), solanezumab (Lilly), PF-04360365 (Pfizer), GSK933776(GlaxoSmithKline), Gammagard (Baxter) or Octagam (Octapharma). In some embodiments, the sigma-2 receptor modulator is combined with an NMDA receptor antagonist that is memantine (NAMENDA®; Forest). In some embodiments, the BACE1 inhibitor is MK- 8931 (Merck). In some embodiments, the sigma-2 receptor modulator is combined with IVIG as described in Magga et al., J Neuroinflam 2010, 7:90, Human intravenous immunoglobulin provides protection against Ab toxicity by multiple mechanisms in a mouse model of Alzheimer’s disease, and Whaley et al., 2011, Human Vaccines 7:3, 349-356, Emerging antibody products and Nicotiana manufacturing; each of which is incorporated herein by reference. In some embodiments, the sigma-2 receptor modulator is combined with a prion protein antagonist as disclosed in Strittmatter et al., US 2010 / 0291090, which is incorporated herein by reference.

[0216] Accordingly, the disclosure provides, in a further aspect, pharmaceutical compositions comprising at least one compound of any of the formulae above or a pharmaceutically acceptable derivative thereof, a second active agent, and optionally a pharmaceutically acceptable carrier.

[0217] When combined in the same formulation it will be appreciated that the two or more compounds must be stable and compatible with each other and the other componentsof the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

[0218] Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

[0219] With respect to combinations including biologies such as monoclonal antibodies or fragments, suitable excipients will be employed to prevent aggregation and stabilize the antibody or fragment in solution with low endotoxin, generally for parenteral, for example, intravenous, administration. For example, see Formulation and Delivery Issues for Monoclonal Antibody Therapeutics, Daugherty et al., in Current Trends in Monoclonal Antibody Development and Manufacturing, Part 4, 2010, Springer, New York pp 103-129.

[0220] The compounds of the disclosure may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the disclosure may be prepared by processes known in the art, for example see WO 02 / 00196 (SmithKline Beecham).

[0221] Routes of Administration and Unit Dosage Forms

[0222] In some embodiments, the therapeutically effective amount of the compounds of Formula I, Formula II, or Formula III is from about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1500 mg, about 0.0001 mg to about 1200 mg, about 0.0001 mg to about 1000 mg, about 0.0001 mg to about 800 mg, about 0.0001 mg to about 500 mg, about 0.0001 mg to about 250 mg, about 0.0001 mg to about 200 mg, or about 0.0001 mg to about 100 mg. In some embodiments, the therapeutically effective amount of the compound of Formula I-III is about 100 mg to about 300 mg. In some embodiments, the therapeutically effective amount of the compounds of Formula I-III is about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 30 mg, about 50 mg, about 90 mg, about 100 mg, about 180 mg, about 280 mg, about 300 mg, about 450 mg, about 560 mg, about 840 mg, about 1120 mg, about 1500 mg, about 2000 mg.

[0223] In some embodiments, the compounds disclosed herein can be administered once daily (QD), twice daily, once in two days, once in three days, once in four days, once in five days, once in six days, or once in seven days. In some embodiments, the compounds disclosed herein can be administered for at least about 6 months. In some embodiments, the compounds disclosed herein can be administered for at least about 12 months. In someembodiments, the compounds disclosed herein can be administered once daily (QD) for 2 consecutive days, for 3 consecutive days, for 4 consecutive days, for 5 consecutive days, for 6 consecutive days, for 7 consecutive days, for 8 consecutive days, for 9 consecutive days, for 10 consecutive days, or for 14 consecutive days. A dosing cycle may include administration for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. After this cycle, a subsequent cycle may begin approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later. The treatment regime may include 1, 2, 3, 4, 5, or 6 cycles, each cycle being spaced apart by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, the dosing can be in fed state or in fasting state.

[0224] In some embodiments, the dosing of the compounds of Formula I-III is such that they can achive a Cmax of about 1 ng / mL to about 2000 ng / mL, about 1 ng / mL to about 1500 ng / mL, about 1 ng / mL to about 1000 ng / mL, about 1 ng / mL to about 750 ng / mL, about 1 ng / mL to about 500 ng / mL, about 1 ng / mL to about 200 ng / mL, about 1 ng / mL to about 100 ng / mL, about 1 ng / mL to about 50 ng / mL, or about 1 ng / mL to about 10 ng / mL. Specific examples include about 1 ng / mL, about 5 ng / mL, about 20 ng / mL, about 80 ng / mL, about 100 ng / mL, about 160 ng / mL, about 240 ng / mL, about 430 ng / mL, about 500 ng / mL, about 560 ng / mL, about 650 ng / mL, about 810 ng / mL, about 850 ng / mL, about 990 ng / mL, about 1460 ng / mL, or about 2000 ng / mL.

[0225] In some embodiments, the Cmax is achieved at about 0.5 hrs to about 5 hrs after administration (i.e. Tmax), about 0.5 hrs to about 4 hrs after administration, about 0.5 hrs to about 3 hrs after administration, about 0.5 hrs to about 2 hrs after administration, or about 0.5 hrs to about 1 hr after administration. Specifc examples include about 0.5 hrs, about 1 hr, about 1.5 hrs, about 2 hrs, about 2.5 hrs, about 3 hrs, about 3.5 hrs, about 4 hrs, about 4.5 hrs, or about 5 hrs

[0226] In some embodiments, the compounds of Formula I-III achieve a target area under the curve (herein after AUC) of about 10 ng.hr / mL to about 10,000 ng.hr / mL over a 24 hour period. In some embodiments, the compounds of Formula I-III achieve a AUC of about 10 ng.hr / mL to about 8,000 ng.hr / mL over a 24 hour period. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 6,000 ng.hr / mL over a 24 hour period. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 5,000 ng.hr / mL over a 24 hour period. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 4,000 ng.hr / mL over a 24 hour period. In some embodiments, the compounds of Formula I-III achieve an AUCof about 10 ng.hr / mL to about 2,000 ng.hr / mL over a 24 hour period. In some embodiments, the compounds of Formula I- III achieve an AUC of about 10 ng.hr / mL to about 1,000 ng.hr / mL over a 24 hour period. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 500 ng.hr / mL over a 24 hour period.

[0227] In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 1000 ng.hr / mL. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 800 ng.hr / mL. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 600 ng.hr / mL. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 500 ng.hr / mL. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 400 ng.hr / mL. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 200 ng.hr / mL. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 100 ng.hr / mL. In some embodiments, the compounds of Formula I-III achieve an AUC of about 10 ng.hr / mL to about 50 ng.hr / mL.

[0228] The routes for administration (delivery) include, but are not limited to, one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), parenteral e.g., by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intracerebroventricular, or other depot administration etc. Administration of an antibody or fragment will generally be by parenteral means.

[0229] Therefore, the compositions of the disclosure include those in a form especially formulated for, the mode of administration. In certain embodiments, the pharmaceutical compositions of the disclosure are formulated in a form that is suitable for oral delivery. For example, compound CB and compound CF are sigma-2 receptor modulator compounds that are orally bioavailable in animal models and have been administered orally once per day and shown efficacy in a fear conditioning model. Orally bioavailable compounds as described herein can be prepared in an oral formulation. In some embodiments, the sigma-2 modulator compound is an orally bioavailable compound, suitable for oral delivery. In other embodiments, the pharmaceutical compositions of the disclosure are formulated in a form that is suitable for parenteral delivery. In some embodiments, the sigma-2 receptor modulator is an antibody or fragment thereof, wherein the antibody or fragment is formulated in a parenteral composition. For example, an anti-sigma-2 receptor antibody such as an anti-PGRMClantibody that blocks binding of Abeta oligomers to the sigma-2 receptor can be formulated for parenteral delivery.

[0230] The compounds of the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine and the disclosure therefore includes within its scope pharmaceutical compositions comprising a compound of the disclosure adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable carriers. Acceptable carriers for therapeutic use are well-known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizing agent(s).

[0231] There may be different composition / formulation requirements depending on the different delivery systems. It is to be understood that not all of the compounds need to be administered by the same route. Likewise, if the composition comprises more than one active component, then those components may be administered by different routes. By way of example, the pharmaceutical composition of the disclosure may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestible solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be delivered by multiple routes.

[0232] The combination of a compound provided herein and an antibody or antibody fragment molecule can be formulated and administered by any of a number of routes and are administered at a concentration that is therapeutically effective in the indication or for the purpose sought. To accomplish this goal, the antibodies may be formulated using a variety of acceptable excipients known in the art. Typically, the antibodies are administered by injection, for example, intravenous injection. Methods to accomplish this administration are known to those of ordinary skill in the art. For example, Gokam et al., 2008, J Pharm Sci 97(8):3051-3066, incorporated herein by reference, describe various high concentration antibody self buffered formulations. For example, monoclonal antibodies in self buffered formulation at e.g.,50 mg / mL mAb in 5.25% sorbitol, pH 5.0 or 60 mg / mL mAb in 5% sorbitol, 0.01% polysorbate 20, pH 5.2; or conventional buffered formulations, for example, 50 mg / mL mAbl in 5.25% sorbitol, 25 or 50 mM acetate, glutamate or succinate, at pH 5.0; or 60 mg / mLin 10 mM acetate or glutamate, 5.25% sorbitol, 0.01% polysorbate 20, pH 5.2; other lower concentration formulations can be employed as known in the art..

[0233] Because compounds for use in the methods described herein cross the blood brain barrier they can be administered in a variety of methods including for example systemic (e.g., by iv, SC, oral, mucosal, transdermal route) or localized methods (e.g., intracranially). Where the compound of the disclosure is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile. For example, the sigma-2 modulator compounds selected from the sigma-2 ligands and prepared for oral administration described above may be coated with an enteric coating layer. The enteric coating layer material may be dispersed or dissolved in either water or in a suitable organic solvent. As enteric coating layer polymers, one or more, separately or in combination, of the following can be used; e.g., solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating layer polymer(s). For environmental reasons, an aqueous coating process may be preferred. In such aqueous processes methacrylic acid copolymers are most preferred.

[0234] Where appropriate, the pharmaceutical compositions can be administered by inhalation, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

[0235] Where the composition of the disclosure is to be administered parenterally, such administration includes without limitation: intravenously, intraarterially, intrathecally, intraventricularly, intracranially, intramuscularly or subcutaneously administering the compound of the disclosure; and / or by using infusion techniques. Antibodies or fragments are typically administered parenterally, for example, intravenously.

[0236] Pharmaceutical compositions suitable for injection or infusion may be in the form of a sterile aqueous solution, a dispersion or a sterile powder that contains the active ingredient, adjusted, if necessary, for preparation of such a sterile solution or dispersionsuitable for infusion or injection. This preparation may optionally be encapsulated into liposomes. In all cases, the final preparation must be sterile, liquid, and stable under production and storage conditions. To improve storage stability, such preparations may also contain a preservative to prevent the growth of microorganisms. Prevention of the action of microorganisms can be achieved by the addition of various antibacterial and antifungal agents, e.g. , paraben, chlorobutanol, or acsorbic acid. In many cases isotonic substances are recommended, e.g., sugars, buffers and sodium chloride to assure osmotic pressure similar to those of body fluids, particularly blood. Prolonged absorption of such injectable mixtures can be achieved by introduction of absorption-delaying agents, such as aluminum monostearate or gelatin.

[0237] Dispersions can be prepared in a liquid carrier or intermediate, such as glycerin, liquid polyethylene glycols, triacetin oils, and mixtures thereof. The liquid carrier or intermediate can be a solvent or liquid dispersive medium that contains, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol or the like), vegetable oils, non-toxic glycerine esters and suitable mixtures thereof. Suitable flowability may be maintained, by generation of liposomes, administration of a suitable particle size in the case of dispersions, or by the addition of surfactants.

[0238] For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

[0239] Sterile injectable solutions can be prepared by mixing a compound of Formula, Formula II, or Formula III, with an appropriate solvent and one or more of the aforementioned carriers, followed by sterile filtering. In the case of sterile powders suitable for use in the preparation of sterile injectable solutions, preferable preparation methods include drying in vacuum and lyophilization, which provide powdery mixtures of the sigma-2 receptor modulators and desired excipients for subsequent preparation of sterile solutions.

[0240] The compounds according to the disclosure may be formulated for use in human or veterinary medicine by injection (e.g., by intravenous bolus injection or infusion or via intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose form, in ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an added preservative. The compositions for injection may be in the form of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain formulatory agents suchas suspending, stabilizing, solubilizing and / or dispersing agents. Alternatively, the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g., sterile, pyrogen- free water, before use.

[0241] The compounds of the disclosure can be administered in the form of tablets, capsules, troches, ovules, elixirs, solutions or suspensions, for immediate-, delayed-, modified- , sustained-, pulsed-or controlled-release applications.

[0242] The compounds of the disclosure may also be presented for human or veterinary use in a form suitable for oral or buccal administration, for example in the form of solutions, gels, syrups, or suspensions, or a dry powder for reconstitution with water or other suitable vehicle before use. Solid compositions such as tablets, capsules, lozenges, troches, pastilles, pills, boluses, powder, pastes, granules, bullets or premix preparations may also be used. Solid and liquid compositions for oral use may be prepared according to methods well- known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.

[0243] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably com, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.

[0244] Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

[0245] The compositions may be administered orally, in the form of rapid or controlled release tablets, microparticles, mini tablets, capsules, sachets, and oral solutions or suspensions, or powders for the preparation thereof. Oral preparations may optionally include various standard pharmaceutical carriers and excipients, such as binders, fillers, buffers, lubricants, glidants, dyes, disintegrants, odorants, sweeteners, surfactants, mold release agents, antiadhesive agents and coatings. Some excipients may have multiple roles in the compositions, e.g., act as both binders and disintegrants.

[0246] Examples of pharmaceutically acceptable disintegrants for oral compositions useful in the disclosure include, but are not limited to, starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and cross-linked polyvinylpyrrolidone.

[0247] Examples of pharmaceutically acceptable binders for oral compositions useful herein include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthine resin, alginates, magnesium-aluminum silicate, polyethylene glycol or bentonite.

[0248] Examples of pharmaceutically acceptable fillers for oral compositions include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium phosphate, calcium carbonate and calcium sulphate.

[0249] Examples of pharmaceutically acceptable lubricants useful in the compositions of the disclosure include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulphate, magnesium lauryl sulphate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.

[0250] Examples of suitable pharmaceutically acceptable odorants for the oral compositions include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions.

[0251] Examples of suitable pharmaceutically acceptable dyes for the oral compositions include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.

[0252] Examples of useful pharmaceutically acceptable coatings for the oral compositions, typically used to facilitate swallowing, modify the release properties, improve the appearance, and / or mask the taste of the compositions include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate -methacrylate copolymers.

[0253] Suitable examples of pharmaceutically acceptable sweeteners for the oral compositions include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.

[0254] Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.

[0255] Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulphate and polysorbates.

[0256] Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0257] As indicated, the compounds of the disclosure can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g.. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g. , using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. , sorbitan trioleate.

[0258] Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0259] For topical administration by inhalation the compounds according to the disclosure may be delivered for use in human or veterinary medicine via a nebulizer.

[0260] The pharmaceutical compositions of the disclosure may contain from 0.01 to 99% weight per volume of the active material. For topical administration, for example, the composition will generally contain from 0.01-10%, more preferably 0.01-1% of the active material.

[0261] The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0262] The pharmaceutical composition or unit dosage form of the disclosure may be administered according to a dosage and administration regimen defined by routine testing in the light of the guidelines given above in order to obtain optimal activity while minimizing toxicity or side effects for a particular patient. However, such fine tuning of the therapeutic regimen is routine in the light of the guidelines given herein.

[0263] The dosage of the compounds of the disclosure may vary according to a variety of factors such as underlying disease conditions, the individual’s condition, weight, sex and age, and the mode of administration. An effective amount for treating a disorder can easily be determined by empirical methods known to those of ordinary skill in the art, for example by establishing a matrix of dosages and frequencies of administration and comparing a group of experimental units or subjects at each point in the matrix. The exact amount to be administered to a patient will vary depending on the state and severity of the disorder and the physical condition of the patient. A measurable amelioration of any symptom or parameter can be determined by a person skilled in the art or reported by the patient to the physician. It will be understood that any clinically or statistically significant attenuation or amelioration of any symptom or parameter of urinary tract disorders is within the scope of the disclosure. Clinically significant attenuation or amelioration means perceptible to the patient and / or to the physician.

[0264] The amount of the compound to be administered can range between about 0.01 and about 25 mg / kg / day, usually between about 0.1 and about 10 mg / kg / day and most often between 0.2 and about 5 mg / kg / day. It will be understood that the pharmaceutical formulations of the disclosure need not necessarily contain the entire amount of the compound that is effective in treating the disorder, as such effective amounts can be reached by administration of a plurality of divided doses of such pharmaceutical formulations.

[0265] In a preferred embodiment of the disclosure, the compounds of Formula I, Formula II, and Formula III are formulated in capsules or tablets, usually containing 10 to 300 mg of the compounds of the disclosure, and are preferably administered to a patient at a total daily dose of 10 to 300 mg, preferably 20 to 150 mg and most preferably about 50 mg, about 100 mg, and about 300 mg.

[0266] A pharmaceutical composition for parenteral administration contains from about 0.01% to about 100% by weight of the active compound of the disclosure, based upon 100% weight of total pharmaceutical composition.

[0267] Generally, transdermal dosage forms contain from about 0.01% to about 100% by weight of the active compound versus 100% total weight of the dosage form.

[0268] The pharmaceutical composition or unit dosage form may be administered in a single daily dose, or the total daily dosage may be administered in divided doses. In addition, co-administration or sequential administration of another compound for the treatment of the disorder may be desirable. To this purpose, the combined active principles are formulated into a simple dosage unit.

[0269] Synthesis of the Compounds

[0270] Compounds of Formula I, Formula II, and Formula III and enantiomers, diastereomers, N-oxides, and pharmaceutically acceptable salts thereof, may be prepared by the general methods outlined in, for example, WO2013 / 029057, incorporated herein by reference, or as described hereinafter, said methods constituting a further aspect of the disclosure.

[0271] It will be appreciated by those skilled in the art that it may be desirable to use protected derivatives of intermediates used in the preparation of the compounds. Protection and deprotection of functional groups may be performed by methods known in the art (see, for example, Green and Wuts Protective Groups in Organic Synthesis. John Wiley and Sons, New York, 1999.). Hydroxy or amino groups may be protected with any hydroxy or amino protecting group. The amino protecting groups may be removed by conventional techniques. For example, acyl groups, such as alkanoyl, alkoxycarbonyl and aroyl groups, may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions. Arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl) may be cleaved by hydrogenolysis in the presence of a catalyst such as palladium-on-charcoal.

[0272] The synthesis of the target compounds is completed by removing any protecting groups which may be present in the penultimate intermediates using standard techniques, which are well-known to those skilled in the art. The deprotected final products are then purified, as necessary, using standard techniques such as silica gel chromatography, HPLC on silica gel and the like, or by recrystallization.

[0273] METHODS

[0274] Methods of Reducing or Maintaining ADAS-Cog

[0275] Embodiments described herein are directed to a method of reducing or maintaining an Alzheimer's Disease Assessment Scale- Cognitive (ADAS-Cog) score in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0276] In some embodiments of the method described herein, any formula described herein is administered for at least about 6 months. In some embodiments, any formula described herein is administered for less than about 6 months.

[0277] In some embodiments of the method described herein, a therapeutically effective amount of any formula described herein is from about 0.0001 mg to about 1120 mg. In some embodiments, the therapeutically effective amount of any formula described herein is about 100 mg to about 300 mg.

[0278] In some embodiments of the method described herein, the ADAS-Cog test is an ADAS-Cog 11 test or an ADAS-Cog 13 test. In some embodiments, an ADAS-Cog score is greater than or equal to 18 is indicative of cognitive impairment. In some embodiments, administering the compound reduces the ADAS-Cog score. In some embodiments, administration of the compound results in a maintenance of the ADAS-Cog score over about 6 months. In some embodiments, administration of the compound results in a maintenance of the ADAS-Cog score over about 1 year. In some embodiments, administration of the compound results in a maintenance of the ADAS-Cog score over about 2 years. In some embodiments, administration of the compound results in a maintenance of the ADAS-Cog score over about 5 years. In some embodiments, administration results in a maintenance of the ADAS-Cog score for about 6 months to about 5 years, or any value between these numbers.

[0279] The ADAS-Cog 14 is a widely used general cognitive measure in clinical trials of AD that assesses multiple cognitive domains including memory, language, praxis, and orientation. A higher score indicates more impairment, a positive change indicates cognitive worsening, the ADAS-Cog 11 subscale was the primary efficacy endpoint of this clinical trial, the ADCS-ADL is a 23-item questionnaire developed by the Alzheimer’s Disease Cooperative Study (ADCS) to assess the ability to perform activities of daily living (ADLs) by participants with AD. The ADCS-ADL scale discriminates well between cognitively normal participants and those with AD and it has good test-retest reliability. The scale ranges from 0-78 and a lower score indicates more impairment. Te MMSE is a brief screening instrument, often used in clinical trials to assess dementia severity, and measures several aspects of memory and cognitive functioning including orientation, attention, concentration, comprehension, recall, and praxis. The scoring range is 0-30, and a lower score indicates more cognitive impairment, the MMSE was administered at screening to determine eligibility for the trial as well as postdose. the CDR-SB Scale is a clinician-rated dementia staging system that tracks the progression of cognitive and functional deterioration. It includes semi-structured interviews with both participants and their caregivers and assesses cognition and function across six domains(memory, orientation, judgement and problem-solving, community afairs, home and hobbies, and personal care). Scores for each domain range from 0 to 3 while total scores range from 0 to 18, with higher scores indicative of greater impairment.

[0280] In some embodiments of the method described herein, the ADAS-Cog score correlates with an increase in expression of biomarkers selected from MYO 19, CMBL, ABHD14B, CAMK2D, NCAM1, PLXND1, JCHAIN, FAM20C, MXRA7, APCS, DNAJB2, F13B, LGALS3, SORCS1, IGHV3-48, TKT, IGHM, GPI, F13A1, CFP, CD5L, IGLV1-40, SPP1, KRT17, FSTL1, LPHN1, GFRA1, MBL2, ADIPOQ, GANAB, BGLAP, ADAM22, B2M, PILRA, LUM, RAB10, PMP2, IGKV2D-29, EIF3J, PCP4, IGHD, ENOPH1, TCN2, ACP2, LXN, RAB14, ATIC, APOB, KIRREL3, CHPF, YWHAE, CSTB, ARF3, RHOA, JAML, ARHGDIA, PTPRS, AK1, IGF1, CFHR5, APOL1, SH3BGRL3, RIN2, PCDHGC3, AP2A1, MET, KIAA0100, PLS3, CDH18, CRK, FBLN2, HSPA1B, SEMA4C, YWHAG, PPIA, TAGLN2, PGLS, IGLV1-47, RNH1, SCN4B, PAFAH1B1, YWHAZ, GLOD4, TBCA, MDK, CAST, A2M, IGLV1-36, GRIA4, FZD1, DCTN2, PGDN, USP14, CNDP1, TXNDC17, COL6A1, VCL, OMG, CNPY3, LANCL1, COLECI 1, LASPI, TPM1, NUDT5, IGKC, MTPN, GLO1, PRDX1, LRP8, PPP2R1A, VMO1, ARSG, VAT1, CBLN1, REEP2, IGHV4- 59, GPLD1, CAPZA1, ENO1, IDH1, C4BPB, NME2, IGHA2, TXN, GALNT10, CREB3L3, TPD52L2, CXCL16, FAM177A1, PRG4, NPC2, and combinations thereof. In some embodiments, the ADAS-Cog score correlates with a decrease in expression of one or more biomarkers selected from Table Bl. In some embodiments, the ADAS-Cog score correlates with an increase in expression of one or more biomarkers selected from Table B2.

[0281] In some embodiments of the method described herein, administering the compound results in an increase in expression of biomarkers including IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in an increase in any one of the biomarkers listed in Table A2.

[0282] In some embodiments of the method described herein, administering the compound results in a decrease in expression of biomarkers including ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5 , ITM2B, MIA3 , NC AM 1 , NFASC, NRP 1 , NRXN 1 , NRXN2, NTNG 1 , OLFM 1 , OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7,and combinations thereof. In some embodiments, administering the compound results in a decrease in any one of the biomarkers listed in Table Al.

[0283] In some embodiments of the method described herein, the biomarkers are measured in cerebrospinal fluid. In some embodiments, the biomarkers are measured in plasma.

[0284] In some embodiments of the method described herein, the reduction or maintenance of the ADAS-Cog score is correlated with modulation of biological processes or biological pathways selected from astrocyte activation involved in immune response; gephyrin clustering involved in postsynaptic density assembly, postsynaptic density protein 95 clustering; negative regulation of metallopeptidase activity, response to vitamin K, regulation of postsynaptic density assembly, regulation of opsonization, positive regulation of aspartic- type peptidase activity, glomerulus morphogenesis, neuron cell-cell adhesion, regulation of aspartic-type peptidase activity, regulation of tau-protein kinase activity, positive regulation of protein kinase A signaling; negative regulation of dendritic spine development; regulation of endothelial cell chemotaxis; neuroligin clustering involved in postsynaptic membrane assembly; gephyrin clustering involved in postsynaptic density assembly; postsynaptic density protein 95 clustering; positive regulation of amyloid fibril formation; NMDA glutamate receptor clustering; negative regulation of dendritic spine maintenance; vocal learning; postsynaptic membrane assembly; positive regulation of aspartic -type endopeptidase activity involved in amyloid precursor protein catabolic process; neurotransmitter-gated ion channel clustering; negative regulation of dendritic spine development; neuron cell-cell adhesion; postsynaptic membrane organization; positive regulation of amyloid precursor protein catabolic process; response to auditory stimulus; positive regulation of excitatory postsynaptic potential; regulation of presynapse assembly; receptor clustering; regulation of dendritic spine development; calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules, and combinations thereof.

[0285] In some embodiments of the method described herein, administering the compound results in a reduction in the level of a-synuclein.

[0286] In some embodiments of the method described herein, administering the compound results in a reduction in the level of Ap. In some embodiments, the Ap is Ap40, Ap42, or a combination of both.

[0287] In some embodiments of the method described herein, the reduction in the ADAS-Cog score is correlated with a change in synaptic function. In some embodiments, the synaptic function is measured by quantitative electroencephalogram (qEEG). In someembodiments, the qEEG is measured by theta power, primary theta power, alpha power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

[0288] Methods of Reducing a-S nuclein

[0289] Embodiments described herein are directed to a method of reducing levels of a-synuclein (aSyn) in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0290] In some embodiments of the method described herein, any formula described herein is administered for at least about 6 months. In some embodiments, any formula described herein is administered for less than about 6 months.

[0291] In some embodiments of the method described herein, a therapeutically effective amount of any formula described herein is from about 0.0001 mg to about 1120 mg. In some embodiments, the therapeutically effective amount of any formula described herein is about 100 mg to about 300 mg.

[0292] In some embodiments of the method described herein, the level of a- synuclein (aSyn) is reduced by about 5% to about 90%.

[0293] In some embodiments of the method described herein, administering the compound results in an increase in expression of biomarkers including IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in an increase in any one of the biomarkers listed in Table A2.

[0294] In some embodiments of the method described herein, administering the compound results in a decrease in expression of biomarkers including ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5 , ITM2B, MIA3 , NC AM 1 , NFASC, NRP 1 , NRXN 1 , NRXN2, NTNG 1 , OLFM 1 , OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in a decrease in any one of the biomarkers listed in Table Al.

[0295] In some embodiments of the method described herein, the reduction in the level of a-synuclein (aSyn) is correlated with modulation of biological processes or biological pathways including positive regulation of axon extension involved in axon guidance; positive regulation of dopamine metabolic process; complement activation, alternative pathway;cytolysis; complement activation, classical pathway; complement activation; chaperone- mediated autophagy; complement activation, alternative pathway; regulation of insulin-like growth factor receptor signaling pathway; positive regulation of synapse assembly; immune response-alternative complement pathway; immune response-alternative complement pathway; immune response-alternative complement pathway; protein folding and maturation, posttranslational processing of neuroendocrine peptides; neurophysiological process synaptic vesicle fusion and recycling in nerve terminals; protein folding and maturation- posttranslational processing of neuroendocrine peptides; neurophysiological process-synaptic vesicle fusion and recycling in nerve terminals; immune response-classical complement pathway; immune response-alternative complement pathway; transport RAB3 regulation pathway, or combinations thereof..

[0296] In some embodiments of the method described herein, the reduction in the level of a-synuclein (aSyn) is correlated with modulation of biomarkers selected from PCDHGB5, IGKV1D-43, FAM177A1, HSPA8, PLXDC1, LINGO1, SERPINA5, TNFSF8, SIRPB2, CDH13, DCBLD1, NA, IGKV6-21 , NRSN2, GMFB, SERPINA3, GLOD4, RAP1B, IGLV3-10, FREM2, RET, IGF2, CD48, ADAMTS16, VM01, GSS, IGKV3D-7, F9, ITM2C, LRG1, DYNLL1, SNX3, SHISA6, FSCN1, ADAMTS13, TPBG, PGM1, DPP10, CDH9, GDA, NCL, SYN2, GFER, IGFBP5, IGFBP2, DMXL2, HLA-DPB1, ABCA13, PEPD, IGHV3-73, IGKV1D-13, LRIG1, FZD8, NAXE, RARRES2, APCS, SLITRK1, IGKV1-9, ADA, CSF1, SLPI, CFAP54, SEMA3B, PPP1R13B, OXT, CCL18, IGKV2-40, ISLR2, ADAMTS4, APOH, and combinations thereof. In some embodiments, the reduction in the level of a-synuclein (aSyn) is correlated with a decrease in expression of one or more biomarkers selected from Table Cl. In some embodiments, the reduction in the level of a- synuclein (aSyn) is correlated with an increase in expression of one or more biomarkers selected from Table C2.

[0297] In some embodiments of the method described herein, administering the compound results in a reduction in the level of Ap. In some embodiments, the Ap is Ap40, Ap42, or a combination of both.

[0298] In some embodiments of the method described herein, the reduction in the level of a-synuclein (aSyn) is correlated with a change in synaptic function.

[0299] In some embodiments of the method described herein, the synaptic function is measured by quantitative electroencephalogram (qEEG). In some embodiments, the qEEG is measured by theta power, primary theta power, alpha power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

[0300] Method of Reducing AH

[0301] Embodiments described herein are directed to a method of reducing levels of Ap in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0302] In some embodiments of the method described herein, any formula described herein is administered for at least about 6 months. In some embodiments, any formula described herein is administered for less than about 6 months.

[0303] In some embodiments of the method described herein, a therapeutically effective amount of any formula described herein is from about 0.0001 mg to about 1120 mg. In some embodiments, the therapeutically effective amount of any formula described herein is about 100 mg to about 300 mg.

[0304] In some embodiments of the method described herein, the Ap is Ap40, Ap42, or a combination of both. In some embodiments, the level of Ap is reduced by about 5% to about 90%.

[0305] In some embodiments of the method described herein, administering the compound results in an increase in expression of biomarkers selected from IGHG1, IGHV3- 64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in an increase in any one of the biomarkers listed in Table A2.

[0306] In some embodiments of the method described herein, administering the compound results in a decrease in expression of biomarkers selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5 , ITM2B, MIA3 , NC AM 1 , NFASC, NRP 1 , NRXN 1 , NRXN2, NTNG 1 , OLFM 1 , OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in a decrease in any one of the biomarkers listed in Table Al.

[0307] In some embodiments of the method described herein, the reduction in the level of Ap is correlated with modulation of biomarkers selected from FABP1, GPNMB, HLA- B, SERPINA, POFUT2, SV2A, ESMI, APA2, and combinations thereof.

[0308] In some embodiments of the method described herein, the reduction in the level of Ap is correlated with modulation of biological processes or biological pathwaysincluding negative regulation of lipoprotein lipase activity; chylomicron remnant clearance, chylomicron remodeling, triglyceride-rich lipoprotein particle remodeling, negative regulation of complement activation; positive regulation of synapse assembly, regulation of complement activation, positive regulation of cell junction assembly, artery morphogenesis, platelet degranulation, and combinations thereof.

[0309] In some embodiments of the method described herein, the reduction in the level of a-synuclein (aSyn) is correlated with a change in synaptic function.

[0310] In some embodiments of the method described herein, the synaptic function is measured by quantitative electroencephalogram (qEEG). In some embodiments, the qEEG is measured by theta power, primary theta power, alpha power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

[0311] Methods of Restoring Synaptic Function

[0312] Embodiments described herein are directed to a method of restoring synaptic function in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0313] In some embodiments of the method described herein, any formula described herein is administered for at least about 6 months. In some embodiments, any formula described herein is administered for less than about 6 months.

[0314] In some embodiments of the method described herein, a therapeutically effective amount of any formula described herein is from about 0.0001 mg to about 1120 mg. In some embodiments, the therapeutically effective amount of any formula described herein is about 100 mg to about 300 mg.

[0315] In some embodiments of the method described herein, the synaptic function is measured by quantitative electroencephalogram (qEEG). In some embodiments, the qEEG is measured by theta power, primary theta power, global relative theta power, central relative theta power, alpha power, secondary alpha power, Amplitude Envelope Correction (AECc), global alpha AECc, temporal alpha AECc, parieto-occipital AECc, and combinations thereof.

[0316] In some embodiments of the method described herein, the theta power is correlated with a decrease in expression of one or more biomarkers selected from Table El . In some embodiments of the method described herein, the theta power is correlated with an increase in expression of one or more biomarkers selected from Table E2.

[0317] In some embodiments of the method described herein, the alpha power is a is correlated with a decrease in expression of one or more biomarkers selected from Table Fl.In some embodiments, the alpha power is correlated with an increase in expression of one or more biomarkers selected from Table F2.

[0318] In some embodiments of the method described herein, administering the compound results in an increase in expression of biomarkers selected from IGHG1, IGHV3- 64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in an increase in any one of the biomarkers listed in Table A2.

[0319] In some embodiments of the method described herein, administering the compound results in a decrease in expression of biomarkers selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5 , ITM2B, MIA3 , NC AM 1 , NFASC, NRP 1 , NRXN 1 , NRXN2, NTNG 1 , OLFM 1 , OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in a decrease in any one of the biomarkers listed in Table Al.

[0320] In some embodiments of the method described herein, the AECc is correlated with modulation of biological processes or biological pathways including extracellular space; proteasome core complex, alpha-subunit complex; extracellular exosome; vesicle; extracellular region; proteasome core complex; collagen type I trimer; proteasome core complex, alpha-subunit complex; fibrillar collagen trimer; proteasome core complex; endoplasmic reticulum lumen; secretory granule lumen; extracellular matrix; collagen- containing extracellular matrix; extracellular exosome, and combinations thereof.

[0321] In some embodiments of the method described herein, the AECc is correlated with modulation of biomarkers including ALDH1A1, ALDH9A1, BAMBI, BTN2A2, CHST7, COL1A2, EIF4B, FAHD1, FZD3, FZD6, GAS1, GRIA3, GXYLT1, HBG1, HIBADH, JAM2, LRRN1, LYPLA1, MATN2, METRNL, NHLRC3, NOTCH 1, NTM, OAF, PCDH9, PGLS, PIK3IP1, PNP, PRDX2, PRG2, PSMA1, PSMA4, PSMA6, PSMB7, SECTM1, SLC4A1, SLIT3, SNX12, ST6GAL2, TKT, UBE2N, WNT4, and combinations thereof. In some embodiments, the AECc is correlated with a decrease in expression of one or more biomarkers selected from Table DI. In some embodiments, the AECc is correlated with an increase in expression of one or more biomarkers selected from Table D2.

[0322] In some embodiments of the method described herein, the compound results in a reduction in the level of a-synuclein.

[0323] In some embodiments of the method described herein, administering the compound results in a reduction in the level of Ap. In some embodiments, the Ap is Ap40, Ap42, or a combination of both.

[0324] Methods of Slowing Neurodeseneration

[0325] Embodiments described herein are directed to a method of slowing neurodegeneration in a subject, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0326] In some embodiments of the method described herein, any formula described herein is administered for at least about 6 months. In some embodiments, any formula described herein is administered for less than about 6 months.

[0327] In some embodiments of the method described herein, a therapeutically effective amount of any formula described herein is from about 0.0001 mg to about 1120 mg. In some embodiments, the therapeutically effective amount of any formula described herein is about 100 mg to about 300 mg.

[0328] In some embodiments of the method described herein, the neurodegeneration is measured by volumetric magnetic resonance imaging (vMRI). In some embodiments, administering the compound reduces the vMRI. In some embodiments, administration of the compound results in a maintenance of the vMRI over 6 months. In some embodiments, administration of the compound results in a maintenance of the vMRI over 1 year. In some embodiments, administration of the compound results in a maintenance of the vMRI over 2 years. In some embodiments, administration of the compound results in a maintenance of the vMRI over 5 years.

[0329] In some embodiments of the method described herein, administering the compound results in an increase in expression of biomarkers including IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in an increase in any one of the biomarkers listed in Table A2.

[0330] In some embodiments of the method described herein, administering the compound results in a decrease in expression of biomarkers including ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8,IL6ST, ITIH5 , ITM2B, MIA3 , NC AM 1 , NFASC, NRP 1 , NRXN 1 , NRXN2, NTNG 1 , OLFM 1 , OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in a decrease in any one of the biomarkers listed in Table Al.

[0331] In some embodiments of the method described herein, the vMRI is correlated with modulation of biomarkers including C4B; C4B 2, SERPINB1, PTN, IGLV1- 51, CNNM3, ADAM9, IGLV1-36, PZP, C4B; C4B 2, KIT, COL5A1, C4BPA, UBE2N, CCT7, FCN3, CFP, FCN2, SMPDL3B, IGLC7, NXPH3, PGD, CACNA2D2, CLP1, UBE2L3, IGHV3-21, FN1, PSMB7, PGLS, C4A, MDGA1, C4BPB, IGLV2-11, PPBP, UFM1,NCALD, TLN1, TXNL1, and combinations thereof. In some embodiments, the vMRI is a is correlated with a decrease in expression of one or more biomarkers selected from Table Gl. In some embodiments, the vMRI is correlated with an increase in expression of one or more biomarkers selected from Table G2.

[0332] In some embodiments of the method described herein, the compound results in a reduction in the level of a-synuclein.

[0333] In some embodiments of the method described herein, administering the compound results in a reduction in the level of Ap. In some embodiments, the Ap is Ap40, Ap42, or a combination of both.

[0334] Method of Treating Alzheimer ’s

[0335] Embodiments described herein are directed to a method of restoring protein expression in a subject with or at risk of developing a synucleinopathy, including administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein.

[0336] In some embodiments of the method described herein, any formula described herein is administered for at least about 6 months. In some embodiments, any formula described herein is administered for less than about 6 months.

[0337] In some embodiments of the method described herein, administration results in an increase in expression of the biomarkers. In some embodiments, the biomarkers are selected from IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in an increase in any one of the biomarkers listed in Table A2.

[0338] In some embodiments of the method described herein, the techniques described herein relate to a method, wherein administration results in a decrease in expression of the biomarkers. In some embodiments, the biomarkers are selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof. In some embodiments, administering the compound results in a decrease in any one of the biomarkers listed in Table Al.

[0339] In some embodiments of the method described herein administering the compound is correlated with modulation of biological processes or biological pathways including phosphatidylcholine-sterol O-acyltransferase activator activity; phosphatidylcholine binding; wnt-protein binding; cholesterol binding; glycosaminoglycan binding; protein folding and maturation_angiotensin system maturation; Immune response_antigen presentation by MHC class I: cross-presentation; O-glycan biosynthesis; Immune response_antigen presentation by MHC class II; signal transduction_angiotensin II / AGTR1 signaling via Notch, Beta-catenin and NF-kB pathways; immune response_antigen presentation by MHC class I, classical pathway; development_regulation of cytoskeleton proteins in oligodendrocyte differentiation and myelination; renin-angiotensin-aldosterone system; development_PEDF signaling; signal transduction_negative regulation of BMP signaling; signal transduction angiotensin IE AGTR1 signaling via p38, ERK and PI3K; immune response lL- 11 signaling via JAK / STAT; protein folding and maturation_regulation of amyloid precursor protein processing; signal transduction BMP signaling via BMPR1A and BMPR1B receptors; development_NOTCH signaling in organogenesis and embryogenesis; protein folding and maturation: bradykinin / kallidin maturation; cell adhesion: ECM remodeling; cell adhesion: cell-matrix glycoconjugates; lipoprotein metabolism; development: ErbB3 signaling, and combinations thereof.

[0340] In some embodiments of the method described herein, the synucleinopathy is Dementia with Lewy Bodies.

[0341] In some embodiments of the method described herein, the compound results in a reduction in the level of a-synuclein.

[0342] In some embodiments of the method described herein, administering the compound results in a reduction in the level of Ap. In some embodiments, the A is Ap40, Ap42, or a combination of both.

[0343] Embodiments described herein are directed to a method of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any formula described herein; wherein the administration of the compound according to Formula I results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the at least one biomarker with increased expression is selected from the group comprising IGHG1, IGHV3- 64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof; and wherein the at least one biomarker with decreased expression is selected from the group comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF1 1, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof. In some embodiments of the method described herein, administering the compound results in an increase in any one of the biomarkers listed in Table A2. In some embodiments, administering the compound results in a decrease in any one of the biomarkers listed in Table Al.

[0344] In some embodiments of the method described herein, any formula described herein is administered for at least about 6 months. In some embodiments, any formula described herein is administered for less than about 6 months.

[0345] In some embodiments of the method described herein, a therapeutically effective amount of any formula described herein is from about 0.0001 mg to about 1120 mg. In some embodiments, a therapeutically effective amount of any formula described herein is about 100 mg to about 300 mg.

[0346] In some embodiments of the method described herein, the biomarkers are measured in cerebrospinal fluid. In some embodiments, the biomarkers are measured in plasma.

[0347] In some embodiments of the method described herein, administering the compound is correlated with modulation of biological processes or biological pathways including phosphatidylcholine-sterol O-acyltransferase activator activity; phosphatidylcholinebinding; wnt-protein binding; cholesterol binding; glycosaminoglycan binding; protein folding and maturation_angiotensin system maturation; immune response_antigen presentation by MHC class I: cross-presentation; O-glycan biosynthesis; Immune response_antigen presentation by MHC class II; signal transduction_angiotensin II / AGTR1 signaling via Notch, Beta-catenin and NF-kB pathways; immune response_antigen presentation by MHC class I, classical pathway; development_regulation of cytoskeleton proteins in oligodendrocyte differentiation and myelination; renin-angiotensin-aldosterone system; development_PEDF signaling; signal transduction_negative regulation of BMP signaling; signal transduction angiotensin IF AGTR1 signaling via p38, ERK and PI3K; immune response lL- 11 signaling via JAK / STAT; protein folding and maturation_regulation of amyloid precursor protein processing; signal transduction BMP signaling via BMPR1A and BMPR1B receptors; development_NOTCH signaling in organogenesis and embryogenesis; protein folding and maturation: bradykinin / kallidin maturation; cell adhesion: ECM remodeling; cell adhesion: cell-matrix glycoconjugates; lipoprotein metabolism; development: ErbB3 signaling, and combinations thereof.

[0348] In some embodiments of the method described herein, the compound results in a reduction in the level of a-synuclein.

[0349] In some embodiments of the method described herein, administering the compound results in a reduction in the level of Ap. In some embodiments, the Ap is Ap40, Ap42, or a combination of both.

[0350] In some embodiments of the method described herein, the synucleinopathy is Dementia with Lewy Bodies.

[0351] In some embodiments of the method described herein, the subject has been diagnosed with Alzheimer's disease. In some embodiments, the subject has been diagnosed with mild cognitive impairment. In some embodiments, the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0352] Alzheimer's disease (AD) is defined histologically by the presence of extracellular p-amyloid (Ap) plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. Various diagnostic and prognostic biomarkers are known in the art, such as magnetic resonance imaging, single photon emission tomography, FDG PET, PiB PET, CSF tau and Abeta analysis, as well as available data on their diagnostic accuracy are discussed in Alves et al., 2012, Alzheimer’s disease: a clinical practice-oriented review, Frontiers in Neurology, April, 2012, vol 3, Article 63, 1-20, which is incorporated herein by reference.

[0353] The diagnosis of dementia, along with the prediction of who will develop dementia, has been assisted by magnetic resonance imaging and positron emission tomography (PET) by using [(18)F]fluorodeoxyglucose (FDG). These techniques are not specific for AD. See, e.g.,Vallabhajosula S. Positron emission tomography radiopharmaceuticals for imaging brain Beta-amyloid. Semin Nucl Med. 2011 Jul;41(4):283-99. Another PET ligand recently FDA approved for imaging moderate to frequent amyloid neuritic plaques in patients with cognitive impairment is Florbetapir F 18 injection, (4-((lE)-2-(6-{2-(2-(2- (18F)fluoroethoxy)ethoxy)ethoxy}pyridin-3-yl)ethenyl)-N- methylbenzenamine,AMYVID®, Lilly). Florbetapir binds specifically to fibrillar Abeta, but not to neurofibrillary tangles. See,e.g., Choi SR, et al., Correlation of amyloid PET ligand florbetapir F 18 binding with A fl aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis Assoc Disord. 2012 Jan;26(l):8-16. The PET ligand florbetapir suffers from low specificity with respect to qualitative visual assessment of the PET scans. Camus et al., 2012, Eur J Nucl Med Mol Imaging 39:621 -631. However, many people with neuritic plaques seem cognitively normal.

[0354] CSF markers for Alzheimer’s disease include total tau, phosphor-tau and Abeta42. See, for example, Andreasen, Sjogren and Blennow, World J Biol Psyciatry, 2003, 4(4): 147-155, which is incorporated herein by reference. Reduced CSF levels of the 42 amino acid form of Abeta (Abeta42) and increased CSF levels of total tau in Alzheimer’s disease have been found in numerous studies. In addition, there are known genetic markers for mutations in the APP gene useful in the identification of subjects at risk for developing AD. See, for example, Goate et al., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease, Nature, 349, 704-706, 1991, which is incorporated herein by reference. In embodiments, any known diagnostic or prognostic method can be employed to identify a subject having or at risk of having Alzheimer’s disease.

[0355] In some embodiments, the administration of a compound or pharmaceutical composition according to any embodiments disclosed herein to a subject with no detectable clinical symptoms of Alzheimer’s disease returns at least one biomarker to baseline levels. In some embodiments, the administration of a compound or pharmaceutical composition according to any embodiments disclosed herein to a subject with no detectable clinical symptoms of Alzheimer’s disease significantly improves biomarker levels toward baseline levels.

[0356] Embodiments of the present disclosure are directed to a method of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any formula or compound disclosed herein. In some embodiments, the administration of a compound or pharmaceutical composition according to any embodiment described herein results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the biomarker is any biomarker disclosed herein. In some embodiments, the administration of a compound of Formula I results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the biomarker is any biomarker disclosed herein. In some embodiments, the administration of a compound of Formula I, Formula II, or Formula III results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the biomarker is any biomarker disclosed herein.

[0357] Disclosed herein are biomarker combinations that are useful in qualifying Alzheimer’s disease status in a patient as well as identifying therapeutic interventions that may be useful in treating and / or preventing the progression of Alzheimer’s disease in a patient. In some embodiments, the biomarker is a protein-based biomarker. In some embodiments, the administration of a compound or pharmaceutical composition according to any embodiment described herein results in a decrease in the expression of any biomarker disclosed herein.

[0358] In some embodiments, a change in protein expression that differs from that of a healthy patient is indicative of a status of Alzheimer’s disease. In some embodiments, a status of Alzheimer’s disease may be demonstrated by an increase in the expression of at least one biomarker; wherein the biomarker is selected from any biomarker disclosed herein. In some embodiments, a status of Alzheimer’s disease may be demonstrated by a decrease in the expression of at least one biomarker; wherein the biomarker is selected from any biomarker disclosed herein.

[0359] In some embodiments, the administration of a compound or pharmaceutical composition according to any embodiment described herein results in an increase in the expression of any biomarker disclosed herein.

[0360] In some embodiments, the administration of a compound or pharmaceutical composition according to any embodiment described herein results in modulation in the expression of any biomarker disclosed herein.

[0361] In some embodiments, the administration of a compound or pharmaceutical composition according to any embodiment described herein results in the regulation of any biological process or biological pathway disclosed herein.

[0362] In some embodiments, a decrease in the expression of any biomarker described herein is indicative of therapeutic efficacy. In some embodiments, an increase in the expression of any biomarker described herein is indicative of therapeutic efficacy. In some embodiments, a change in the expression of any biomarker described herein is indicative of therapeutic efficacy.

[0363] In some embodiments, an increase in the expression of at least one of any biomarker described herein is indicative of disease progression. In some embodiments, a decrease in the expression of at least one of any biomarker described herein is indicative of disease progression. In some embodiments, a change in the expression of at least one of any biomarker described herein is indicative of disease progression.

[0364] In some embodiments, an increase in the expression of at least one of any biomarker described herein is indicative of a lack of disease progression. In some embodiments, a decrease in the expression of at least one of any biomarker described herein is indicative of a lack of disease progression. In some embodiments, a change in the expression of at least one of any biomarker described herein is indicative of a lack of disease progression.

[0365] In some embodiments, an increase in the expression of at least one of any biomarker described herein is indicative of disease regression. In some embodiments, a decrease in the expression of at least one of any biomarker described herein is indicative of disease regression. In some embodiments, a change in the expression of at least one of any biomarker described herein is indicative of disease regression.

[0366] In some embodiments, an increase in the expression of at least one of any biomarker described herein is indicative of a lack of disease regression. In some embodiments, a decrease in the expression of at least one of any biomarker described herein is indicative of a lack of disease regression. In some embodiments, a change in the expression of at least one of any biomarker described herein is indicative of a lack of disease regression.

[0367] Diagnostic Measures

[0368] Any biomarkers according to any embodiment disclosed herein can be used in diagnostic tests to assess Alzheimer’s disease status in a subject, e.g., to diagnose Alzheimer’s disease. The phrase “Alzheimer’s disease status” includes any distinguishable manifestation of the disease, including non-disease. For example, Alzheimer’s disease statusincludes, without limitation, the presence or absence of disease (e.g., Alzheimer’s disease v. non- Alzheimer’s disease), the risk of developing disease, the stage of the disease, the progression of disease (e.g., progress of disease or remission of disease over time) and the effectiveness or response to treatment of disease.

[0369] Disease course refers to changes in disease status over time, including disease progression (worsening) and disease regression (improvement). Over time, the amounts or relative amounts (e.g., the pattern) of the biomarkers changes. Accordingly, this method involves measuring one or more biomarkers in a subject for at least two different time points, e.g., a first time and a second time, and comparing the change in amounts, if any. The course of disease is determined based on these comparisons.

[0370] The correlation of test results with Alzheimer’s disease status may involve applying a classification algorithm of some kind to the results to generate the status. The classification algorithm may be as simple as determining whether or not the amount of biomarker measured is above or below a particular cut-off number or baseline measurement. When multiple biomarkers are used, the classification algorithm may be a linear regression formula. Alternatively, the classification algorithm may be the product of any of a number of learning algorithms described herein.

[0371] In the case of complex classification algorithms, it may be necessary to perform the algorithm on the data, thereby determining the classification, using a computer, e.g., a programmable digital computer. In either case, one can then record the status on tangible medium, for example, in computer-readable format such as a memory drive or disk or simply printed on paper. The result also could be reported on a computer screen.

[0372] Methods of the invention may further comprise reporting the status to the subject, recording the status on a tangible medium, and / or managing subject treatment based on the status.

[0373] Additional embodiments of the invention relate to the communication of assay results or diagnoses or both to technicians, physicians or patients, for example. In certain embodiments, computers will be used to communicate assay results or diagnoses or both to interested parties, e.g., physicians and their patients. In some embodiments, the assays will be performed or the assay results analyzed in a country or jurisdiction which differs from the country or jurisdiction to which the results or diagnoses are communicated.

[0374] In certain embodiments of the methods of qualifying Alzheimer’s disease status, the methods further comprise managing subject treatment based on the status. Such management includes the actions of the physician or clinician subsequent to determiningAlzheimer’s disease status. For example, if a physician makes a diagnosis of Alzheimer’s disease, then a certain regime of treatment, such as prescription or administration of therapy might follow. Alternatively, a diagnosis of non- Alzheimer’s disease might be followed with further testing to determine a specific disease that the patient might be suffering from. Also, if the diagnostic test gives an inconclusive result on Alzheimer’s disease status, further tests may be called for.

[0375] In some embodiments, data derived from the spectra (e.g., mass spectra or time- of- flight spectra) that are generated using samples such as “known samples” can then be used to “train” a classification model. A “known sample” is a sample that has been preclassified. The data that are derived from the spectra and are used to form the classification model can be referred to as a “training data set.” Once trained, the classification model can recognize patterns in data derived from spectra generated using unknown samples. The classification model can then be used to classify the unknown samples into classes. This can be useful, for example, in predicting whether or not a particular biological sample is associated with a certain biological condition (e.g., diseased versus non-diseased).

[0376] Classification models can be formed using any suitable statistical classification (or “learning”) method that attempts to segregate bodies of data into classes based on objective parameters present in the data.

[0377] This disclosure provides methods for determining the presence or absence of Alzheimer’s disease in a subject (status: Alzheimer’s disease v. non- Alzheimer’s disease). The presence or absence of Alzheimer’s disease is determined by measuring the relevant biomarker or biomarkers and then either submitting them to a classification algorithm or comparing them with a reference amount and / or pattern of biomarkers that is associated with the particular risk level. In some embodiments, the presence or absence of Alzheimer’s disease in a subject can be determined prior to the manifestation of any clinical symptoms indicative of the presence of Alzheimer’s disease in a subject.

[0378] Some embodiments are directed to qualifying Alzheimer’s disease status in a subject comprising: (a) measuring the level of at least one biomarker and any combination thereof in a biological sample from the subject being screened for Alzheimer’s disease; and (b) correlating the measurement of an increased level or any combination thereof in a biological sample from a healthy subject. In some embodiments, the at least one biomarker is measured by mass spectrometry. In some embodiments, the mass spectrometry is SELDI-MS. In some embodiments, the level of at the at least one biomarker is measured by immunoassay. In some embodiments, the sample is blood or a blood derivative. In some embodiments, the bloodderivative is serum. In some embodiments, the sample is cerebrospinal fluid. In some embodiments, the correlating is performed by executing a software classification algorithm. Some embodiments further comprise (c) reporting the status to the subject. Some embodiments further comprising: recording the status on a tangible medium. Some embodiments further comprise (c) managing subject treatment based on the status. Some embodiments further comprise: (d) measuring the level of the at least one biomarker after subject management and correlating the measurement with disease progression. In some embodiments, the subject does not exhibit clinical symptoms of Alzheimer’s disease.

[0379] In one embodiment, this invention provides methods for determining the risk of developing Alzheimer’s disease in a subject. In some embodiments, the subject does not exhibit clinical symptoms of Alzheimer’s disease. The risk of developing a disease is determined by measuring the relevant biomarker or biomarkers and then either submitting them to a classification algorithm or comparing them with a reference amount and / or pattern of biomarkers that is associated with the Alzheimer’s disease. In some embodiments, an increase in the expression of any biomarker described herein is indicative that a subject is at risk of developing Alzheimer’s disease.

[0380] In some embodiments, a decrease in the expression of any biomarker described herein may be indicative that a subject is at risk of developing Alzheimer’s disease. In some embodiments, an increase in the expression of any biomarker described herein may be indicative that a subject is at risk of developing Alzheimer’s disease. In some embodiments, a change in the expression of any biomarker described herein may be indicative that a subject is at risk of developing Alzheimer’s disease.

[0381] In some embodiments, a decrease in the expression of any biomarker described herein may be indicative that a subject is at low risk of developing Alzheimer’s disease. In some embodiments, an increase in the expression of any biomarker described herein may be indicative that a subject is at low risk of developing Alzheimer’s disease. In some embodiments, a change in the expression of any biomarker described herein may be indicative that a subject is at low risk of developing Alzheimer’s disease.

[0382] Some embodiments are directed to methods for determining the stage of disease in a subject. Each stage of the disease has a characteristic amount of a biomarker or relative amounts of a set of biomarkers (a pattern). The stage of a disease is determined by measuring the relevant biomarker or biomarkers and then either submitting them to a classification algorithm or comparing them with a reference amount and / or pattern ofbiomarkers that is associated with the particular stage. For example, one can classify between mild, moderate and severe Alzheimer’s disease.

[0383] In one embodiment, this invention provides methods for determining the course of disease in a subject. Disease course refers to changes in disease status over time, including disease progression (worsening) and disease regression (improvement). Over time, the amounts or relative amounts (e.g., the pattern) of the biomarkers changes. Accordingly, this method involves measuring one or more of any biomarker described herein in a subject for at least two different time points, e.g., a first time and a second time, and comparing the change in amounts, if any. The course of disease is determined based on these comparisons.

[0384] Subjects

[0385] In some embodiments, the subject is a mammal. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a human with a diagnosis of Alzheimer’s disease.

[0386] In some embodiments, the subject has been diagnosed with Alzheimer’s disease. In some embodiments, the subject does not exhibit any detectable clinical symptoms of Alzheimer’s disease. In some embodiments, the subject has no cognitive impairment. In some embodiments, the subject has been diagnosed with mild cognitive impairment. In some embodiments, the subject has been diagnosed with mild Alzheimer’s disease. In some embodiments, the subject has been diagnosed with mild to moderate Alzheimer’s disease. In some embodiments, the subject has been diagnosed with moderate Alzheimer’s disease. In some embodiments, the subject has been diagnosed with moderate to severe Alzheimer’s disease. In some embodiments, the subject has been diagnosed with severe Alzheimer’s disease.

[0387] In some embodiments of the method described herein, the method, wherein the subject has been diagnosed with a synucleinopathy. In some embodiments, the synucleinopathy is Dementia with Lewy Bodies. Synucleinopathies (also called a- Synucleinopathies) are neurodegenerative diseases characterized by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibers or glial cells. There are three main types of synucleinopathy: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).

[0388] In some embodiments, the subject is aged between 50 and 80 years. In some embodiments the subject is younger than 50 years. In some embodiments, the subject is aged 80 years old or older.

[0389] In some embodiments, the subject has an MMSE score between about 18- 26. In some embodiments, the subject has an MMSE score between about 18-26, corresponding to mild to moderate cognitive impairment. In some embodiments, the subject has an MMSE score greater than or equal to 24. In some embodiments, the subject has an MMSE score greater than or equal to 24, corresponding to mild cognitive impairment to normal cognitive ability. In some embodiments, the subject has an MMSE score between about 10 to about 18. In some embodiments, the subject has an MMSE score between about 10 to about 18, corresponding moderate to severe Alzheimer’s disease. In some embodiments, the subject has mild Alzheimer’s disease. In some embodiments, the subject has mild to moderate Alzheimer’s disease. In some embodiments, the subject has moderate to severe Alzheimer’s disease. In some embodiments, the subject does not exhibit any detectable clinical symptoms of Azheimer’s disease. In some embodiments, the subject has no cognitive impairment.

[0390] In some embodiments, the subject has an MMSE score between about 18- 26. In some embodiments, the subject has an MMSE score between about 18-26, corresponding to mild to moderate cognitive impairment. In some embodiments, the subject has an MMSE score greater than or equal to 24. In some embodiments, the subject has an MMSE score greater than or equal to 24, corresponding to mild cognitive impairment to normal cognitive ability. In some embodiments, the subject has an MMSE score between about 10 to about 18. In some embodiments, the subject has an MMSE score between about 10 to about 18, corresponding moderate to severe Alzheimer’s disease. In some embodiments, the subject has mild Alzheimer’s disease. In some embodiments, the subject has mild to moderate Alzheimer’s disease. In some embodiments, the subject has moderate to severe Alzheimer’s disease. In some embodiments, the subject does not exhibit any detectable clinical symptoms of Alzheimer’s disease. In some embodiments, the subject has no cognitive impairment.

[0391] Biomarkers

[0392] In some embodiments, the at least one biomarker is a protein. In some embodiments, the at least one biomarker is a network of proteins. In some embodiments, the at least one biomarker is a ribonucleic acid (RNA). In some embodiments, the at least one biomarker is a network of RNA. In some embodiments, the at least one biomarker is measured longitudinally across patients.

[0393] Any biomarker according to any embodiment described herein, can be detected by any suitable method. Detection paradigms include optical methods, electrochemical methods (voltametry and amperometry techniques), atomic force microscopy,and radio frequency methods, e.g., multipolar resonance spectroscopy. Illustrative of optical methods, in addition to microscopy, both confocal and non-confocal, are detection of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, and birefringence or refractive index (e.g., surface plasmon resonance, ellipsometry, a resonant mirror method, a grating coupler waveguide method or interferometry).

[0394] Any biomarker according to any embodiment described herein, can be measured by liquid chromatography-mass spectrometry. In some embodiment, one or more biomarkers disclosed herein may be measured by mass spectrometry. The mass spectrometry may be SELDI-MS. In a further aspect, one or more biomarkers may be measured by immunoassay. In some embodiments, the immunoassay is an ELISA assay. In some embodiments, the biomarkers disclosed herein are detected by mass spectrometry, a method that employs a mass spectrometer to detect gas phase ions. Examples of mass spectrometers are time-of-flight, magnetic sector, quadrupole filter, ion trap, ion cyclotron resonance, electrostatic sector analyzer and hybrids of these. In some embodiments, the biomarkers disclosed herein may be measured by liquid chromatography-mass spectrometry.

[0395] In some embodiments, the mass spectrometer is a laser desorption / ionization mass spectrometer. In laser desorption / ionization mass spectrometry, the analytes are placed on the surface of a mass spectrometry probe, a device adapted to engage a probe interface of the mass spectrometer and to present an analyte to ionizing energy for ionization and introduction into a mass spectrometer. A laser desorption mass spectrometer employs laser energy, typically from an ultraviolet laser, but also from an infrared laser, to desorb analytes from a surface, to volatilize and ionize them and make them available to the ion optics of the mass spectrometer. The analysis of proteins by LDI can take the form of MALDI or of SELDI.

[0396] According to any embodiment described herein, the biomarkers of the invention are measured by a method other than mass spectrometry or other than methods that rely on a measurement of the mass of the biomarker. In one such embodiment that does not rely on mass, the biomarkers of this invention are measured by immunoassay. Immunoassay requires biospecific capture reagents, such as antibodies, to capture the biomarkers. Antibodies can be produced by methods well known in the art, e.g., by immunizing animals with the biomarkers. Biomarkers can be isolated from samples based on their binding characteristics. Alternatively, if the amino acid sequence of a polypeptide biomarker is known, the polypeptide can be synthesized and used to generate antibodies by methods well known in the art.

[0397] This invention contemplates traditional immunoassays including, for example, sandwich immunoassays including ELISA or fluorescence-based immunoassays, as well as other enzyme immunoassays. Nephelometry is an assay done in liquid phase, in which antibodies are in solution. Binding of the antigen to the antibody results in changes in absorbance, which is measured. In the SELDI-based immunoassay, a biospecific capture reagent for the biomarker is attached to the surface of an MS probe, such as a pre-activated ProteinChip array. The biomarker is then specifically captured on the biochip through this reagent, and the captured biomarker is detected by mass spectrometry.

[0398] According to any embodiment described herein, one or more biomarkers may be measured by Liquid chromatography-mass spectrometry. In some embodiment, one or more biomarkers disclosed herein may be measured by mass spectrometry. The mass spectrometry suitably may be SELDI-MS. In a further aspect, one or more biomarkers may be measured by immunoassay. In some embodiments, the immunoassay is an ELISA assay.

[0399] According to any embodiment described herein, a sample can be analyzed by means of a biochip. A biochip generally comprises a solid substrate having a substantially planar surface, to which a capture reagent (also called an adsorbent or affinity reagent) is attached. Frequently, the surface of a biochip comprises a plurality of addressable locations, each of which has the capture reagent bound there. Protein biochips are biochips adapted for the capture of polypeptides. Many protein biochips are described in the art.

[0400] In some embodiments, the at least one biomarker is measured by Liquid chromatography-mass spectrometry. In some embodiments, the at least one biomarker is measured by mass spectrometry. In some embodiments, the mass spectrometry is SELDI-MS. In some embodiments, the level of at the at least one biomarker is measured by immunoassay. In some embodiments, the level of at the at least one biomarker is measured by a weighted gene co-expression network analysis (WGCNA).

[0401] In some embodiments, the sample is blood or a blood derivative. In some embodiments, the blood derivative is serum. In some embodiments, the sample is cerebrospinal fluid. In some embodiments, the correlating is performed by executing a software classification algorithm. In some embodiments, the subject is a cell capable of expressing any gene described herein. In some embodiments, the subject is a cell capable of producing any protein described herein.

[0402] A variety of biological samples may be employed in any of the methods of the invention as described herein, including e.g. where the biological sample comprises blood or a blood derivative such as plasma, or where the biological sample comprises cerebrospinalfluid. In some embodiments, the biological sample is plasma, cerebrospinal fluid or a combination thereof.

[0403] One of skill in the art will recognize that the techniques used to measure the activity of a particular biomarker will vary depending on the function and properties of the biomarker. For example, an enzymatic activity of a biomarker may be assayed provided that an appropriate substrate is available and provided that the concentration of the substrate or the appearance of the reaction product is readily measurable. The ability of potentially therapeutic test compounds to inhibit or enhance the activity of a given biomarker may be determined by measuring the rates of catalysis in the presence or absence of the test compounds. The ability of a test compound to interfere with a non-enzymatic (e.g., structural) function or activity of one or more of the biomarkers herein may also be measured. For example, the self-assembly of a multi-protein complex which includes one or more of the biomarkers herein may be monitored by spectroscopy in the presence or absence of a test compound. Alternatively, if the biomarker is a non-enzymatic enhancer of transcription, test compounds which interfere with the ability of the biomarker to enhance transcription may be identified by measuring the levels of biomarker-dependent transcription in vivo or in vitro in the presence and absence of the test compound.

[0404] In some embodiments, a compound or pharmaceutical composition according to any embodiment described herein is administered for at least about 6 months. In some embodiments, a compound of Formula I is administered for at least about 6 months. In some embodiments, a compound or pharmaceutical composition of according to any of the embodiments described herein is administered for at least about 6 months. In some embodiments, a compound or pharmaceutical composition of according to any of the embodiments described herein is administered daily for about 6 months. In some embodiments, the compound of Formula I is administered for at least about 6 months. In some embodiments, the therapeutically effective amount of the compound of Formula I is administered daily for about 6 months.

[0405] Therapeutic Screenins

[0406] Some embodiments are directed to methods of screening for compounds that may be useful in the treatment and / or prevention of Alzheimer’s disease comprising: (a) measuring the level of any biomarker described herein, and any combination thereof in a first biological sample obtained from a test subject; (b) administering the test compound to the test subject; (c) measuring the level of the at least one biomarker after administration of the testcompound in a second biological sample from the test subject; and (d) correlating a decrease or increase in the expression of any biomarker described herein and any combination thereof, with potential therapeutic efficacy of the test compound.

[0407] Some embodiments are directed to methods of screening for compounds that may be useful in the treatment and / or prevention of Alzheimer’s disease comprising: (a) measuring the level of any biological pathway or any biological process as described herein, in a first biological sample obtained from a test subject; (b) administering the test compound to the test subject; (c) measuring the level of the at least one biological pathway or process after administration of the test compound in a second biological sample from the test subject; and (d) correlating a decrease or increase in the expression of any biomarker described herein.

[0408] In some embodiments, a test compound with potential therapeutic efficacy will result in an increase in the expression of any biomarker described herein. In some embodiments, a test compound with potential therapeutic efficacy will result in an increase in the expression of any biomarker described herein is measured in CSF. In some embodiments, a test compound with potential therapeutic efficacy will result in an increase in the expression of any biomarker described herein is measured in plasma.

[0409] In some embodiments, a test compound with potential therapeutic efficacy will result in a decrease in the expression of any biomarker described herein. In some embodiments, any biomarker described herein with decreased expression is measured in the CSF. In some embodiments, any biomarker described herein with decreased expression is measured in the plasma.

[0410] In another embodiment, this invention provides methods for determining the therapeutic efficacy of a pharmaceutical drug. These methods are useful in performing clinical trials of the drug, as well as monitoring the progress of a patient on the drug. Therapy or clinical trials involve administering the drug in a particular regimen. The regimen may involve a single dose of the drug or multiple doses of the drug over time. The doctor or clinical researcher monitors the effect of the drug on the patient or subject over the course of administration. If the drug has a pharmacological impact on the condition, the amounts or relative amounts (e.g., the pattern or profile) of the biomarkers of this invention changes toward a non-disease profile. Therefore, one can follow the course of the amounts of these biomarkers in the subject during the course of treatment. Accordingly, this method involves measuring one or more biomarkers in a subject receiving drug therapy, and correlating the amounts of the biomarkers with the disease status of the subject. One embodiment of this method involves determining the levels of the biomarkers for at least two different time points during a course of drug therapy, e.g., afirst time and a second time, and comparing the change in amounts of the biomarkers, if any. For example, the biomarkers can be measured before and after drug administration or at two different time points during drug administration. The effect of therapy is determined based on these comparisons. If a treatment is effective, then the biomarkers will trend toward normal, while if treatment is ineffective, the biomarkers will trend toward disease indications. In some embodiments, the biomarker may be selected from any biomarker described herein.

[0411] Compounds suitable for therapeutic testing may be screened initially by identifying compounds which modulate the expression of any biomarker described herein. Compounds suitable for therapeutic testing may be screened initially by identifying compounds which increase the expression of any biomarker described herein. Compounds suitable for therapeutic testing may be screened initially by identifying compounds which decrease the expression of any biomarker described herein.

[0412] Test compounds capable of modulating the expression and / or activity of any of the biomarkers described herein may be administered to patients who are suffering from or are at risk of developing Alzheimer’s disease. Test compounds capable of increasing the expression and / or activity of any of the biomarkers described herein may be administered to patients who are suffering from or are at risk of developing Alzheimer’s disease. Test compounds capable of decreasing the expression and / or activity of any of the biomarkers described herein may be administered to patients who are suffering from or are at risk of developing Alzheimer’s disease.

[0413] Some embodiments are directed to methods for identifying compounds useful for the treatment of disorders such as Alzheimer’s disease which are associated with changes in the expression of at least one biomarker described herein. In some embodiments, a useful therapeutic agent is an agent that when administered results in a change in biomarker expression that is inverse to a change in biomarker expression typically observed in a subject with Alzheimer’s disease compared with a healthy subject.

[0414] In some embodiments, a useful therapeutic agent is an agent that when administered results in an increase in the expression of at least one biomarker described herein. In some embodiments, a useful therapeutic agent is an agent that when administered results in a decrease in the expression of at least one biomarker described herein. In some embodiments, a useful therapeutic agent is an agent that when administered results in a change in the expression of at least one biomarker described herein.

[0415] In some embodiments, screening a test compound includes obtaining samples from test subjects before and after the subjects have been exposed to a test compound.The levels in the samples of one or more of the biomarkers any combination thereof may be measured and analyzed to determine whether the levels of the biomarkers change after exposure to a test compound. The samples may be analyzed by mass spectrometry, as described herein, or the samples may be analyzed by any appropriate means known to one of skill in the art. may be measured directly by Western blot using radio- or fluorescently-labeled antibodies which specifically bind to the biomarkers. Alternatively, changes in the levels of mRNA encoding the one or more biomarkers may be measured and correlated with the administration of a given test compound to a subject. In a further embodiment, the changes in the level of expression of one or more of the biomarkers may be measured using in vitro methods and materials. For example, human tissue cultured cells which express, or are capable of expressing, one or more of the biomarkers selected from the group Subjects who have been treated with test compounds will be routinely examined for any physiological effects which may result from the treatment. In particular, the test compounds will be evaluated for their ability to decrease disease likelihood in a subject. Alternatively, if the test compounds are administered to subjects who have previously been diagnosed with Alzheimer’s disease, test compounds will be screened for their ability to slow or stop the progression of the disease.

[0416] The methods of the present disclosure have other applications as well. For example, the biomarkers can be used to screen for compounds that modulate the expression of the biomarkers in vitro or in vivo, which compounds in turn may be useful in treating or preventing Alzheimer’s disease in patients. In another example, the biomarkers can be used to monitor the response to treatments for Alzheimer’s disease. In yet another example, the biomarkers can be used in heredity studies to determine if the subject is at risk for developing Alzheimer’s disease.

[0417] TABLESTable Al includes proteins that decreased after treatment in SHINEA, SPARC and SEQUEL studies, sorted by Log2, from lowest to highest, including only downregulated proteins.Table A2 includes proteins that increased after treatment in the SHINEA, SPARC and SEQUEL studies, sorted by Log2 from highest to lowest, including only upregulated proteins.Table Bl includes proteins correlated with ADAS-Cogl 1 values after treatment in the SHINE study, sorted by the total correlation score from lowest to highest and including only negatively correlated proteins.Table B2 includes proteins correlated with ADAS-Cogl 1 values after treatment in the SHINE study, sorted by the total correlation score from highest to lowest and including only positively correlated proteins.Table Cl includes proteins correlated with a-synuclein values after treatment in the SEQUEL study, sorted by the total correlation score from lowest to highest and including only negatively correlated proteins.Table C2 includes proteins correlated with a-synuclein values after treatment in the SEQUEL study, sorted by the total correlation score from highest to lowest and including only positively correlated proteins.Table DI includes proteins correlated with alpha EEG measures AECc after treatment in the SEQUEL study, sorted by the total correlation score from lowest to highest and including only negatively correlated proteins.Table El includes proteins correlated with theta EEG measures after treatment in the SEQUEL study, sorted by the total correlation score from lowest to highest and including only negatively correlated proteins.Table E2 includes proteins correlated with theta EEG measures after treatment in the SEQUEL study, sorted by the total correlation score from highest to lowest and including only positively correlated proteins.Table F 1 includes proteins correlated with alpha EEG measures after treatment in the SEQUEL study, sorted by the total correlation score from lowest to highest and including only negatively correlated proteins.Table F2 includes proteins correlated with alpha EEG measures after treatment in the SEQUEL study, sorted by the total correlation score from highest to lowest and including only positively correlated proteins.Table G1 includes proteins correlated with vMRI measures after treatment in the SPARC study, sorted by the total correlation score from lowest to highest and including only negatively correlated proteins.Table G2 includes proteins correlated with vMRI measures after treatment in the SPARC study, sorted by the total correlation score from highest to lowest and including only positively correlated proteins.

[0418] Further Embodiments:

[0419] Embodiment 1. A method of reducing or maintaining an Alzheimer's Disease Assessment Scale- Cognitive (ADAS-Cog) score in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any compound described herein.

[0420] Embodiment 2. The method of embodiment 1, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0421] Embodiment 3. The method of embodiment 1, wherein the compound of Formula I is:pharmaceutically acceptable salt thereof.

[0423] Embodiment 4. The method of embodiment 3, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate salts.

[0424] Embodiment 5. The method of embodiment 3, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0425] Embodiment 6. The method of any one of embodiments 1-5, wherein the compound of Formula I is administered for at least about 6 months.

[0426] Embodiment 7. The method of any one of embodiments 1-5, wherein the compound of Formula I is administered for less than about 6 months.

[0427] Embodiment 8. The method of any one of embodiments 1-5, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

[0428] Embodiment 9. The method of any one of embodiments 1-5, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

[0429] Embodiment 10. The method of any one of embodiment 1-5, wherein the ADAS-Cog test is an ADAS-Cog 11 test or an ADAS-Cog 13 test.

[0430] Embodiment 11. The method of any one of embodiments 1-5, wherein the ADAS-Cog score greater than or equal to 18 is indicative of cognitive impairment.

[0431] Embodiment 12. The method of any one of embodiments 1-5, wherein administering the compound reduces the ADAS-Cog score.

[0432] Embodiment 13. The method of any one of embodiments 1-5, wherein administration of the compound results in a maintenance of the ADAS-Cog score over 6 months.

[0433] Embodiment 14. The method of any one of embodiments 1-5, wherein administration of the compound results in a maintenance of the ADAS-Cog score over 1 year.

[0434] Embodiment 15. The method of any one of embodiments 1-5, wherein administration of the compound results in a maintenance of the ADAS-Cog score over 2 years.

[0435] Embodiment 16. The method of any one of embodiments 1-5, wherein administration of the compound results in a maintenance of the ADAS-Cog score over 5 years.

[0436] Embodiment 17. The method of any one of embodiments 1-5, wherein administering the compound correlates in an increase in expression of biomarkers selected from MYO 19, CMBL, ABHD14B, CAMK2D, NCAM1, PLXND1, JCHAIN, FAM20C, MXRA7, APCS, DNAJB2, F13B, LGALS3, SORCS1, IGHV3-48, TKT, IGHM, GPI, F13A1, CFP, CD5L, IGLV1-40, SPP1, KRT17, FSTL1, LPHN1, GFRA1, MBL2, ADIPOQ, GANAB, BGLAP, ADAM22, B2M, PILRA, LUM, RAB10, PMP2, IGKV2D-29, EIF3J, PCP4, IGHD, ENOPH1, TCN2, ACP2, LXN, RAB14, ATIC, APOB, KIRREL3, CHPF, YWHAE, CSTB, ARF3, RHOA, JAML, ARHGDIA, PTPRS, AK1, IGF1, CFHR5, APOL1, SH3BGRL3, RIN2, PCDHGC3, AP2A1, MET, KIAA0100, PLS3, CDH18, CRK, FBLN2, HSPA1B, SEMA4C, YWHAG, PPIA, TAGLN2, PGLS, IGLV1-47, RNH1, SCN4B, PAFAH1B1, YWHAZ, GLOD4, TBCA, MDK, CAST, A2M, IGLV1-36, GRIA4, FZD1, DCTN2, PGDN, USP14, CNDP1, TXNDC17, COL6A1, VCL, OMG, CNPY3, LANCL1, COLECI 1, LASPI, TPM1, NUDT5, IGKC, MTPN, GLO1, PRDX1, LRP8, PPP2R1A, VMO1, ARSG, VAT1, CBLN1, REEP2, IGHV4-59, GPLD1, CAPZA1, ENO1, IDH1, C4BPB, NME2, IGHA2, TXN, GALNT10, CREB3L3, TPD52L2, CXCL16, FAM177A1, PRG4, NPC2, and combinations thereof.

[0437] Embodiment 18. The method of embodiment 17, wherein the biomarkers are measured in cerebrospinal fluid.

[0438] Embodiment 19. The method of embodiment 17, wherein the biomarkers are measured in plasma.

[0439] Embodiment 20. The method of any one of embodiments 1-5, wherein administering the compound results in an increase in expression of biomarkers comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0440] Embodiment 21. The method of embodiment 20, wherein the biomarkers are measured in cerebrospinal fluid.

[0441] Embodiment 22. The method of embodiment 20, wherein the biomarkers are measured in plasma.

[0442] Embodiment 23. The method of any one of embodiments 1-5, wherein administering the compound results in a decrease in expression of biomarkers comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0443] Embodiment 24. The method of embodiment 22, wherein the biomarkers are measured in cerebrospinal fluid.

[0444] Embodiment 25. The method of embodiment 22, wherein the biomarkers are measured in plasma.

[0445] Embodiment 26. The method of any one of embodiments 1-5, wherein the reduction or maintenance of the ADAS-Cog score is correlated with modulation of biological processes or biological pathways selected from astrocyte activation involved in immune response; gephyrin clustering involved in postsynaptic density assembly, postsynaptic density protein 95 clustering; negative regulation of metallopeptidase activity, response to vitamin K, regulation of postsynaptic density assembly, regulation of opsonization, positive regulation of aspartic-type peptidase activity, glomerulus morphogenesis, neuron cell-cell adhesion, regulation of aspartic-type peptidase activity, regulation of tau-protein kinase activity, positive regulation of protein kinase A signaling; negative regulation of dendritic spine development; regulation of endothelial cell chemotaxis; neuroligin clustering involved in postsynaptic membrane assembly; gephyrin clustering involved in postsynaptic density assembly; postsynaptic density protein 95 clustering; positive regulation of amyloid fibril formation;NMDA glutamate receptor clustering; negative regulation of dendritic spine maintenance; vocal learning; postsynaptic membrane assembly; positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process; neurotransmitter-gated ion channel clustering; negative regulation of dendritic spine development; neuron cell-cell adhesion; postsynaptic membrane organization; positive regulation of amyloid precursor protein catabolic process; response to auditory stimulus; positive regulation of excitatory postsynaptic potential; regulation of presynapse assembly; receptor clustering; regulation of dendritic spine development; calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules, and combinations thereof.

[0446] Embodiment 27. The method of any one of embodiments 1-5, wherein administering the compound results in a reduction in the level of a-synuclein.

[0447] Embodiment 28. The method of embodiment 27, wherein the a-synuclein is measured in cerebrospinal fluid.

[0448] Embodiment 29. The method of embodiment 27, wherein the a-synuclein is measured in plasma.

[0449] Embodiment 30. The method of any one of embodiments 1-5, wherein administering the compound results in a reduction in the level of Ap.

[0450] Embodiment 31. The method of embodiment 30, wherein the Ap is Ap40, Ap42, or a combination of both.

[0451] Embodiment 32. The method of embodiment 30, wherein the Ap is measured in cerebrospinal fluid.

[0452] Embodiment 33. The method of embodiment 30, wherein the Ap is measured in plasma.

[0453] Embodiment 34. The method of any one of embodiments 1-5, wherein the reduction in the ADAS-Cog score is correlated with a change in synaptic function.

[0454] Embodiment 35. The method of embodiment 34, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

[0455] Embodiment 36. The method of embodiment 35, wherein the qEEG is measured by primary theta power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

[0456] Embodiment 37. The method of any one of embodiments 1-5, wherein the subject has been diagnosed with a synucleinopathy.

[0457] Embodiment 38. The method of embodiment 37, wherein the synucleinopathy is Dementia with Lewy Bodies.

[0458] Embodiment 39. The method of any one of embodiments 1-5, wherein the subject has been diagnosed with Alzheimer's disease.

[0459] Embodiment 40. The method of any one of embodiments 1-5, wherein the subject has been diagnosed with mild cognitive impairment.

[0460] Embodiment 41. The method of any one of embodiments 1-5, wherein the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0461] Embodiment 42. The method of any one of embodiments 1-5, wherein the subject is aged less than 50 years.

[0462] Embodiment 43. The method of any one of embodiments 1-5, wherein the subject is aged between 50 and 80 years.

[0463] Embodiment 44. The method of any one of embodiments 1-5, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

[0464] Embodiment 45. The method of any one of embodiments 1-5, wherein the subject has an MMSE score greater than, or equal to 24.

[0465] Embodiment 46. A method of reducing levels of a-synuclein (aSyn) in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any compound described herein.

[0466] Embodiment 47. The method of embodiment 46, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0467] Embodiment 48. The method of embodiment 46, wherein the compound ofFormula I is:

[0468] pharmaceutically acceptable salt thereof.

[0469] Embodiment 49. The method of embodiment 48, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate salts.

[0470] Embodiment 50. The method of embodiment 48, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0471] Embodiment 51. The method of any one of embodiments 46-50, wherein the compound of Formula I is administered for at least about 6 months.

[0472] Embodiment 52. The method of any one of embodiments 46-50, wherein the compound of Formula I is administered for less than about 6 months.

[0473] Embodiment 53. The method of any one of embodiments 46-50, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

[0474] Embodiment 54. The method of any one of embodiments 46-50, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

[0475] Embodiment 55. The method of any one of embodiments 46-50, wherein the level of a-synuclein (aSyn) is reduced by about 5% to about 90%.

[0476] Embodiment 56. The method of any one of embodiments 46-50, wherein administering the compound results in an increase in expression of biomarkers comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1 , NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0477] Embodiment 57. The method of embodiment 56, wherein the biomarkers are measured in cerebrospinal fluid.

[0478] Embodiment 58. The method of embodiment 56, wherein the biomarkers are measured in plasma.

[0479] Embodiment 59. The method of any one of embodiments 46-50, wherein administering the compound results in a decrease in expression of biomarkers comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0480] Embodiment 60. The method of embodiment 59, wherein the biomarkers are measured in cerebrospinal fluid.

[0481] Embodiment 61. The method of embodiment 59, wherein the biomarkers are measured in plasma.

[0482] Embodiment 62. The method of any one of embodiments 46-50, wherein the reduction in the level of a-synuclein (aSyn) is correlated with modulation of biological processes or biological pathways comprising positive regulation of axon extension involved in axon guidance; positive regulation of dopamine metabolic process; complement activation, alternative pathway; cytolysis; complement activation, classical pathway; complement activation; chaperone-mediated autophagy; complement activation, alternative pathway; regulation of insulin-like growth factor receptor signaling pathway; positive regulation of synapse assembly; immune response-alternative complement pathway; immune responsealternative complement pathway; immune response-alternative complement pathway; protein folding and maturation, posttranslational processing of neuroendocrine peptides; neurophysiological process synaptic vesicle fusion and recycling in nerve terminals; protein folding and maturation-posttranslational processing of neuroendocrine peptides; neurophysiological process-synaptic vesicle fusion and recycling in nerve terminals; immune response-classical complement pathway; immune response-alternative complement pathway; transport RAB3 regulation pathway, or combinations thereof..

[0483] Embodiment 63. The method of any one of embodiments 46-50, wherein the reduction in the level of a-synuclein (aSyn) is correlated with modulation of biomarkers selected from PCDHGB5, IGKV1D-43, FAM177A1, HSPA8, PLXDC1, LINGO1, SERPINA5, TNFSF8, SIRPB2, CDH13, DCBLD1, NA, IGKV6-21, NRSN2, GMFB, SERPINA3, GLOD4, RAP1B, IGLV3-10, FREM2, RET, IGF2, CD48, ADAMTS16, VM01, GSS, IGKV3D-7, F9, ITM2C, LRG1, DYNLL1, SNX3, SHISA6, FSCN1, ADAMTS13, TPBG, PGM1, DPP10, CDH9, GDA, NCL, SYN2, GFER, IGFBP5, IGFBP2, DMXL2, HLA- DPB1, ABCA13, PEPD, IGHV3-73, IGKV1D-13, LRIG1, FZD8, NAXE, RARRES2, APCS, SLITRK1, IGKV1-9, ADA, CSF1, SLPI, CFAP54, SEMA3B, PPP1R13B, OXT, CCL18, IGKV2-40, ISLR2, ADAMTS4, APOH, and combinations thereof.

[0484] Embodiment 64. The method of embodiment 63, wherein the Ap is measured in cerebrospinal fluid.

[0485] Embodiment 65. The method of embodiment 63, wherein the Ap is measured in plasma.

[0486] Embodiment 66. The method of any one of embodiments 46-50, wherein administering the compound results in a reduction in the level of Ap.

[0487] Embodiment 67. The method of embodiment 66, wherein the Ap is Ap40, Ap42, or a combination of both.

[0488] Embodiment 68. The method of embodiment 66, wherein the Ap is measured in cerebrospinal fluid.

[0489] Embodiment 69. The method of embodiment 66, wherein the Ap is measured in plasma.

[0490] Embodiment 70. The method of any one of embodiments 46-50, wherein the reduction in the level of a-synuclein (aSyn) is correlated with a change in synaptic function.

[0491] Embodiment 71. The method of embodiment 70, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

[0492] Embodiment 72. The method of embodiment 71, wherein the qEEG is measured by primary theta power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

[0493] Embodiment 73. The method of any one of embodiments 46-50, wherein the subject has been diagnosed with a synucleinopathy.

[0494] Embodiment 74. The method of embodiment 73, wherein the synucleinopathy is Dementia with Lewy Bodies.

[0495] Embodiment 75. The method of any one of embodiments 46-50, wherein the subject has been diagnosed with Alzheimer's disease.

[0496] Embodiment 76. The method of any one of embodiments 46-50, wherein the subject has been diagnosed with mild cognitive impairment.

[0497] Embodiment 77. The method of any one of embodiments 46-50, wherein the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0498] Embodiment 78. The method of any one of embodiments 46-50, wherein the subject is aged less than 50 years.

[0499] Embodiment 79. The method of any one of embodiments 46-50, wherein the subject is aged between 50 and 80 years.

[0500] Embodiment 80. The method of any one of embodiments 46-50, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

[0501] Embodiment 81. The method of any one of embodiments 46-50, wherein the subject has an MMSE score greater than, or equal to 24.

[0502] Embodiment 82. A method of reducing levels of Ap in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any compound described herein.

[0503] Embodiment 83. The method of embodiment 82, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0504] Embodiment 84. The method of embodiment 82, wherein the compound ofFormula I is:

[0505] pharmaceutically acceptable salt thereof.

[0506] Embodiment 85. The method of embodiment 84, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0507] Embodiment 86. The method of any one of embodiments 82-85, wherein the compound of Formula I is administered for at least about 6 months.

[0508] Embodiment 87. The method of any one of embodiments 82-85, wherein the compound of Formula I is administered for less than about 6 months.

[0509] Embodiment 88. The method of any one of embodiments 82-85, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

[0510] Embodiment 89. The method of any one of embodiments 82-85, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

[0511] Embodiment 90. The method of embodiment 82, wherein the Ap is Ap40, Ap42, or a combination of both.

[0512] Embodiment 91. The method of embodiment 90, wherein the Ap is measured in cerebrospinal fluid.

[0513] Embodiment 92. The method of embodiment 90, wherein the Ap is measured in plasma.

[0514] Embodiment 93. The method of any one of embodiments 82-85, wherein the level of Ap is reduced by about 5% to about 90%.

[0515] Embodiment 94. The method of any one of embodiments 82-85, wherein administering the compound results in an increase in expression of biomarkers selected from IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1 , NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0516] Embodiment 95. The method of embodiment 94, wherein the biomarkers are measured in cerebrospinal fluid.

[0517] Embodiment 96. The method of embodiment 94, wherein the biomarkers are measured in plasma.

[0518] Embodiment 97. The method of any one of embodiments 82-85, wherein administering the compound results in a decrease in expression of biomarkers selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0519] Embodiment 98. The method of embodiment 97, wherein the biomarkers are measured in cerebrospinal fluid.

[0520] Embodiment 99. The method of embodiment 97, wherein the biomarkers are measured in plasma.

[0521] Embodiment 100. The method of any one of embodiments 82-85, wherein the reduction in the level of Ap is correlated with modulation of biomarkers selected from FABP1, GPNMB, HLA-B, SERPINA, POFUT2, SV2A, ESMI, APA2, and combinations thereof.

[0522] Embodiment 101. The method of any one of embodiments 82-85, wherein the reduction in the level of Ap is correlated with modulation of biological processes or biological pathways comprising negative regulation of lipoprotein lipase activity; chylomicron remnant clearance, chylomicron remodeling, triglyceride-rich lipoprotein particle remodeling, negative regulation of complement activation; positive regulation of synapse assembly, regulation of complement activation, positive regulation of cell junction assembly, artery morphogenesis, platelet degranulation, and combinations thereof.

[0523] Embodiment 102. The method of any one of embodiments 82-85, wherein the reduction in the level of Ap is correlated with a change in synaptic function.

[0524] Embodiment 103. The method of embodiment 102, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

[0525] Embodiment 104. The method of embodiment 103, wherein the qEEG is measured by primary theta power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

[0526] Embodiment 105. The method of any one of embodiments 82-85, wherein the subject has been diagnosed with a synucleinopathy.

[0527] Embodiment 106. The method of embodiment 105, wherein the synucleinopathy is Dementia with Lewy Bodies.

[0528] Embodiment 107. The method of any one of embodiments 82-85, wherein the subject has been diagnosed with Alzheimer's disease.

[0529] Embodiment 108. The method of any one of embodiments 82-85, wherein the subject has been diagnosed with mild cognitive impairment.

[0530] Embodiment 109. The method of any one of embodiments 82-85, wherein the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0531] Embodiment 110. The method of any one of embodiments 82-85, wherein the subject is aged less than 50 years.

[0532] Embodiment 111. The method of any one of embodiments 82-85, wherein the subject is aged between 50 and 80 years.

[0533] Embodiment 112. The method of any one of embodiments 82-85, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

[0534] Embodiment 113. The method of any one of embodiments 82-85, wherein the subject has an MMSE score greater than, or equal to 24.

[0535] Embodiment 114. A method of restoring synaptic function in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any compound described herein.

[0536] Embodiment 115. The method of embodiment 114, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0537] Embodiment 1 16. The method of embodiment 114, wherein the compound of Formula I is:pharmaceutically acceptable salt thereof.

[0539] Embodiment 117. The method of embodiment 116, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0540] Embodiment 118. The method of any one of embodiments 114-117, wherein the compound of Formula I is administered for at least about 6 months.

[0541] Embodiment 119. The method of any one of embodiments 114-117, wherein the compound of Formula I is administered for less than about 6 months.

[0542] Embodiment 120. The method of any one of embodiments 114-117, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

[0543] Embodiment 121. The method of any one of embodiments 114-117, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

[0544] Embodiment 122. The method of any one of embodiments 114-117, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

[0545] Embodiment 123. The method of embodiment 122, wherein the qEEG is measured by primary theta power, global relative theta power, centra relative theta power, secondary alpha power, Amplitude Envelope Correction (AECc), global alpha AECc, temporal alpha AECc, parieto-occipital AECc, and combinations thereof.

[0546] Embodiment 124. The method of any one of embodiments 114-117, wherein administering the compound results in an increase in expression of biomarkers selected from IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1 , NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0547] Embodiment 125. The method of embodiment 124, wherein the biomarkers are measured in cerebrospinal fluid.

[0548] Embodiment 126. The method of embodiment 124, wherein the biomarkers are measured in plasma.

[0549] Embodiment 127. The method of any one of embodiments 114-117, wherein administering the compound results in a decrease in expression of biomarkers selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0550] Embodiment 128. The method of embodiment 127, wherein the biomarkers are measured in cerebrospinal fluid.

[0551] Embodiment 129. The method of embodiment 127, wherein the biomarkers are measured in plasma.

[0552] Embodiment 130. The method of any one of embodiments 114-117, wherein the AECc is correlated with modulation of biological processes or biological pathwayscomprising extracellular space; proteasome core complex, alpha-subunit complex; extracellular exosome; vesicle; extracellular region; proteasome core complex; collagen type I trimer; proteasome core complex, alpha-subunit complex; fibrillar collagen trimer; proteasome core complex; endoplasmic reticulum lumen; secretory granule lumen; extracellular matrix; collagen-containing extracellular matrix; extracellular exosome, and combinations thereof.

[0553] Embodiment 131. The method of any one of embodiments 114-117, wherein the AECc is correlated with modulation of biomarkers comprising ALDH1A1, ALDH9A1, BAMBI, BTN2A2, CHST7, COL1A2, EIF4B, FAHD1, FZD3, FZD6, GAS1, GRIA3, GXYLT1, HBG1, HIBADH, JAM2, LRRN1, LYPLA1, MATN2, METRNL, NHLRC3, NOTCH 1, NTM, OAF, PCDH9, PGLS, PIK3IP1, PNP, PRDX2, PRG2, PSMA1, PSMA4, PSMA6, PSMB7, SECTM1, SLC4A1, SLIT3, SNX12, ST6GAL2, TKT, UBE2N, WNT4, and combinations thereof.

[0554] Embodiment 132. The method of any one of embodiments 114-117, wherein administering the compound results in a reduction in the level of a-synuclein.

[0555] Embodiment 133. The method of embodiment 132, wherein the a-synuclein is measured in cerebrospinal fluid.

[0556] Embodiment 134. The method of embodiment 132, wherein the a-synuclein is measured in plasma.

[0557] Embodiment 135. The method of any one of embodiments 114-117, wherein administering the compound results in a reduction in the level of Ap.

[0558] Embodiment 136. The method of embodiment 135, wherein the Ap is Ap40, Ap42, or a combination of both.

[0559] Embodiment 137. The method of embodiment 135, wherein the Ap is measured in cerebrospinal fluid.

[0560] Embodiment 138. The method of embodiment 135, wherein the Ap is measured in plasma.

[0561] Embodiment 139. The method of any one of embodiments 114-117, wherein the subject has been diagnosed with a synucleinopathy.

[0562] Embodiment 140. The method of embodiment 139, wherein the synucleinopathy is Dementia with Lewy Bodies.

[0563] Embodiment 141. The method of any one of embodiments 114-117, wherein the subject has been diagnosed with Alzheimer's disease.

[0564] Embodiment 142. The method of any one of embodiments 114-117, wherein the subject has been diagnosed with mild cognitive impairment.

[0565] Embodiment 143. The method of any one of embodiments 114-117, wherein the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0566] Embodiment 144. The method of any one of embodiments 114-117, wherein the subject is aged less than 50 years.

[0567] Embodiment 145. The method of any one of embodiments 114-117, wherein the subject is aged between 50 and 80 years.

[0568] Embodiment 146. The method of any one of embodiments 114-117, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

[0569] Embodiment 147. The method of any one of embodiments 114-117, wherein the subject has an MMSE score greater than, or equal to 24.

[0570] Embodiment 148. A method of slowing neurodegeneration in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any compound described herein.

[0571] Embodiment 149. The method of embodiment 148, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0572] Embodiment 150. The method of embodiment 148, wherein the compound of Formula I is: or a pharmaceutically acceptable salt thereof.

[0574] Embodiment 151. The method of embodiment 150, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0575] Embodiment 152. The method of any one of embodiments 148- 151, wherein the compound of Formula I is administered for at least about 6 months.

[0576] Embodiment 153. The method of any one of embodiments 148-151, wherein the compound of Formula I is administered for less than about 6 months.

[0577] Embodiment 154. The method of any one of embodiments 148- 151, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

[0578] Embodiment 155. The method of any one of embodiments 148-151, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

[0579] Embodiment 156. The method of any one of embodiments 148-151, wherein the neurodegeneration is measured by volumetric magnetic resonance imaging (vMRI).

[0580] Embodiment 157. The method of any one of embodiments 148-151, wherein administering the compound reduces the vMRE

[0581] Embodiment 158. The method of any one of embodiments 148-151, wherein administration of the compound results in a maintenance of the vMRI over 6 months.

[0582] Embodiment 159. The method of any one of embodiments 148-151, wherein administration of the compound results in a maintenance of the vMRI over 1 year.

[0583] Embodiment 160. The method of any one of embodiments 148-151, wherein administration of the compound results in a maintenance of the vMRI over 2 years.

[0584] Embodiment 161. The method of any one of embodiments 148-151, wherein administration of the compound results in a maintenance of the vMRI over 5 years.

[0585] Embodiment 162. The method of any one of embodiments 148-151, wherein administering the compound results in an increase in expression of biomarkers comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1 , NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0586] Embodiment 163. The method of embodiment 162, wherein the biomarkers are measured in cerebrospinal fluid.

[0587] Embodiment 164. The method of embodiment 162, wherein the biomarkers are measured in plasma.

[0588] Embodiment 165. The method of any one of embodiments 148-151, wherein administering the compound results in a decrease in expression of biomarkers comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0589] Embodiment 166. The method of embodiment 165, wherein the biomarkers are measured in cerebrospinal fluid.

[0590] Embodiment 167. The method of embodiment 165, wherein the biomarkers are measured in plasma.

[0591] Embodiment 168. The method of any one of embodiments 148-151, wherein the vMRI is correlated with modulation of biomarkers comprising C4B; C4B 2, SERPINB1,PTN, IGLV1-51, CNNM3, ADAM9, IGLV1-36, PZP, C4B; C4B 2, KIT, C0L5A1, C4BPA, UBE2N, CCT7, FCN3, CFP, FCN2, SMPDL3B, IGLC7, NXPH3, PGD, CACNA2D2, CLP1, UBE2L3, IGHV3-21, FN1, PSMB7, PGLS, C4A, MDGA1, C4BPB, IGLV2-11, PPBP, UFM1, NCALD, TLN1, TXNL1, and combinations thereof.

[0592] Embodiment 169. The method of any one of embodiments 148-151, wherein administering the compound results in a reduction in the level of a-synuclein.

[0593] Embodiment 170. The method of embodiment 169, wherein the a-synuclein is measured in cerebrospinal fluid.

[0594] Embodiment 171. The method of embodiment 169, wherein the a-synuclein is measured in plasma.

[0595] Embodiment 172. The method of any one of embodiments 148-151, wherein administering the compound results in a reduction in the level of Ap.

[0596] Embodiment 173. The method of embodiment 172, wherein the Ap is Ap40, Ap42, or a combination of both.

[0597] Embodiment 174. The method of embodiment 172, wherein the Ap is measured in cerebrospinal fluid.

[0598] Embodiment 175. The method of embodiment 172, wherein the Ap is measured in plasma.

[0599] Embodiment 176. The method of any one of embodiments 148-151, wherein the subject has been diagnosed with a synucleinopathy.

[0600] Embodiment 177. The method of embodiment 176, wherein the synucleinopathy is Dementia with Lewy Bodies.

[0601] Embodiment 178. The method of any one of embodiments 148-151, wherein the subject has been diagnosed with Alzheimer's disease.

[0602] Embodiment 179. The method of any one of embodiments 148-151, wherein the subject has been diagnosed with mild cognitive impairment.

[0603] Embodiment 180. The method of any one of embodiments 148-151, wherein the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0604] Embodiment 181. The method of any one of embodiments 148-151, wherein the subject is aged less than 50 years.

[0605] Embodiment 182. The method of any one of embodiments 148-151, wherein the subject is aged between 50 and 80 years.

[0606] Embodiment 183. The method of any one of embodiments 148-151, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

[0607] Embodiment 184. The method of any one of embodiments 148- 151, wherein the subject has an MMSE score greater than, or equal to 24.

[0608] Embodiment 185. A method of restoring protein expression in a subject with or at risk of developing a synucleinopathy, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any compound described herein.

[0609] Embodiment 186. The method of embodiment 185, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0610] Embodiment 187. The method of embodiment 185, wherein the compound of Formula I is:pharmaceutically acceptable salt thereof.

[0611] Embodiment 188. The method of embodiment 187, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0612] Embodiment 189. The method of any one of embodiments 185-188, wherein the compound of Formula I is administered for at least about 6 months.

[0613] Embodiment 190. The method of any one of embodiments 185-188, wherein the compound of Formula I is administered for less than about 6 months.

[0614] Embodiment 191. The method of any one of embodiments 185-188, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

[0615] Embodiment 192. The method of any one of embodiments 185-188, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

[0616] Embodiment 193. The method of any one of embodiments 185-188, wherein administration results in an increase in expression of the biomarkers.

[0617] Embodiment 194. The method of embodiment 193, wherein the biomarkers are selected from IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2- 18, S 100A8, SERPINA1 , NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0618] Embodiment 195. The method of embodiment 193, wherein the biomarkers are measured in cerebrospinal fluid.

[0619] Embodiment 196. The method of embodiment 193, wherein the biomarkers are measured in plasma.

[0620] Embodiment 197. The method of any one of embodiments 185-188, wherein administration results in a decrease in expression of the biomarkers.

[0621] Embodiment 198. The method of embodiment 197, wherein the biomarkers are selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

[0622] Embodiment 199. The method of embodiment 197, wherein the biomarkers are measured in cerebrospinal fluid.

[0623] Embodiment 200. The method of embodiment 197, wherein the biomarkers are measured in plasma.

[0624] Embodiment 201. The method of any one of embodiments 185-188, wherein administering the compound is correlated with modulation of biological processes or biological pathways comprising phosphatidylcholine-sterol O-acyltransferase activator activity; phosphatidylcholine binding; wnt-protein binding; cholesterol binding; glycosaminoglycan binding; protein folding and maturation_angiotensin system maturation; Immune response_antigen presentation by MHC class I: cross-presentation; O-glycan biosynthesis; Immune response_antigen presentation by MHC class II; signal transduction_angiotensin II / AGTR1 signaling via Notch, Beta-catenin and NF-kB pathways; immune response_antigen presentation by MHC class I, classical pathway; development_regulation of cytoskeleton proteins in oligodendrocyte differentiation and myelination; renin-angiotensin-aldosterone system; development_PEDF signaling; signal transduction_negative regulation of BMP signaling; signal transduction_angiotensin II / AGTR1 signaling via p38, ERK and PI3K; immune response_IL- 11 signaling via JAK / STAT; protein folding and maturation_regulation of amyloid precursor protein processing; signal transduction_BMP signaling via BMPR1 A and BMPR1B receptors; development NOTCH signaling in organogenesis and embryogenesis; protein folding and maturation: bradykinin / kallidin maturation; cell adhesion: ECM remodeling; cell adhesion: cell-matrix glycoconjugates; lipoprotein metabolism; development: ErbB3 signaling, and combinations thereof.

[0625] Embodiment 202. The method of any one of embodiments 185-188, wherein administering the compound results in a reduction in the level of a-synuclein.

[0626] Embodiment 203. The method of embodiment 202, wherein the a-synuclein is measured in cerebrospinal fluid.

[0627] Embodiment 204. The method of embodiment 202, wherein the a-synuclein is measured in plasma.

[0628] Embodiment 205. The method of any one of embodiments 185-188, wherein administering the compound results in a reduction in the level of Ap.

[0629] Embodiment 206. The method of embodiment 205, wherein the Ap is Ap40,Ap42, or a combination of both.

[0630] Embodiment 207. The method of embodiment 205, wherein the Ap is measured in cerebrospinal fluid.

[0631] Embodiment 208. The method of embodiment 205, wherein the Ap is measured in plasma.

[0632] Embodiment 209. The method of any one of embodiments 185-188, wherein the synucleinopathy is Dementia with Lewy Bodies.

[0633] Embodiment 210. The method of any one of embodiments 185-188, wherein the subject has been diagnosed with Alzheimer's disease.

[0634] Embodiment 211. The method of any one of embodiments 185-188, wherein the subject has been diagnosed with mild cognitive impairment.

[0635] Embodiment 212. The method of any one of embodiments 185-188, wherein the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0636] Embodiment 213. The method of any one of embodiments 185-188, wherein the subject is aged less than 50 years.

[0637] Embodiment 214. The method of any one of embodiments 185-188, wherein the subject is aged between 50 and 80 years.

[0638] Embodiment 215. The method of any one of embodiments 185-188, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

[0639] Embodiment 216. The method of any one of embodiments 185-188, wherein the subject has an MMSE score greater than, or equal to 24.

[0640] Embodiment 217. A method of treating Alzheimer's disease in a subject in need thereof, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to any compound described herein; wherein the administration of the compound according to Formula I results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the at least one biomarker with decreasedexpression is selected from the group comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof; and wherein the at least one biomarker with increased expression is selected from the group comprising AD AMTS 8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof.

[0641] Embodiment 218. The method of embodiment 217, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0642] Embodiment 219. The method of embodiment 217, wherein the compound of Formula I is: or a pharmaceutically acceptable salt thereof.

[0644] Embodiment 220. The method of embodiment 219, wherein the pharmaceutically acceptable salt is the fumarate salt.

[0645] Embodiment 221. The method of any one of embodiments 217-220, wherein the compound of Formula I is administered for at least about 6 months.

[0646] Embodiment 222. The method of any one of embodiments 217-220, wherein the compound of Formula I is administered for less than about 6 months.

[0647] Embodiment 223. The method of any one of embodiments 217-220, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

[0648] Embodiment 224. The method of any one of embodiments 217-220, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

[0649] Embodiment 225. The method of any one of embodiments 217-220, wherein the biomarkers are measured in cerebrospinal fluid.

[0650] Embodiment 226. The method of any one of embodiments 217-220, wherein the biomarkers are measured in plasma.

[0651] Embodiment 227. The method of any one of embodiments 217-220, wherein administering the compound is correlated with modulation of biological processes or biological pathways comprising phosphatidylcholine-sterol O-acyltransferase activator activity; phosphatidylcholine binding; wnt-protein binding; cholesterol binding; glycosaminoglycan binding; protein folding and maturation_angiotensin system maturation; immune response_antigen presentation by MHC class I: cross-presentation; O-glycan biosynthesis; Immune response_antigen presentation by MHC class II; signal transduction_angiotensin II / AGTR1 signaling via Notch, Beta-catenin and NF-kB pathways; immune response_antigen presentation by MHC class I, classical pathway; development_regulation of cytoskeleton proteins in oligodendrocyte differentiation and myelination; renin-angiotensin-aldosterone system; development_PEDF signaling; signal transduction_negative regulation of BMP signaling; signal transduction_angiotensin II / AGTR1 signaling via p38, ERK and PI3K; immune response_IL- 11 signaling via JAK / STAT; protein folding and maturation_regulation of amyloid precursor protein processing; signal transduction_BMP signaling via BMPR1 A and BMPR1B receptors; development NOTCH signaling in organogenesis and embryogenesis; protein folding and maturation: bradykinin / kallidin maturation; cell adhesion: ECM remodeling; cell adhesion: cell-matrix glycoconjugates; lipoprotein metabolism; development: ErbB3 signaling, and combinations thereof.

[0652] Embodiment 228. The method of any one of embodiments 217-220, wherein administering the compound results in a reduction in the level of a-synuclein.

[0653] Embodiment 229. The method of embodiment 228, wherein the a-synuclein is measured in cerebrospinal fluid.

[0654] Embodiment 230. The method of embodiment 228, wherein the a-synuclein is measured in plasma.

[0655] Embodiment 231. The method of any one of embodiments 217-220, wherein administering the compound results in a reduction in the level of Ap.

[0656] Embodiment 232. The method of embodiment 231 , wherein the Ap is Ap40,Ap42, or a combination of both.

[0657] Embodiment 233. The method of embodiment 231, wherein the a-synuclein is measured in cerebrospinal fluid.

[0658] Embodiment 234. The method of embodiment 231, wherein the a-synuclein is measured in plasma.

[0659] Embodiment 235. The method of any one of embodiments 217-220, wherein the synucleinopathy is Dementia with Lewy Bodies.

[0660] Embodiment 236. The method of any one of embodiments 217-220, wherein the subject has been diagnosed with Alzheimer's disease.

[0661] Embodiment 237. The method of any one of embodiments 217-220, wherein the subject has been diagnosed with mild cognitive impairment.

[0662] Embodiment 238. The method of any one of embodiments 217-220, wherein the subject does not exhibit any detectable clinical symptoms of Alzheimer's disease.

[0663] Embodiment 239. The method of any one of embodiments 217-220, wherein the subject is aged less than 50 years.

[0664] Embodiment 240. The method of any one of embodiments 217-220, wherein the subject is aged between 50 and 80 years.

[0665] Embodiment 241. The method of any one of embodiments 217-220, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

[0666] Embodiment 242. The method of any one of embodiments 217-220, wherein the subject has an MMSE score greater than, or equal to 24.

[0667]

[0668] EXAMPLES

[0669] Example 1: SHINE-A Clinical Trial

[0670] A clinical trial was conducted for oral once daily (QD) administration for 6 months (SHINE, COG0201) with 144 subjects having a diagnosis of AD, with an MMSE of 18-26, and a positive biomarker for PET or CSF Amyloid AD. The study included an interim analysis for 24 subjects. Three study groups were included with 8 subjects each for the interim analysis: one group was treated with 300 mg of CT1812, another group was treated with 100 mg of CT1812, and the control group was treated with a placebo. Subjects were screened with blood tests, physical exams, MRI, and brain amyloid PET. Assessments conducted included cognitive testing and CSF biomarkers.

[0671] TMT-MS proteomics methods included collection of CSF samples followed by TMT labeling of the samples and subjecting the samples to mass spectrometry. To validate the quantitative nature of the MS approach, proteins of interest were measured using clinically validated assays (ELISA) and correlation analyses were performed against the >2,000 proteins measured using TMT-MS. 2,161 CSF proteins were detected, and protein abundance values as detected by MS were plotted against protein abundance values as detected by ELISA to validate the MS proteomics method.

[0672] To benchmark the SHINE-A cohort at baseline against a known AD cohort and to further validate the quantitative use of TMT-MS, baseline SHINE-A CSF proteomes were compared to those of pooled Emory control (healthy) individuals and pooled Emory AD patient reference population CSF samples. As a benchmark, the SHINE-A cohort was analyzed at baseline with MS proteomics. The control CSF group included 37 patients, with samples collected and pooled as a control CSF sample. The Emory AD group included 46 patients, with samples collected and pooled as an AD CSF sample. The SHINE-A AD group included 18 patients, with individual patient samples analyzed separately as baseline CSF samples.

[0673] T o quantify changes in C SF proteome following treatment with CT 1812 and identify possible CT1812 pharmacodynamic biomarkers, change from baseline CT1812- and placebo-treated patient CSF proteomes were compared. After 6 months, samples were collected from each participant to measure the change from baseline for CT1812 pharmacodynamic biomarkers. 11 participants treated with CT 1812 completed the study, and 7 participants treated with placebo completed the study. The samples were each subjected to MS proteomics and analysis.

[0674] Proteome analysis pipeline. Differentially abundant proteins were identified, mapped to established brain modules, assessed for interconnectivity and biological relevance, and using STRING, Metacore, and Gene Ontology. Proteins abundances that correlated with AD traits such as Ab and ADAS-Cogl 1 were also identified and analyzed.

[0675] Validation of TMT-MS proteomics as a quantitative method. Pearson correlation analysis compared levels of AD core biomarkers in SHINE-A patient CSF samples measured using clinically validated assays to those measured using TMT-MS proteomics (N=36: protein levels in 2 samples, baseline and 6 months, per participant). The strength of correlations between levels of key proteins related to AD from each method were plotted on a heat map to visualize the high degree of correlation between ELISA and quantitative TMT- MS, with results described as follows: correlation between SYT1 and qTau was 0.8, SYT1 and qNfl was 0.2, SYT1 and qNrgn was 0.8, SYT1 and qSytl was 0.7, NRGN and qTau was 0.8, NRGN and qNfl was 0.2, NRGN and qNrgn was 0.9, NRGN and qSytl was 0.7, NEFL and qTau was 0.4, NEFL and qNfl was 0.9, NEFL and qNrgn was 0.4, NEFL and qSytl was 0.3, MAPT and qTau was 0.9, MAPT and qNfl was 0.3, MAPT and qNrgn was 0.9, and correlation between MAPT and qSytl was 0.7. Scatter plots illustrated the congruency between levels of each core AD biomarker examined (quantitative (q) NfL (qNfL), qTau, qNrgn, qSytl), and the levels detected via TMT-MS. FIG. 1 illustrates the correlation between SYT1 abundance and qSYTl (upper left), the correlation between NRGN abundance and qNrgn (upper right), thecorrelation between NEFL abundance and qNfL (lower left) and between the abundance of MAPT and qTau (lower right).

[0676] For each AD core biomarker measured using a clinically validated assay, the number of TMT-MS proteins highly correlated (r > |0.50| and p < 0.01), along with directionality (either positively (+) or negatively (-) correlated) is indicated in Table 2.Table 2*(r) >|0.50| and p < 0.01

[0677] The top 5 strongest positively and negatively correlated TMT-MS proteins to qNfL are listed with NEFL and NEFM identified as the most strongly correlated are indicated in Table 3.Table 3

[0678] A STRING (vl 1.5) protein-protein interaction (PPI) map of all significantly correlated proteins (n = 52; r > |0.50| and p < 0.01) indicated that NEFL and NEFM are central hubs. Proteins analyzed included ATPIF1, GAA, PAPPA2, PCSK2, SIAE, TPP1, GALNS, PAPLN, CDH7, FABP3, GSN, EPDR1, HEXB, ARSA, SMPLDL3A, RPS10-NUDT3, GRID2, CA10, AKR1B1, MFI2, VSN, SPTBN1, NEFL, NEFM, CA11, KLK7, ROBO2, SEMA6B, SEMA7A, VASN, BAB, MPZ, UCHL1, TRHDE, SEMA7A, EFNA5, RTN4, RTN4R, SEMA4A, SNCG, IBM2A, CD300A, ITM2A, GAS6, PEA 15, MRC1, CD300A, AND KITLG. Proteins involved in nervous system development biological processes include PCSK2, TPP1, GSN, HEXB, GRID2, CA10, SPTBN1, NEFL, ROBO2, SEMA6B, SPTBN1, SEMA7A, BAB, RTN4, RTN4R, MPZ, EFNA5, SEMA4A, UCHL1, and GAS6.

[0679] Gene Ontology analysis of these 52 proteins identified the top-most enriched 10 pathways (ranked by FDR p-value), described in Table 4 below. Processes related to axon dynamics are strongly represented.Table 4. Top 10 Biological Processes for qNfL-correlated MS proteins, r > | 0.50 | andp < 0.01

[0680] Identification of proteins disrupted in AD, and characterization of the SHINE-A proteomic phenotype at baseline.

[0681] Differential abundance of proteomes as measured vis TMT-MS from pooled AD patient CSF was compared to pooled control (healthy) CSF (from the Emory ADRC reference population) and assessed (AD vs. control; FDR < 0.05, BH = Benjamini-Hochbergcorrection). Log2 abundance and significance for each protein detected was analyzed AD priority biomarkers. 509 proteins (277 down and 232 up) were found to be significantly differentially abundant. Proteins of interest are indicated with royal blue arrows: APOA2, apolipoprotein A2; APOE, apolipoprotein E; BACE1, Beta-Secretase 1; CHI3L1, chitinase-3- like protein 1; CLU, clusterin; GM2A, ganglioside activator; GPNMB, Glycoprotein nonmetastatic melanoma protein B; HLA-DRB1, human leukocyte antigen class II histocompatibility D related beta chain; IGKC, Immunoglobulin kappa constant; MAPT, microtubule-associated protein tau; MEGF10, Multiple EGF-like-domains 10; NEFL, neurofilament light chain; NEFM, neurofilament medium chain; NRGN, neurogranin; NRXN3, neurexin 3; OLFML3, olfactomedin-like protein 3; TF, transferrin; S100A1, S100 calcium binding protein Al; SHBG, sex hormone binding globulin; SMOC1, SPARC-related modular calcium-binding protein 1; SYT1, synaptotagmin 1; YWHAZ, 14-3-3 protein zeta / delta.

[0682] The proteins identified as significantly differentially abundant (FDR < 0.01) were mapped to previously established AD co-expression modules, and the top related modules to which the proteins belong were determined. In order from the greatest representation of proteins ascribed to the module to the least representation of proteins ascribed to the module, a list of modules is as follows: M26 complement / acute phase, M7 MAPK / metabolism, M21 MHC complex / immune, M4 synapse / neuron, M3 oligo / myelination, M27 extracellular matrix, Ml synapse / neuron, M14 protein folding, MH cell-ECM interaction, M42 matrisome, M5 post-synaptic density, and M40 ambiguous.

[0683] Abundances of AD-related genes were compared between healthy control, the Emory AD population, and the SHINE-A baseline CSF proteomes were plotted (Log2 abundance) to determine how SHINE-A CSF compares to CSF of either healthy or AD known populations. Data is presented as mean abundance (line within box) + / - SEM (box height) and + / - SD (error bars). Proteins shown in FIG. 2A, FIG. 2B, and FIG. 2C include Complement / Acute phase protein TF ; MAPK7 Metabolism protein CLU; MHC Complex / Immune protein ITGB2 (beta 2 integrin); Synapse / Neuron protein NPTXR (neuronal pentraxin receptor); Oligo / Myelination protein NEFM ; Extracellular Matrix protein TGFB 1 (transforming growth factor-beta-induced); Synapse / Neuron protein MCM3AP (minichromosome maintenance complex component 3 associated protein), Oligo / Myelination protein NEFL; Axon Node / Ion Channel protein MAPT; Matrisome protein APOE; Synapse / Neuron protein NRXN3; MHC Complex / Immune protein HLA-DRB1; matrisome protein OLFML3, and spondin-1 in the thrombospondin family SPON 1.

[0684] Analysis of differentially abundant proteins in CT1812- and placebo-treated patient CSF proteomes. Differential abundance of change from baseline levels of protein measured via TMT-MS was assessed via ANOVA (CT1812 vs placebo; p<0.05). Log2 abundance and significance for each protein detected were assessed. There were 122 proteins (70 down, 52 up), found to be significantly differentially abundant (CT1812 vs. placebo; p<0.05). Proteins of interestinclude proteins of increased abundance (52 total): SHBG, sex hormone binding globulin; FABP1, fatty acid-binding protein 1; ; ITGB1, beta 1 integrin; ITGB2, beta 2 integrin; NPC 1 , Niemann- Pick disease, type C 1 ; IGKC, Immunoglobulin kappa constant; and TF, transferrin. Also included are proteins of decreased abundance (70 total): NRXN2, neurexin 2; LTBP1, Latent-transforming growth factor beta-binding protein 1; CLU, clusterin; HTRA1, HtrA serine peptidase 1 ; S100A1, SI 00 calcium binding protein Al; GM2A, ganglioside activator; MEGF10, multiple EGF-like-domains 10; HLA-DRB1, human leukocyte antigen class II histocompatibility D related beta chain; APP, amyloid precursor protein; and SPON1, spondin 1.

[0685] The significantly (p < 0.05) differentially abundant proteins were mapped to previously established AD co-expression modules. The list of modules ordered from top to least most represented includes: M4 synapse / neuron; M3 oligo / myelination; M21 MHC complex / immune; M42 matrisome; MH cell-ECM interaction; Ml 7 transcription; Ml synapse / neuron; M29 glycosylation / ER; M7 MAPK / metabolism; and Ml 3 RNA splicing.

[0686] STRING (vl 1.5) Protein-Protein Interaction analyses of the significantly (p < 0.05) differentially abundant proteins (medium confidence; proteins not connected not listed here) included the following proteins: LTBP1, MEGF10, SPON1, APP, CLU, TF, GM2A, FABP1, ITGB2, ITGB1, SHBG, HLA-DRB1, NRXN2, NPC1, and APLP2. In this analysis, APP is a hub protein that was significantly lower in CT1812-treated patient CSF than in placebo-treated patient CSF. Pathway analyses using both STRING (Table 5) and Metacore (Table 6) mapping show synapse, inflammatory, and amyloid pathways to be most significantly altered with CT1812 treatment when compared to placebo-treated controls.Table 5. Top 10 Biological Processes (CT1812 vs. placebo; p < 0.05)Table 6.

[0687] CT1812 pharmacodynamic biomarkers of disease modification. FIG. 3A is a forest plot of proteins found to move in the opposition of disease state abundance (p < 0.05), by functional category of protein. CSF proteins found to be disrupted in AD (AD vs healthy control reference standards; p < 0.05) and significantly normalized (in opposing direction of AD vs control) by CT1812 (CT1812 vs placebo, p < 0.05) were plotted. CFB = change from baseline Fig. 3B is a graph illustrating abundance of clusterin in the healthy control, the pooled AD cohort, and the SHINE treated subjects. Clusterin had higher abundance in the pooled AD cohort than in healthy control CSF (left graph). CT1812-treated patient CSF had significantly lower (p = 0.02) clusterin change from baseline abundance than did placebo-treated patient CSF, movement in the opposite direction of disease state.

[0688] FIG. 3C is a graph illustrating abundance of HLA-DRB1 (HLA class II histocompatibility antigen, DRB 1 beta chain) abundance in the healthy control, the pooled AD cohort, and the SHINE baseline subjects (left), and abundance of HLA-DRB1 in the difference between the reference AD and control, the placebo CFB, and the treated CFB CT- 1812 group (right). Abundance of HLA-DRB1 was higher in the pooled AD cohort than healthy control CSF (FIG. 3C, left graph), but CT1812-treated patient CSF had significantly lower (p = 0.036) change from baseline abundance than did placebo-treated patient CSF, movement in the opposite direction of disease state.

[0689] Reduction in Ab with CT1812 treatment with molecular correlates. A statistically significant lowering of Ap42 and Ap40, as assessed via Lumipulse assay, was found in CT1812- vs. placebo-treated treatment-compliant patient CSF (n = 7, placebo; n = 12, CT1812, p=0.0060) The average change from baseline for Ap42 for CT1812 treated patients was about - 100 pg / ml, while the average change from baseline for placebo-treated patients was about 80 pg / ml. For Ap40, the average change from baseline was about -1500 pg / mL for CT1812 treated patients while it was about 1200 pg / mL for placebo treated patients.

[0690] STRING (vl l.5) Protein-Protein Interaction (PPI) analyses of MS protein CFB levels found several proteins to be significantly correlated (r > |0.50| and p < 0.05) with Ab42 CFB levels for 121 proteins, with medium confidence, including HLA-DRB 1 , HLA class II histocompatibility antigen, DRB1 beta chain; MMP2, matrix metallopeptidase 2; TGFRB2, Transforming growth factor, beta receptor II; THBS1, Thrombospondin 1; SERPINA10, serpin family A member 10; FABP 1 , fatty acid binding protein 1 ; APOC3, apolipoprotein C3 ; APOB, Apolipoprotein B; LPA, Lipoprotein(a); C1QA, Complement Clq subcomponent subunit A; HLA-B, major histocompatibility complex, class I, B; PRND, Prion protein 2 (doublet); and GPNMB, Glycoprotein non-metastatic B...

[0691] Top-ranked (by Strength) Biological Process and Cellular Component terms revealed high representation of lipoprotein-related networks and immune-related pathways (Table 7).Table 7. Ap42: Top 10 ranked (by strength) STRING-identified pathways for correlated MS proteins, r>0.5 and p<0.05.

[0692] Scatter plots were graphed to show correlations between A 42 CFB and TMT-MS CFB levels for FABP1, GPNMB, HLA-B, and SERPINA proteins (FIG. 4). Each dot is a value from an individual participant. STRING (vl 1.5) PPI analyses of MS protein CFB levels found to be significantly correlated (r > |0.50| and p < 0.05) with Ab42 / 40 ratio CFB (104 proteins, medium confidence, disconnected nodes not shown) were conducted. Proteins of interest include: APOB; CLU, clusterin; ESMI, endothelial cell specific molecule 1; FN1, fibronectin 1; GPNMB; HSPA1B, heat shock protein IB; HSPB1, heat shock protein family B (small) member 1; LILRB4, leukocyte immunoglobulin like receptor B4; LPA; NOTCH3, notch receptor 3; SV2A, synaptic vesicle glycoprotein 2a; SYT11, synaptotagmin 11; TGFRB2.

[0693] Top -ranked (by Strength) Biological Process and Cellular Component terms revealed high representation of synapse, lipoprotein, and secretion-related networks (Table 8).Table 8. Ap42 / 40: Top ranked (by FDR) STRING-identified pathways for correlated MS proteins, r > | 0.50 | and p < 0.05

[0694] FIG. 5 is a set of graphs illustrating correlations between Scatter plots show correlations between AJ342 / 40 CFB and TMT-MS CFB levels for POFUT2, protein O- fucosyltransferase 2; SV2A, synaptic vesicle glycoprotein 2a; ESMI; and APA2, Aspartic proteinase A2.

[0695] Analysis and identification of molecular correlates with cognitive outcomes. Change from baseline (CFB) ADAS-Cogl 1 scores by treatment group over course of 6 months were plotted with all 24 patients (intent to treat, FIG. 6). No statistically significant change, as assessed via ANCOVA, due to treatment with CT1812 was observed; a 3 point, clinically meaningful difference was found.

[0696] To identify molecular correlates with CFB in cognitive function (ADAS- Cog 11) at 6mo, Pearson correlation analysis (p<0.05) was performed with CFB levels of proteins assessed via proteomics analysis from a) all patients (i.e., both placebo and CT1812 treated patients) and b) only CT1812-treated patients. For the former analysis (a), 245 CSF biomarkers were significantly correlated with ADAS-Cogl 1 CFB. In the CT1812-treated group only (b), a total of 608 proteins were found to be correlated with ADAS-Cogl 1 CFB. Of these, 183 were also found correlated in the all-treatment group. The 183 correlates detected in both CT1812- and placebo-treated CSF samples were removed, and the 425 remaining CT1812 group correlates (i.e., proteins determined to correlate with ADAS-Cogl 1 only in CT1812- treated patients) were analyzed using STRING (vl2.0). Top-ranked (by Strength) Biological Process GO terms (top panel) and Disease-Gene Associations (bottom panel) are shown in Table 9.Table 9.

[0697] FIG. 7 is a set of scatter plots showing individual patient LTBP1 log2 abundance CFB and ADAS-Cogl l CSF values are shown for Placebo treated patients only (left) and CT 1812-treated only (right), illustrating the correlation is driven by CT 1812 and thus this may be a cognitive correlate attributable to a CT1812-specific mechanism of action.

[0698] Of the 425 proteins identified that were correlated with ADAS-Cog in the CT1812 group only, 53 were determined to also be differentially abundant in CT1812 vs. placebo CSF (FIG. 6). These 53 proteins were analyzed using STRING (vl2.0) and the Protein- Protein Interaction (PPI) analysis indicated proteins of interest including: NLGN2, neuroligin 2; NRXN 1 and 2, neurexin 1 and 2; GRIA4, glutamate ionotropic receptor AMPA type subunit 4; APOE, apolipoprotein E; APP, amyloid beta precursor protein; MEGF 10, multiple EGF like domains 10; GAS6, growth arrest specific 6; and HTRA1, HtrA serine peptidase 1.

[0699] Top-ranked (by Strength) Biological Process GO terms are shown in Table10.Table 10.

[0700] The correlation of LTBP1 with AGAS-Cogl 1 in individual CT1812-treated patients is shown in FIG. 8 (left; each dot is CFB value from individual participant; differential log2 abundance of LTBP1 in AD vs control CSF, and in SHINE placebo- or CT1812-treated CSF at 6 months).

[0701] Candidate PD Biomarkers of CT1812: Support for the hypothesized CT1812 mechanism of action. CT1812 binds the sigma-2 receptor (S2R), also known as TMEM97. TMEM97 is localized on the membrane in a complex with the LDL receptor (LDLR) and PGRMC1. A oligomers bind the oligomer receptor complex, which includes PrPc, Nogo, and LilrB2. Ap monomers do not bind. Binding of CT1812 to the S2R complex induces a conformational change in the oligomer receptor complex, disengaging the oligomer from the synapse (Izzo et al., 2021). Several biomarkers identified in the SHINE interim CSF proteomics analysis suggest CT1812 impacts synapses (NRXN1, NRNX2, ITGB1, ITGB2). NRXN1 was reduced (p=0.03), NRNX2 was reduced (p=0.05), ITGB1 was increased (p 0.03 ), and ITGB2 was increased (p=0.03). NPC1, ITGB2, and ITGB1 suggest the LDLR may be impacted by CT1812 treatment- and these biomarkers may reflect target engagement. NPC1, ITGB2, and ITGB1 all increased (pA).O5, pA).O3, and pA).O3, respectively). In addition, the observed APP reduction (p=0.02) is consistent with a PrPc-related mechanism of action. Reductions in APP, CLU, and SPON 1 were consistent with a negative regulation of Ap, and may also reflect pathway engagement. APP, CLU, and SPON1 were reduced with p=0.02, p=0.02, and p=0.04, respectively. CLU and HLA-DRB1, which were increased in abundance in AD vs. control CSF but decreased in abundance in CT1812 vs placebo-treated patient CSF (p=0.02 and p=0.04, respectively), are two candidate biomarkers of disease-modification. Pathway engagement biomarkers include APP, NPC1, ITGB1, ITGB2, NRXN1, NRXN2, SPON1, and CLU. Candidate disease modification biomarkers (normalized by CT1812) include SPON1, CLU, MEGF10, HLA-DRB1, and HTRA1. Candidate disease modificationbiomarkers (correlated with cognitive change) include APP, LTBP1, and HTRA1. APP, LTBP1, and HTRA1 were identified as molecular correlates of ADAS-Cog and may also be candidate surrogate biomarkers of efficacy.Table 11 indicates proteins increased and decreased after treatment in the SHINE-A study, comparing drug vs. placebo.Table 12 indicates proteins increased and decreased after treatment in the SHINE clinical trial, as analyzed with ADAS-Cogl 1.

[0702] Validation of the TMT-MS proteomics approach as a quantitative method. The individual patient values for the core AD biomarker qNfL, measured using quantitative assay, and TMT-MS-detected NEFM, were highly correlated (1^0.88, p=1.95e-12; FIG. 9). Gene ontology term analysis using STRING was performed on the correlates identified for each AD core biomarker. The top 3 (ranked by false discovery rate p-value) enriched pathways identified for each core biomarker are listed in Table 13.Table 13*STRING pathway analysis performed on MS proteins correlated (r)> |0.50| and p <0.01 ; genes named “0” removed for STRING. GO = Gene Ontology; FDR = False Discovery Rate; Top 6 ranked pathways are displayed.

[0703] STRING (vl l.5) PPI analysis for qNrgn MS correlates (166 proteins, r > |0.70| andp < 0.01) was performed, and proteins of interest are described forthose with medium confidence, excluding disconnected nodes. Proteins of interest include: APLP1, amyloid betaprecursor like protein 1; NRGN, neurogranin; BINI, bridging integrator 1; and CP, ceruloplasmin. Table 14 lists the top enriched (ranked by FDR) Cellular Component terms for qNrgn MS correlates; relevant terms have asterisks.Table 14 describes the top-ranked cellular component pathways for qNrgn MS correlated proteins [(r) > |0.70|, p < 0.01].

[0704] Top-ranked (by FDR) Cellular Component terms for qSytl (62 proteins) and qTau (97 proteins) MS correlates are shown (r > |0.70| and p < 0.01). Relevant terms are indicated with an asterisk; synapses and synaptic areas are strongly represented.Table 15 lists the top-ranked cellular component pathways for qSyt MS correlated proteins (r|0.70| and p < 0.01).Table 16 lists top-ranked cellular component pathways for qTau MS correlated proteins (r |0.70| and p < 0.01).

[0705] Example 2: SPARC Clinical Trial

[0706] For the SPARC (COGO 105) 6-month study, tandem-mass tag mass spectrometry (TMT-MS) followed by unbiased quantification of CSF proteomes was conducted on baseline and CSF collected after 6 months of treatment. All biomarker analyses reported herein were exploratory, and for the purpose of identifying pharmacodynamic changes of CT1812, only patients who were actively taking their treatment, as indicated by bioanalysis of drug exposure levels, were included in the analysis. Change from baseline was calculated, and treatment effects were assessed through differential abundance analysis (pooled drug vs placebo; p<0.05), followed by pathway analyses using STRING and Metacore. 8 patients were included in the CT1812 300 mg study arm, 8 patients were included in the CT1812 100 mg study arm, and 7 patients were treated with a placebo. Patients were screened with labs, exams, MRI, and a brain amyloid PET scan. At baseline, all patients were assessed with UCB-J and FDG PET, fMRI, vMRI, clinical outcomes, and CSF biomarkers. At 3 months, patients were assessed with UCB-J and FDG PET, fMRI, vMRI, and clinical outcomes. At 6 months, patients were again assessed with UCB-J and FDG PET, fMRI, vMRI, clinical outcomes, and CSF biomarkers.

[0707] Differential Expression Analysis Identifies CSF Biomarkers of CT1812 after 6 Months of Treatment: 256 proteins were significantly altered (p < 0.05) in CT1812 vs placebo CSF from AD patients. Proteins of interest included LRP1, CLU (clusterin), and SMOC1. Differentially expressed proteins (CT1812 vs placebo; p<0.05) were mapped to previously generated AD brain co-expression network modules built from 516 brain samples with healthy individuals, asymptomatic and symptomatic AD patients to understand how CSF biomarkers altered by CT1812 might impact brain networks disrupted in AD. The synapse / neuron module M4 was the top module identified; in descending order, the other top modules identified were: M27 extracellular matrix, M26 complement / acute phase, M7 MAPK / metabolism, M3 oligo / myelination, Ml synapse / neuron, M42 matrisome, M21 MHC complex / immune, M2 mitochondria, M14 protein folding, M15 ambiguous, M9 golgi, MH cell-ECM interaction, M29 glycosylation / ER, M5 post-synaptic density, M 19 axonogenesis, M25 sugar metabolism, M17 transcription, M40 ambiguous, M16 RNA binding.Table 17 lists proteins increased or decreased, compared to placebo, after treatment for 6 months in the SMARC trial.

[0708] Metacore pathway analysis (v 23.4.71500) was performed using the 256 differentially expressed proteins in the 6mo CSF Drug-Placebo (p<0.05) SPARC trial. Included in Table 18 are the Top 15 Pathway maps (p<0.05), excluding non-relevant tissues or diseases.Table 18 includes immune response and protein folding regulation pathways significantly altered in CSF as determined by pathway analysis.

[0709] Meta-analysis and Comparative Analyses: Common Diff Ex proteins between SPARC v2.0; SHINE-A v2.0; and Meta-Analysis (using SPARC v2.0; SHINE-A v2.0)

[0710] Objectives: A meta-analysis of CSF proteomes from Alzheimer’s disease (AD) patients from the SHINE and SPARC clinical trials was performed to identify pharmacodynamic biomarkers of the sigma-2 receptor (S2R) modulator CT1812.

[0711] Methods: Tandem-mass tag mass spectrometry (TMT-MS) proteomics measurements on CSF from patients in two trials, a) the first part of the SHINE trial, SHINE- A, and b) SPARC, were completed and the pharmacodynamic biomarkers of CT1812 were identified along with their impact on AD and synapse biology. Although encouraging findings, replication in larger well-powered studies were needed. Towards this end, a meta-analysis was performed, leveraging the similarities across trials: a) same treatment duration (6 mo), same patient population (mild to moderate AD), and same methods applied to assess CSF proteomes. Collapsing the two studies increased the sample size from N=18 to N=35, resulting in an increased power for statistical analyses to identify pharmacodynamic biomarkers of CT1812 reaching significance across clinical trial cohorts.

[0712] The SHINE-A cohort (CSF) included 36 samples, including baseline and 6mo proteomic data for 18 AD subjects. The placebo group included 7 patients, the 100 mg treatment group included 4 patients, and the 300 mg treatment group included 7 patients. The SPARC cohort (CSF) included 34 samples, including baseline and 6mo proteomic data for 17 AD subjects. The placebo group included 6 subjects, the 100 mg treatment group included 5 subjects, and the 300 mg treatment group included 6 subjects. Overall, the SHINE-A and SPARC multi- consensus (CSF) included 70 samples with baseline and 6mo proteomics data for 35 AD subjects. The placebo group in the consensus group included 13 subjects, the 100 mg treatment group included 9 subjects, and the 300 mg treatment group included 13 subjects.

[0713] The combined data was then analyzed. First, the data was preprocessed to remove batch effects to remove technical variance, followed by an assessment of the treatment effects of CT1812 (CT1812 vs placebo; p < 0.05). Treatment related networks, or modules, were determined by assessing differential expression comparative analyses and pathway analyses. These analyses were completed using MetaCore and STRING, brain mapping, and weighted gene co-expression network analysis (WGCNA). More than 2,000 proteins were detected in each CSF sample. The longitudinal change from baseline was calculated per protein per patient top determine changes in protein expression related to treatment with CT1812 vs placebo. The expression profiles of individual biomarkers were analyzed;- 2,102 proteins were used for downstream analysis (proteins common to SHINE A and SPARC cohorts; less than 50% missingness). Biological pathways were identified that were significantly ( p < 0.05) impacted by CT1812 vs placebo. Finally, a network analysis was performed to identifysummary insights into the method of action of CT1812. In summary, biomarker differential expression analysis was performed (identification of significantly (p<0.05) differentially expressed proteins in drug vs. placebo), followed by assessment of drug impact (deep dive into profiles of individual biomarkers), identification of biological functions and pathways implicated (pathways significantly p<0.05 impacted by drug vs placebo), and creation of a summary level of insights / assessment of drug mechanisms of action (network analysis to identify summary insights into drug mechanisms of action).

[0714] Differential Expression Analysis Identifies CSF Biomarkers of CT1812 after 6 Months of Treatment: 302 proteins were significantly altered (p < 0.05) in CT 1812 vs placebo CSF from AD patients with proteins of interest including 165 downregulated biomarkers, including CLU, APP, SPON1, and SYT7. There were 137 upregulated biomarkers.Table 19 describes proteins significantly altered after 6mo of treatment in the combined dataset of SHINE-A and SPARC.

[0715] Differentially expressed proteins (CT1812 vs placebo; p<0.05) were mapped to previously generated AD brain co-expression network modules built from 516 brain samples with healthy individuals, asymptomatic and symptomatic AD patients to understandhow CSF biomarkers altered by CT1812 might impact brain networks disrupted in AD. These network modules are discussed in Johnson et al. Nat Medicine 26: 769-780 (2020). Top modules represented include (listed in descending order) synapse / neuron module M4, M26 complement / acute phase, M42 matrisome, Ml synapse / neuron, M21 MHC complex / immune, M7 MAPK / metabolism, M14 protein folding, M3 oligo / myelination, M29 glycosylation / ER, MH cell-ECM interaction, M27 extracellular matrix, M9 golgi, and M5 post-synaptic density.

[0716] Priority AD Biomarkers Altered, and Visualization of Clear Separation due to Treatment with CT1812 vs Placebo: Biomarkers implicated in AD pathology were significantly regulated by CT1812 treatment. Table 20 lists 11 AD priority biomarkers were found to be significantly regulated by CT1812 vs placebo.Table 20 includes a list of informative biomarkers.

[0717] Examples of most highly significant biomarkers illustrate robust treatment effects are illustrated in FIG. 10, including the M41 ambiguous module, the M 1 synapse / neuron module, the M3 oligo / myelination module, and another module.

[0718] Comparative analyses point to robust candidate pharmacodynamic biomarkers of CT1812: Table 21 is a list of biomarkers identified, including three biomarkers identified in both SHINE-A and SPARC that were not identified in the meta-analysis(SERPINA1, GALC and NPC1). 77 biomarkers were identified solely in the SHINE-A analysis, 307 biomarkers were identified solely in the SPARC analysis. 3 biomarkers were identified in both of the SHINE-A and SPARC analyses but not the meta-analysis. As mentioned, 59 biomarkers were identified in the SHINE-A, SPARC, and meta-analysis. 108 biomarkeers were identified in the SHINE-A and meta-analysis, 226 biomarkers were identified in the SPARC and meta-analysis. 151 biomarkers were solely identified in the meta- analysis. Biomarker replication (statistical significance and directionality) across two independent cohorts was observed (the 59 combined biomarkers at p<0.1).Table 21 includes a list of biomarkers identified using a comparative analysis assessing the overlap of biomarkers identified from independent cohorts and analyses.

[0719] Example 3: Meta-Analysis of SHINE-A and SPARC Clinical Trials

[0720] Comparative analyses point to robust candidate pharmacodynamic biomarkers of CT1812: A comparative analysis assessing the overlap of biomarkers identified from independent cohorts and analyses was performed. Biomarker replication (statistical significance and directionality) across two independent cohorts was observed (5 biomarkers at p<0.05, see Table 22). 122 biomarkers were identified in the SHINE-A analysis and 256 were identified in the SPARC analysis. 40 biomarkers were identified only in the SHINE-A analysis, and 167 biomarkers were identified only in the SPARC analysis. One biomarker was identified in both SHINE-A and SPARC analysis, NPC 1 , which is interesting because it was shown to directly bind TMEM97, but it moved in different directions across trials. 66 biomarkers were identified in both the SHINE-A and meta-analysis but not in the SPARC analysis, and 79 biomarkers were identified in both the SPARC and meta-analysis but not in the SHINE-A analysis.Table 22 is a list of the five biomarkers identified in the SHINE-A, SPARC and meta-analysis.

[0721] Network Analysis Identifies Treatment- Associated Networks Illuminating Mechanistic Insights of CT1812 in AD patients'. WGCNA was used to identify networks (modules) of proteins that are co-expressed longitudinally across patients. Seven out of 20 modules were significantly associated with treatment (CT1812 vs placebo, FIG. 11A and FIG.1 IB), including MH : Cell-ECM Interaction, M7: MAPK / Metabolism, MIO: Ambiguous, M12: Cytoskeleton, M8: Protein Transport, M15: Ambiguous, and M2: Mitochondria.

[0722] Conclusions'. This meta-analysis allowed for the assessment of CT1812 treatment effects on CSF biomarkers by increasing the power for statistical analyses. 302 pharmacodynamic biomarkers of CT1812 were identified. Brain network mapping and Pathway analysis of differentially abundant proteins supports a prominent role of CT1812 in synaptic biology. Priority AD biomarkers were identified, and comparative analyses illuminated robust candidate pharmacodynamic biomarkers of CT1812, that replicate across independent trials / patient cohorts and / or analyses, further highlighting a prominent role of CT1812 in regulating synaptic and Ap biology. Network analysis identified networks in CSF that were significantly associated with CT 1812 treatment, enabling further mechanistic understanding of how CT1812 may impact patients with Alzheimer’s disease. The networks altered included hub proteins such as Prion protein (PRNP) known to interact with S2R, and APP, known to be regulated by PRNP.

[0723] Example 4: SEQUEL Clinical Trial

[0724] SEQUEL (COG0202): Single-site qEEG Study in 16 Adults with Mild-to- moderate Alzheimer’s Disease: The SEQUEL study was a two-group cross-over design. Inclusion criteria included CSF positive for Ap, an MRI consistent with AD diagnosis, and MMSE 18-26. For the first period of 29 days, 8 patients were treated with 300 mg of CT1812 and 8 patients were treated with placebo (oral QD administration). For the second period of 29 days, the 8 patients first treated with CT 1812 were treated with placebo, and the 8 patients first treated with placebo were treated with CT 1812 300 mg. Assessments included safety and pK, measurement of synaptic function via qEEG (primary theta power, secondary alpha power), CSF and plasma biomarkers. Quantitative EEG (qEEG) refers to the analysis of digital EEG signals using sophisticated mathematical algorithms that can identify and differentiate between nuances of brain wave patterns.

[0725] Method: Participants were randomized to receive 29 days of either CT1812 (300 mg, PO, qD) or placebo during the first treatment period. Following a two-week washout, participants then switched treatment for another 29 days period. Tandem-mass tag mass spectrometry (TMT-MS) proteomics was performed on CSF collected at baseline, day 29 (immediately after the first treatment period) and day 72 (immediately following the second treatment period). Treatment effects were assessed through differential abundance analysesusing two statistical levels (p<0.1, p<0.05) followed by pathway analyses (MetaCore, STRING).

[0726] Differential Expression Analysis Identifies CSF Biomarkers of CT1812 after 29 Days of Treatment: 163 proteins were significantly altered (p < 0.05) in CT1812 vs placebo CSF from AD patients, including 36 downregulated proteins and 127 upregulated proteins.Table 23 includes a list of biomarkers significantly altered in the SEQUEL study.

[0727] Pathway Analysis Identify Cholesterol, Lipoprotein Biology, and Wnt Signaling Pathways Significantly Altered in CSF: Differentially abundant proteins at p<0.05 in CSF samples were analyzed for pathway enrichment using Metacore (v. 23.2.71300) and STRING pathway analysis (v. 12.0). Top pathways are listed below (non-relevant disease pathologies / organs excluded).

[0728] Top Metacore Pathway Maps identified with p<0.05 include protein folding and maturation: Bradykinin / Kallidin maturation (p < 5.92E-11), cell adhesion: ECM remodeling (p < 2.98E-06), cell adhesion: cell-matrix glycoconjugates (p < 8.13E-06), lipoprotein metabolism (p < 1.04E-05), and development: ErbB3 signaling (p < 9.85E-05). Proteins identified included G0:0060228 with phosphatidylcholine-sterol O-acyltransferase activator activity, at a strength of 1.95 (p < 5.8E-04); G0:0031210 with phosphatidylcholine binding activity at a strength of 1.27 (p < 2.7E-02); G0:0017147 with wnt-protein binding activity at a strength of 1.25 (p < 2.8E-02); G0:0015485 with cholesterol binding activity at a strength of 1.11 (p < 1.8E-02), and G0:0005539 with glycosaminoglycan binding activity at a strength of 1.06 (p < 3.3E-12).

[0729] Conclusions - CT1812 treatment: These results provide insight into potential pathway engagement biomarkers of CT1812 after 29 days of treatment. The analysis indicate that biological pathways, including cholesterol, lipid biology, inflammation, and WNT / p-catenin signaling are impacted by CT1812 treatment.

[0730] SEQUEL Correlation Analysis with EEG Background and Purpose of the Study: The goal of the SEQUEL study was to identify CT1812-driven correlates of functionalconnectivity that may be pharmacodynamic biomarkers of CT1812 linked to EEG parameters. Synaptic function and brain functional connectivity is impaired in Alzheimer’s disease (AD), and in the SEQUEL clinical trial in AD patients, it has been shown that CT 1812 can favorably impact the brain functional connectivity as measured by the quantitative EEG measure Amplitude Envelope Correction (AECc 0.034).

[0731] Correlation Analysis Workflow: Following CSF sample analysis via TMT- proteomics, Pearson correlation analyses were performed on the change from baseline values across multiple AECc parameters and on each protein in the CSF proteome (p<0.05) from CT1812-treated only patients (n=8). Proteins determined to be correlates only in the CT1812- treated group were subject to pathway analyses using STRING (vl2.0) (p<0.05).Table 24 includes proteins determined to be correlated in the SEQUEL study.

[0732] Proteasome, secretory granule, extracellular exosome are among the top biological processes associated with Global alpha AECc

[0733] Table 25 is a list of biological process identified using STRING pathway analysis. STRING was performed for a list of 160 proteins (p<0.05) correlated with Global alpha AECc only in the CT1812-treated group. GO terms sorted by strength.Table 25

[0734] Comparative Analyses of Correlates Across Multiple alpha AECc Parameters: Sets of proteins were identified to be significantly correlated using Pearson correlation analyses with global alpha AECc power, Temporal AECc and Parieto Occipital AECc. There were 18 proteins identified only in the global alpha AECc analysis, 101 proteins identified only in the temporal AECc analysis, and 27 proteins identified only in the parieto occiptal AEc. 36 proteins were identified both in the global alpha AECc and the temporal AECc analyses, 7 proteins were identified both in the temporal AECc and parieto occiptal analyses, and 16 proteins were identified both in the parieto occiptal and global alpha AECc analyses. 42 proteins were identified in all three analyses, which are listed in Table 26 (p<0.05).Table 26 lists the 42 proteins identified in all three AECc analyses.

[0735] STRING Pathway analysis (vl2.0) indicated an impact on proteasomal (PSMA, PSMB), extracellular exosomal (WNT4, ALDH1A1) and vesicular (PRDX2) biologies, with implicated proteins listed in Table 27.Table 27 lists biological process identified with STRING pathway analysis for AECc parameters.

[0736] Conclusion: Potential CT1812 molecular correlates to parameters of brain activity as assessed via EEG and were identified, along with potential surrogate candidate biomarkers of an impact of CT1812 on brain activity. Proteins highly correlated to Global Alpha AECc are associated with AD phenotype and pathways related to proteasome, secretory granule and extracellular exosome biologies. Comparative analyses across multiple alpha AECc parameters identified proteins associated to biological pathways, e.g vesicle, relevant to CT1812 mechanisms of action.

[0737] SEQUEL correlation analysis with aSyn Background and Purpose of the Study: The presynaptic protein a-synuclein (aSyn), mainly associated with synucleinopathies like Parkinson and dementia with Lewy bodies, is also involved in the pathophysiology of Alzheimer’s disease. Higher levels of aSyn in the CSF of patients with AD have been linked to cognitive decline. Preclinical evidence indicates that CT1812 can displace toxic amyloid-p oligomers (ApO) and aSyn oligomers from binding to neuronal synapses.

[0738] The goals of the study were to understand if the small molecule CT1812 can modulate aSyn CSF level in the AD patients enrolled in the SEQUEL trial and to identify proteins that highly correlated with the aSyn CSF level changes.

[0739] Analysis of CSF Samples from a Phase 2 Clinical Trial in Alzheimer's Patients shows that CT1812 can modulate a-synuclein. After 29 days, a statistically significantchange from placebo was seen for aSyn in CSF samples of CT1812-treated patients (placebo n=7; CT1812-treated patients n=5; p<0.05 Student's t-test, FIG. 12).

[0740] Following CSF sample analysis via TMT-proteomics, Pearson correlation analysis was performed between CSF aSyn levels and each protein in the CSF proteome (p<0.05 andp<0.01) from CT1812-treated only patients (n=5) to identify proteins that correlate to aSyn. Correlated proteins were subjected to pathway analyses using STRING (vl2.0) and Metacore (v23.4.71500) using two different p-value criteria (p<0.05 and p<0.01 ).Table 28 lists proteins identified as correlating with treatment in the SEQUEL study aSyn analyses.

[0741] aSyn Correlates are Connected to S2R Complex Components: STRING analysis illustrated the interconnectivity between the top 50 correlates to aSyn CSF levels in CT1812-treated only patients (p<0.01 r=|0.9|). The top 50 proteins correlating to alphaSyn CSF levels were highly interconnected per STRING analysis. The S2R complex components (TMEM97 (S2R)), were added to this analysis to understand the relationship to CT1812’s mechanism of action through S2R, PRNP and PGRMC1 and aSyn (SNCA). S2R, PRNP and PGRMC1 and aSyn proteins were highly connected to the proteins identified in the aSyn analysis.

[0742] Pathway Analyses Identify Immune Response, Protein Folding and Maturation Pathways Significantly Associated to aSyn Correlates: aSyn-correlated proteins (p<0.05; p<0.01; r>|0.7|) were analyzed for pathway enrichment using Metacore (v23.4.71500). Top pathways are listed in Table 29 (non-relevant disease pathologies / organs excluded).Table 29 is a list of pathways identified with Metacore analysis on aSyn correlates.

[0743] GO Terms Complement, Synaptic and Dopamine Metabolic Processes are Associated with aSyn Correlates.Table 30 is a list of results from STRING (v 12.0) pathway analysis of correlates to aSyn CSF levels in CT1812-treated only patients (p<0.05; p<0.01; r>|0.7|). GO terms sorted by strength.

[0744] A significant decrease in CSF total aSyn levels was observed in AD patients after 29 days of treatment with CT1812. Proteins highly correlated to CSF aSyn levels were associated with AD phenotype and pathways related to complement, inflammation and synapse biology. Protein-protein interaction mapping showed a highly interconnected network with aSyn as a hub, and illustrated the connectivity with proteins comprising S2R.

[0745] Example 5: Correlates Across All Trials

[0746] Correlates Identified that Replicate Across Independent Cohorts / Trials: Commonly correlated proteins were determined by combining analyses of EEG (multipleparameters), ADAS-Cogl l and vMRI (multiple regions) across the SHINE, SEQUEL and SPARC trials, using data from drug only treatments and including only treatment compliant subjects, when correlations were p <0.05. Including all the analyses, 61 proteins were correlated in all three trials; 85 proteins were correlated in both SHINE and SEQUEL trials but not the SPARC trial; 52 proteins were correlated in the SEQUEL and SPARC trials but not the SHINE trial; 103 proteins were correlated in the SPARC and SHINE trials but not the SEQUEL trial; 331 proteins were correlated only in the SHINE trial, 377 proteins were correlated only in the SEQUEL trial, and 287 proteins were correlated only in the SPARC trial.

[0747] Correlation analysis was completed for synaptic function measured with the quantitative EEG measures global (primary) theta power, secondary (central) theta power, and amplitude envelope correction (AECc) in the SEQUEL clinical trial (29 days). All correlate lists for different parameters in the EEG studies were combined. In the combined analysis, the global relative theta power was correlated at p=0.123. The central relative theta power was correlated at p=0.006. The global alpha AECc was correlated at p=0.034. The temporal alpha AECc was correlated at p=0.02. The parieto occipital alpha AECc was correlated at p=0.04.

[0748] Correlation analysis was also completed for all ADAS-Cogl l data (6 months). In addition, correlation analysis for volumetric MRI (6 ...

Claims

CLAIMSWhat is Claimed is:

1. A method of reducing or maintaining an Alzheimer’s Disease Assessment Scale- Cognitive (ADAS-Cog) score in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to Formula I:wherein:Ri and R2 are each independently selected from H, C a1l-kCy6l, or CH2OR1; where R1= H or C1-C6alkyl;R3, R4, Rs, and Re are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1- C6alkyl)OH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl,C1-C6hydroxyalkyl, C1-6alkoxy Ci -ealky 1, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4 alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4alkyl), and C(O)NH(C1-4alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-Ce haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1-yl, piperidin- 1 -yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(C1-4alky 1)2, wherein optionally substituted group is selected from alCky1-lC o6r C2-C7 acyl; or R3 and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, hetero arylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are eachindependently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2 methylene-O- group; or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a -O-C1-2 methylene-O- group;R7, Rs, R9, Rio, and Rn are each independently selected from H, C1-C a6lkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1- hCy6droxyalkyl, C 1-6 alkoxy Cuealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(CI-4 alkyl), N(C1-4alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(Cn4allcyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 allcyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl, aryl, alkylaryl, piperazin- 1 -yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(C1-4alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R7 and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group, wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:

2. The method of claim 1, wherein the compound of Formula I is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the pharmaceutically acceptable salt is the fumarate salt.

4. The method of claim 1, wherein the compound of Formula I isor a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the pharmaceutically acceptable salt is the fumarate salt.

6. The method of any one of claims 1-5, wherein the compound of Formula I is administered for at least about 6 months.

7. The method of any one of claims 1-5, wherein a therapeutically effective amount of the compound of Formula I is from about 0.0001 mg to about 1120 mg.

8. The method of any one of claims 1-5, wherein a therapeutically effective amount of the compound of Formula I is about 100 mg to about 300 mg.

9. The method of any one of claim 1-5, wherein the ADAS-Cog test is an ADAS-Cog 11 test or an ADAS-Cog 13 test.

10. The method of any one of claims 1-5, wherein administering the compound results in an increase in expression of biomarkers selected from MYO 19, CMBL, ABHD14B, CAMK2D, NCAM1, PLXND1, JCHAIN, FAM20C, MXRA7, APCS, DNAJB2, F13B, LGALS3, SORCS1, IGHV3-48, TKT, IGHM, GPI, F13A1, CFP, CD5L, IGLV1-40, SPP1, KRT17, FSTL1, LPHN1, GFRA1, MBL2, ADIPOQ, GANAB, BGLAP, ADAM22, B2M, PILRA, LUM, RAB10, PMP2, IGKV2D-29, EIF3J, PCP4, IGHD, ENOPH1, TCN2, ACP2, LXN, RAB14, ATIC, APOB, KIRREL3, CHPF, YWHAE, CSTB, ARF3, RHOA, JAML, ARHGDIA, PTPRS, AK1, IGF1, CFHR5, APOL1, SH3BGRL3, RIN2, PCDHGC3, AP2A1, MET, KIAA0100, PLS3, CDH18, CRK, FBLN2, HSPA1B, SEMA4C, YWHAG, PPIA, TAGLN2, PGLS, IGLV1-47, RNH1, SCN4B, PAFAH1B1, YWHAZ, GLOD4, TBCA, MDK, CAST, A2M, IGLV1-36, GRIA4, FZD1, DCTN2, PODN, USP14, CNDP1, TXNDC17, COL6A1, VCL, OMG, CNPY3, LANCL1, COLECI 1, LASPI, TPM1, NUDT5, IGKC, MTPN, GLO1, PRDX1, LRP8, PPP2R1A, VM01, ARSG, VAT1, CBLN1, REEP2, IGHV4-59, GPLD1, CAPZA1, ENO1, IDH1, C4BPB, NME2, IGHA2, TXN, GALNT10, CREB3L3, TPD52L2, CXCL16, FAM177A1, PRG4, NPC1, NPC2, and combinations thereof.

11. The method of any one of claims 1-5, wherein administering the compound results in an increase in expression of biomarkers comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

12. The method of any one of claims 1-5, wherein administering the compound results in a decrease in expression of biomarkers comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

13. The method of any one of claims 1-5, wherein the reduction or maintenance of the ADAS-Cog score is correlated with modulation of biological processes or biological pathways selected from astrocyte activation involved in immune response; gephyrin clustering involved in postsynaptic density assembly, postsynaptic density protein 95 clustering; negative regulation of metallopeptidase activity, response to vitamin K, regulation of postsynaptic density assembly, regulation of opsonization, positive regulation of aspartic- type peptidase activity, glomerulus morphogenesis, neuron cell-cell adhesion, regulation of aspartic-type peptidase activity, regulation of tau-protein kinase activity, positive regulation of protein kinase A signaling; negative regulation of dendritic spine development; regulation of endothelial cell chemotaxis; neuro ligin clustering involved in postsynaptic membrane assembly; gephyrin clustering involved in postsynaptic density assembly; postsynaptic density protein 95 clustering; positive regulation of amyloid fibril formation; NMDA glutamate receptor clustering; negative regulation of dendritic spine maintenance; vocal learning; postsynaptic membrane assembly; positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process; neurotransmitter-gated ion channel clustering; negative regulation of dendritic spine development; neuron cell-cell adhesion; postsynaptic membrane organization; positive regulation of amyloid precursor protein catabolic process; response to auditory stimulus; positive regulation of excitatory postsynaptic potential; regulation of presynapse assembly; receptor clustering; regulation of dendritic spine development; calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules, and combinations thereof.

14. The method of any one of claims 1-5, wherein administering the compound results in a reduction in the level of a-synuclein.

15. The method of any one of claims 1-5, wherein administering the compound results in a reduction in the level of Ap.

16. The method of claim 15, wherein the Ap is Ap40, Ap42, or a combination of both.

17. The method of any one of claims 1-5, wherein the reduction in the ADAS-Cog score is correlated with a change in synaptic function.

18. The method of claim 17, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

19. The method of claim 18, wherein the qEEG is measured by primary theta power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

20. The method of any one of claims 1-5, wherein the subject has been diagnosed with a synucleinopathy.

21. The method of claim 20, wherein the synucleinopathy is Dementia with Lewy Bodies.

22. The method of any one of claims 1-5, wherein the subject has been diagnosed with Alzheimer’s disease.

23. The method of any one of claims 1-5, wherein the subject is aged less than 50 years.

24. The method of any one of claims 1-5, wherein the subject is aged between 50 and 80 years.

25. The method of any one of claims 1-5, wherein the subject has a mini-mental state examination (MMSE) score between about 18-26.

26. The method of any one of claims 1-5, wherein the subject has an MMSE score greater than, or equal to 24.

27. A method of reducing levels of a-synuclein (aSyn) in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to FormulaI:wherein:Ri and R2 are each independently selected from H, C1-C a6lkyl, or CH2OR1; where R1= H or C1-C a6lkyl;R3, R4, Rs, and Re are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-Ce haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(CI-4 alkyl), N(C1-4alkyl)2, NH(Cw cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4 alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(CI-4 alky 1)2, wherein optionally substituted group is selected from aClky1-lC6or C2-C7 acyl; or R3 and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2 methylene-O- group; or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a -O-C1-2 methylene-O- group;R7, Rs, R9, Rio, and Rn are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1- hCy6droxyalkyl, C 1-6 alkoxy Cuealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4alkyl)2, NH(C3.7cycloalkyl), NHC(O)(Cn4allcyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 allcyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl, aryl, alkylaryl, piperazin- 1 -yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(C1-4alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R7 and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group, wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:

28. The method of claim 27, wherein the compound of Formula I is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the pharmaceutically acceptable salt is the fumarate salt.

30. The method of claim 27, wherein the compound of Formula I isor a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the pharmaceutically acceptable salt is the fumarate salt.

32. The method of any one of claims 27-31, wherein the level of a-synuclein (aSyn) is reduced by about 5% to about 90%.

33. The method of any one of claims 27-31, wherein administering the compound results in an increase in expression of biomarkers comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1- 17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

34. The method of any one of claims 27-31, wherein administering the compound results in a decrease in expression of biomarkers comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

35. The method of any one of claims 27-31, wherein the reduction in the level of a-synuclein (aSyn) is correlated with modulation of biological processes or biological pathways comprising positive regulation of axon extension involved in axon guidance; positive regulation of dopamine metabolic process; complement activation, alternative pathway; cytolysis; complement activation, classical pathway; complement activation; chaperone- mediated autophagy; complement activation, alternative pathway; regulation of insulin-like growth factor receptor signaling pathway; positive regulation of synapse assembly; immune response-alternative complement pathway; immune response-alternative complement pathway; immune response-alternative complement pathway; protein folding and maturation, posttranslational processing of neuroendocrine peptides; neurophysiological process synaptic vesicle fusion and recycling in nerve terminals; protein folding and maturation- posttranslational processing of neuroendocrine peptides; neurophysiological process-synaptic vesicle fusion and recycling in nerve terminals; immune response-classical complement pathway; immune response-alternative complement pathway; transport RAB3 regulation pathway, or combinations thereof..

36. The method of any one of claims 27-31, wherein the reduction in the level of a-synuclein (aSyn) is correlated with modulation of biomarkers selected from PCDHGB5, IGKV1D-43, FAM177A1, HSPA8, PLXDC1, LING01, SERPINA5, TNFSF8, SIRPB2, CDH13, DCBLD1, NA, IGKV6-21, NRSN2, GMFB, SERPINA3, GL0D4, RAP1B, IGLV3-10, FREM2, RET, IGF2, CD48, ADAMTS16, VM01, GSS, IGKV3D-7, F9, ITM2C, LRG1, DYNLL1, SNX3, SHISA6, FSCN1, ADAMTS13, TPBG, PGM1, DPP10, CDH9, GDA, NCL, SYN2, GFER, IGFBP5, IGFBP2, DMXL2, HLA-DPB1, ABCA13, PEPD, IGHV3-73, IGKV1D-13, LRIG1, FZD8, NAXE, RARRES2, APCS, SLITRK1, IGKV1-9, ADA, CSF1, SLPI, CFAP54, SEMA3B, PPP1R13B, OXT, CCL18, IGKV2-40, ISLR2, ADAMTS4, APOH, and combinations thereof.

37. The method of any one of claims 27-31, wherein administering the compound results in a reduction in the level of Ap.

38. The method of claim 37, wherein the Ap is Ap40, Ap42, or a combination of both.

39. The method of any one of claims 27-31, wherein the reduction in the level of a-synuclein (aSyn) is correlated with a change in synaptic function.

40. The method of claim 39, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

41. The method of claim 40, wherein the qEEG is measured by primary theta power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

42. A method of reducing levels of Ap in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to Formula I:wherein:Ri and R2 are each independently selected from H, C1-C a6lkyl, or CH2OR1; where R1= H or C1-C a6lkyl;R3, R4, Rs, and Re are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-Ce haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4alkyl)2, NH(Cw cycloalkyl), NHC(O)(CI-4 allcyl), CONR'2, NC(O)R', NS(O)nR’, S(O)nNR'2, S(O)nR, C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 allcyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, Cs-Ce alkyl, C1-C6haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1 -yl, piperidin- 1 -yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4 alkyl), or NH(CI-4 alkyl)2, wherein optionally substituted group is selected from C al1k-yCl6or C2-C? acyl; or R3and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4, or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3and R4 are linked together to form a -O-C1-2 methylene-O- group; or R4 and Rs, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and Rs are linked together to form a -O-C1-2 methylene-O- group;R7, Rs, R9, Rio, and Rn are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1- hCy6droxyalkyl, C 1-6 alkoxy Cuealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(CI-4 alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(C1-4allcyl), CONR'2, NC(O)R',NS(O)nR', S(O)nNR'2, S(O)nR', C(0)0(C1-4 alkyl), OC(O)N(R’)2, C(0) (C1-4alkyl), and C(0)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl, aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(C1-4alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R7 and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group, wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:

43. The method of claim 42, wherein the compound of Formula I is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the pharmaceutically acceptable salt is the fumarate salt.

45. The method of claim 42, wherein the compound of Formula I isor a pharmaceutically acceptable salt thereof.

46. The method of claim 45, wherein the pharmaceutically acceptable salt is the fumarate salt.

47. The method of claim 42, wherein the Ap is Ap40, Ap42, or a combination of both.

48. The method of any one of claims 42-46, wherein the level of Ap is reduced by about 5% to about 90%.

49. The method of any one of claims 42-46, wherein administering the compound results in an increase in expression of biomarkers selected from IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

50. The method of any one of claims 42-46, wherein administering the compound results in a decrease in expression of biomarkers selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

51. The method of any one of claims 42-46, wherein the reduction in the level of Ap is correlated with modulation of biomarkers selected from FABP1, GPNMB, HLA-B, SERPINA, POFUT2, SV2A, ESMI, APA2, and combinations thereof.

52. The method of any one of claims 42-46, wherein the reduction in the level of Ap is correlated with modulation of biological processes or biological pathways comprising negative regulation of lipoprotein lipase activity; chylomicron remnant clearance, chylomicron remodeling, triglyceride-rich lipoprotein particle remodeling, negative regulation of complement activation; positive regulation of synapse assembly, regulation of complement activation, positive regulation of cell junction assembly, artery morphogenesis, platelet degranulation, and combinations thereof.

53. The method of any one of claims 42-46, wherein the reduction in the level of Ap is correlated with a change in synaptic function.

54. The method of claim 53, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

55. The method of claim 54, wherein the qEEG is measured by primary theta power, secondary alpha power, Amplitude Envelope Correction (AECc), and combinations thereof.

56. A method of restoring synaptic function in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to Formula I:wherein:Ri and R2 are each independently selected from H, C1-C a6lkyl, or CH2OR1; where R1= H or C1-C a6lkyl;R3, R4, Rs, and Re are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2, C1-Ce haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(CI-4 alkyl), N(C1-4alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4 alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(CI-4 alky 1)2, wherein optionally substituted group is selected from aClky1-lC6or C2-C7 acyl; or R3 and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2 methylene-O- group; or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a -O-C1-2 methylene-O- group; R7, R8, R9, R10, and R11are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1- hCy6droxyalkyl, C 1-6 alkoxy C1-6aklyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4alkyl)2, NH(C3.7cycloalkyl), NHC(O)(Cn4allcyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 allcyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl, aryl, alkylaryl, piperazin- 1 -yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(C1-4alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R7 and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group, wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:

57. The method of claim 56, wherein the compound of Formula I is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the pharmaceutically acceptable salt is the fumarate salt.

59. The method of claim 56, wherein the compound of Formula I isor a pharmaceutically acceptable salt thereof.

60. The method of claim 59, wherein the pharmaceutically acceptable salt is the fumarate salt.

61. The method of any one of claims 56-60, wherein the synaptic function is measured by quantitative electroencephalogram (qEEG).

62. The method of claim 61, wherein the qEEG is measured by primary theta power, global relative theta power, centra relative theta power, secondary alpha power, Amplitude Envelope Correction (AECc), global alpha AECc, temporal alpha AECc, parieto-occipital AECc, and combinations thereof.

63. The method of any one of claims 56-60, wherein administering the compound results in an increase in expression of biomarkers selected from IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

64. The method of any one of claims 56-60, wherein administering the compound results in a decrease in expression of biomarkers selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

65. The method of any one of claims 56-60, wherein the AECc is correlated with modulation of biological processes or biological pathways comprising extracellular space; proteasome core complex, alpha-subunit complex; extracellular exosome; vesicle; extracellular region; proteasome core complex; collagen type I trimer; proteasome core complex, alpha-subunit complex; fibrillar collagen trimer; proteasome core complex; endoplasmic reticulum lumen; secretory granule lumen; extracellular matrix; collagen-containing extracellular matrix; extracellular exosome, and combinations thereof.

66. The method of any one of claims 56-60, wherein the AECc is correlated with modulation of biomarkers comprising ALDH1A1, ALDH9A1, BAMBI, BTN2A2, CHST7, COL1A2, EIF4B, FAHD1, FZD3, FZD6, GAS1, GRIA3, GXYLT1, HBG1, HIBADH, JAM2, LRRN1,LYPLA1, MATN2, METRNL, NHLRC3, N0TCH1, NTM, OAF, PCDH9, PGLS, PIK3IP1, PNP, PRDX2, PRG2, PSMA1, PSMA4, PSMA6, PSMB7, SECTM1, SLC4A1, SLIT3, SNX12, ST6GAL2, TKT, UBE2N, WNT4, and combinations thereof.

67. The method of any one of claims 56-60, wherein administering the compound results in a reduction in the level of a-synuclein.

68. The method of any one of claims 56-60, wherein administering the compound results in a reduction in the level of Ap.

69. The method of claim 68, wherein the Aβ is Ap40, Ap42, or a combination of both.

70. The method of any one of claims 56-60, wherein the subject has been diagnosed with a synucleinopathy.

71. A method of slowing neurodegeneration in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to Formula I:wherein:Ri and R2 are each independently selected from H, C1-C a6lkyl, or CH2OR1; where R1= H or C1-C a6lkyl;R3, R4, Rs, and Re are each independently selected from H, C1- C6alkyl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyljOH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2,C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4 alkyl), OC(O)N(R’)2, C(O) (C1-4alkyl), and C(O)NH(C1-4alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1-yl,piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4 alkyl), or NH(CI-4 alkyl)2, wherein optionally substituted group is selected from C al1k-yCl6or C2-C7 acyl; or R3 and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2 methylene-O- group; or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a -O-C1-2 methylene-O- group;R7, Rs, R9, Rio, and Rn are each independently selected from H, C1- aClk6yl, OH, 0CH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6 haloalkyl, C1h-Cyd6roxyalkyl, C 1-6 alkoxy Cuealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(CI-4 alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(C1-4allcyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR, C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 allcyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6 haloalkyl, aryl, alkylaryl, piperazin- 1 -yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(C1-4alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R? and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group, wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:

72. The method of claim 71, wherein the compound of Formula I is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

73. The method of claim 72, wherein the pharmaceutically acceptable salt is the fumarate salt.

74. The method of claim 71, wherein the compound of Formula I isor a pharmaceutically acceptable salt thereof.

75. The method of claim 74, wherein the pharmaceutically acceptable salt is the fumarate salt.

76. The method of any one of claims 71-75, wherein the neurodegeneration is measured by volumetric magnetic resonance imaging (vMRI).

77. The method of any one of claims 71-75, wherein administering the compound reduces the vMRI.

78. The method of any one of claims 71-75, wherein administering the compound results in an increase in expression of biomarkers comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1- 17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

79. The method of any one of claims 71-75, wherein administering the compound results in a decrease in expression of biomarkers comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, 0LFM1, OLFML3,PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

80. The method of any one of claims 71-75, wherein the vMRI is correlated with modulation of biomarkers comprising C4B; C4B 2, SERPINB1, PTN, IGLV1-51, CNNM3, ADAM9, IGLV1-36, PZP, C4B; C4B 2, KIT, COL5A1, C4BPA, UBE2N, CCT7, FCN3, CFP, FCN2, SMPDL3B, IGLC7, NXPH3, PGD, CACNA2D2, CLP1, UBE2L3, IGHV3-21, FN1, PSMB7, PGLS, C4A, MDGA1, C4BPB, IGLV2-11, PPBP, UFM1, NCALD, TLN1, TXNL1, and combinations thereof.

81. The method of any one of claims 71-75, wherein administering the compound results in a reduction in the level of a-synuclein.

82. The method of any one of claims 71-75, wherein administering the compound results in a reduction in the level of Ap.

83. The method of claim 82, wherein the Ap is Ap40, Ap42, or a combination of both.

84. A method of restoring protein expression in a subject with or at risk of developing a synucleinopathy, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to Formula I:wherein:RI and R2 are each independently selected from H, C1-C a6lkyl, or CH2OR1; where R1= H or C1-C a6lkyl;R3, R4, Rs, and Re are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyljOH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2,C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4alkyl)2, NH(Cw cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR’, S(O)nNR'2, S(O)nR, C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 allcyl), and C(0)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CHa, C3-C6alkyl, C1-C6haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1 -yl, piperidin- 1 -yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(CI-4 alkyl)2, wherein optionally substituted group is selected from C al1k-yCl6or C2-C? acyl; or R3 and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2 methylene-O- group; or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a -O-C1-2 methylene-O- group;R7, Rs, R9, Rio, and R11 are each independently selected from H, C a1l-kCy6l, OH, 0CH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1- hCy6droxyalkyl, C 1-6 alkoxy Cuealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4 alkyl), N(C1-4alkyl)2, NH(C3-7 cycloalkyl), NHC(O)(Cn4alkyl), CONR’2, NC(O)R’, NS(O)nR', S(O)nNR'2, S(O)nR, C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl, aryl, alkylaryl, piperazin- 1 -yl, piperidin- 1-yl,morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4alkyl), or NH(C1-4alkyl)2; or R? and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R7 and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group, wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:

85. The method of claim 84, wherein the compound of Formula I is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

86. The method of claim 85, wherein the pharmaceutically acceptable salt is the fumarate salt.

87. The method of claim 84, wherein the compound of Formula I isor a pharmaceutically acceptable salt thereof.

88. The method of claim 87, wherein the pharmaceutically acceptable salt is the fumarate salt.

89. The method of any one of claims 84-88, wherein administration results in an increase in expression of the biomarkers.

90. The method of claim 89, wherein the biomarkers are selected from IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

91. The method of any one of claims 84-88, wherein administration results in a decrease in expression of the biomarkers.

92. The method of claim 91, wherein the biomarkers are selected from ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and combinations thereof.

93. The method of any one of claims 84-88, wherein administering the compound is correlated with modulation of biological processes or biological pathways comprising phosphatidylcholine-sterol O-acyltransferase activator activity; phosphatidylcholine binding; wnt-protein binding; cholesterol binding; glycosaminoglycan binding; protein folding and maturation_angiotensin system maturation; Immune response_antigen presentation by MHC class I: cross-presentation; O-glycan biosynthesis; Immune response_antigen presentation by MHC class II; signal transduction_angiotensin II / AGTR1 signaling via Notch, Beta-catenin and NF-kB pathways; immune response_antigen presentation by MHC class I, classical pathway; development_regulation of cytoskeleton proteins in oligodendrocyte differentiation and myelination; renin-angiotensin-aldosterone system; development_PEDF signaling; signal transduction_negative regulation of BMP signaling; signal transduction_angiotensin IE AGTR1 signaling via p38, ERK and PI3K; immune response lL- 11 signaling via JAK / STAT; protein folding and maturation_regulation of amyloid precursor protein processing; signal transduction BMP signaling via BMPR1 A and BMPR1B receptors; development_NOTCH signaling in organogenesis and embryogenesis; protein folding and maturation: bradykinin / kallidin maturation; cell adhesion: ECM remodeling; cell adhesion: cell-matrix glycoconjugates; lipoprotein metabolism; development: ErbB3 signaling, and combinations thereof.

94. The method of any one of claims 84-88, wherein administering the compound results in a reduction in the level of a-synuclein.

95. The method of any one of claims 84-88, wherein administering the compound results in a reduction in the level of Ap.

96. The method of claim 95, wherein the Ap is Ap40, Ap42, or a combination of both.

97. A method of treating Alzheimer’s disease in a subject in need thereof, comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof, according to Formula I:wherein:RI and R2 are each independently selected from H, C1-C a6lkyl, or CH2OR1; where R1= H or C1-C a6lkyl;R3, R4, Rs, and Re are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), F, Cl, Br, I, CF3, CN, NO2, NH2,C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-6alkoxy C1-ealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(C1-4alkyl), N(C1-4alkyl)2, NH(Cw cycloalkyl), NHC(O)(C1-4alkyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4 alkyl), OC(O)N(R’)2, C(O) (C1-4 alkyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R1are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl; or optionally substituted aryl, alkylaryl, piperazin- 1-yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(C1-4 alkyl), or NH(CI-4 alky 1)2, wherein optionally substituted group is selected from alCky1-lC6or C2-C7 acyl; or R3 and R4, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R3 and R4 are linked together to form a -O-C1-2 methylene-O- group;or R4 and R5, together with the C atom to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heteroaryl, or heterocycloalkyl that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R3and R4or R4and R5, are each independently selected from a bond, C, N, S, and O; or R4 and R5 are linked together to form a -O-C1-2 methylene-O- group;R7, Rs, R9, Rio, and Rn are each independently selected from H, C1- aClk6yl, OH, OCH3, OCH(CH3)2, OCH2CH(CH3)2, OC(CH3)3, O(C1-C6alkyl), OCF3, OCH2CH2OH, O(C1-C6alkyl)OH, O(C1-C6haloalkyl), O(CO)R’, F, Cl, Br, I, CF3, CN, NO2, NH2, C1-C6haloalkyl, C1- hCy6droxyalkyl, C 1-6 alkoxy Cuealkyl, aryl, heteroaryl, C3-7 cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO2R’, C(O)R’, NH(CI-4 alkyl), N(C1-4alkyl)2, NH(C3.7cycloalkyl), NHC(O)(Cn4allcyl), CONR'2, NC(O)R', NS(O)nR', S(O)nNR'2, S(O)nR', C(O)O(C1-4alkyl), OC(O)N(R’)2, C(O) (C1-4 allcyl), and C(O)NH(CI-4 alkyl); where n= 0, 1, or 2; R' are each independently H, CH3, CH2CH3, C3-C6alkyl, C1-C6haloalkyl, aryl, alkylaryl, piperazin- 1 -yl, piperidin-l-yl, morpholinyl, heterocycloalkyl, heteroaryl, C1-6alkoxy, NH(CI-4 alkyl), or NH(CI-4 alkyl)2; or R7 and Rs, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7- or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or R7 and Rs are linked together to form a -O-C1-2 methylene-O- group; or Rs and R9, together with the N or C atoms to which they are attached form a form a 4-, 5-, 6- 7-or 8- membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl and R9and R10are each independently selected from a bond, C, N, S, and O; or Rs and R9 are linked together to form a -O-C1-2 methylene-O- group,wherein each of the O, C1-6alkyl, C1-6haloalkyl, heteroaryl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl is optionally independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH, amino, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; with the proviso that the following compounds are excluded:wherein the administration of the compound according to Formula I results in a decrease in the expression of at least one biomarker, an increase in the expression of at least one biomarker of the subject in need thereof, or a combination of both; wherein the at least one biomarker with decreased expression is selected from the group comprising IGHG1, IGHV3-64, IGHV5-51, IGKV1-17, IGKV2-30, IGLV1-44, IGLV2-18, S100A8, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof; and wherein the at least one biomarker with increased expression is selected from the group comprising ADAMTS8, APLP2, APP, ATP6AP1, B4GAT1, BMP1, CHRD, CHST10, CLU, CNTNAP3, COL6A1, CPE, DDAH1, DNAJC3, ECM2, GDF11, GNPTG, GPR37, HLA-C, HLA-E, HS6ST1, IGSF8, IL6ST, ITIH5, ITM2B, MIA3, NCAM1, NFASC, NRP1, NRXN1, NRXN2, NTNG1, OLFM1, OLFML3, PCDHGC3, PLD3, PRNP, PRSS23, SDF4, SEMA3F, SEMA4B, SEZ6, SPOCK2, SPON1, SPRN, SYT7, TNFSF8, TNR, XYLT1, SERPINA1, NPC1, GALC, CFH, MXRA7, and any combination thereof.

98. The method of claim 97, wherein the compound of Formula I is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

99. The method of claim 98, wherein the pharmaceutically acceptable salt is the fumarate salt.

100. The method of claim 97, wherein the compound of Formula I isor a pharmaceutically acceptable salt thereof.

101. The method of claim 100, wherein the pharmaceutically acceptable salt is the fumarate salt.

102. The method of any one of claims 97-101, wherein administering the compound is correlated with modulation of biological processes or biological pathways comprising phosphatidylcholine-sterol O- acyltransferase activator activity; phosphatidylcholine binding; wnt-protein binding; cholesterol binding; glycosaminoglycan binding; protein folding and maturation angiotensin system maturation; immune response antigen presentation by MHC class I: cross-presentation; O-glycan biosynthesis; Immune response antigen presentation by MHC class II; signal transduction angiotensin II / AGTR1 signaling via Notch, Beta-catenin and NF-kB pathways; immune response antigen presentation by MHC class I, classical pathway; development regulation of cytoskeleton proteins in oligodendrocyte differentiation and myelination; renin-angiotensin-aldosterone system; development PEDF signaling; signal transduction negative regulation of BMP signaling; signal transduction angiotensin II / AGTR1 signaling viap38, ERK and PI3K; immune response lL- 11 signaling viaJAK / STAT; protein folding and maturation_regulation of amyloid precursor protein processing; signal transduction BMP signaling via BMPR1 A and BMPR1B receptors; development_NOTCH signaling in organogenesis and embryogenesis; protein folding and maturation: bradykinin / kallidin maturation; cell adhesion: ECM remodeling; cell adhesion: cell-matrix glycoconjugates; lipoprotein metabolism; development: ErbB3 signaling, and combinations thereof.

103. The method of any one of claims 97-101, wherein administering the compound results in a reduction in the level of a-synuclein.

104. The method of any one of claims 97-101, wherein administering the compound results in a reduction in the level of Ap.

105. The method of claim 104, wherein the Ap is Ap40, Ap42, or a combination of both.

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