Neuroactive steroids for the treatment of Alzheimer's disease

Abstract

The present disclosure relates to compositions, kits, and methods for treating Alzheimer's disease, comprising administering an NMDA receptor positive allosteric modulator or a CYP46A1 inhibitor.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application Nos. 63 / 321,598, filed March 18, 2022, 63 / 289,081, filed December 13, 2021, and 63 / 209,929, filed June 11, 2021, the disclosures of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disease that begins with the loss of episodic memory and cognitive function, progressing to mild cognitive impairment (MCI) and / or dementia, potentially leading to the loss of the ability to carry on a conversation and respond to the environment. Furthermore, patients with AD-mild cognitive impairment (AD-MCI) are at high risk of developing dementia, which accounts for the majority of dementia cases. The most common early symptom is difficulty remembering recent events. As the disease progresses, symptoms may include problems related to language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As their condition worsens, subjects with AD often withdraw from their families and society. Over time, subjects lose physical function and ultimately die.

[0003] Alzheimer's disease (AD) remains devoid of effective and stable therapeutic strategies. Currently, available medications for AD are symptomatic and focus on managing behavioral and psychological symptoms. Recent clinical studies have investigated treatments that target the underlying pathologies characteristic of AD, including beta-amyloid (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, and vascular changes. However, to date, tested drugs have not shown clinical benefit in terms of improving cognitive function and dementia manifested in AD patients.

[0004] NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some situations and excitotoxicity in others. These receptors mediate Ca release following binding of the neurotransmitters glutamate and glycine. 2+ NMDA receptors are ligand-gated ion channels that accept excitatory receptors (NMDA receptors) and underlie excitatory neurotransmission and normal CNS function. NMDA receptors are heteromeric complexes composed of NR1, NR2, and / or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. Positive modulators may be useful as therapeutic agents with potential clinical applications as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or absent (see, e.g., Horak et al., J. Neuroscience, 2004, 24(46), 10318-10325). Thus, there remains a need for new and improved therapies for treating Alzheimer's disease. The compositions, kits, and methods disclosed herein are directed to this end. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Horak et al.,J.Neuroscience,2004,24(46),10318-10325 Summary of the Invention [Means for solving the problem]

[0006] Provided herein are methods of treating Alzheimer's disease, including methods of treating mild cognitive impairment (MCI) or mild dementia associated with Alzheimer's disease.

[0007] In one aspect, there is provided a method of treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, comprising administering to a subject a compound of formula: [ka] A compound having or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, Compound 1 is administered to a subject daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0009] In one aspect, provided herein are methods of improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0010] In one aspect, provided herein is a method of improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0011] In one aspect, provided herein are methods of improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0012] In one aspect, provided herein are methods of improving learning and working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0013] In one aspect, provided herein is a method of treating mild dementia associated with Alzheimer's disease in a subject, the method comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0014] In one aspect, provided herein are methods of improving executive function in a subject having mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0015] In one aspect, provided herein is a method of improving working memory in a subject having mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0016] In one aspect, provided herein is a method of improving learning in a subject having mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0017] In one aspect, provided herein are methods of improving learning and working memory in a subject having mild dementia associated with Alzheimer's disease, the method comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.

[0018] In some embodiments, the subject is an adult human. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with another monotherapy.

[0019] In one aspect, the present disclosure provides a pharmaceutical composition comprising: (a) an NMDA receptor positive allosteric modulator; (b) an anti-amyloid beta antibody or antigen-binding fragment thereof; and (c) a pharmaceutically acceptable carrier.

[0020] In one aspect, the present invention provides a pharmaceutical composition comprising: (a) a CYP46A1 inhibitor; (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof; and (c) a pharmaceutically acceptable carrier.

[0021] In one aspect, the invention provides a kit comprising a first container, a second container, and a package insert, wherein the first container comprises a composition comprising an NMDA receptor positive allosteric modulator, the second container comprises a composition comprising an anti-amyloid beta antibody or antigen-binding fragment thereof, and the package insert comprises instructions for treating Alzheimer's disease in a subject.

[0022] In one aspect, the invention provides a kit comprising a first container, a second container, and a package insert, wherein the first container contains a composition comprising a CYP46A1 inhibitor, the second container contains a composition comprising an anti-amyloid beta antibody or antigen-binding fragment thereof, and the package insert comprises instructions for treating Alzheimer's disease in a subject.

[0023] In one aspect, the present disclosure provides a method for treating or preventing Alzheimer's disease, comprising administering to a subject in need of treatment or prevention (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for treating Alzheimer's disease, comprising administering to a subject in need of treatment (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for preventing Alzheimer's disease, comprising administering to a subject in need of prevention (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0024] In one aspect, the present disclosure provides a method for treating or preventing cognitive impairment in a subject with Alzheimer's disease, comprising administering to the subject (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for treating cognitive impairment in a subject with Alzheimer's disease, comprising administering to the subject (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for preventing cognitive impairment in a subject with Alzheimer's disease, comprising administering to the subject (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0025] In one aspect, the present disclosure provides a method for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, the method comprising administering to the subject (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for treating cognitive impairment caused by Alzheimer's disease in a subject, the method comprising administering to the subject (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for preventing cognitive impairment caused by Alzheimer's disease in a subject, the method comprising administering to the subject (a) an NMDA receptor-positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the cognitive impairment is mild cognitive impairment.

[0026] In one aspect, the disclosure provides a method for improving cognition in a subject having Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0027] In one aspect, the present disclosure provides a method for delaying cognitive decline due to Alzheimer's disease in a subject, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0028] In one aspect, the present disclosure provides a method of treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0029] In one aspect, the present disclosure provides a method of improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0030] In one aspect, the present disclosure provides a method of improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0031] In one aspect, the present disclosure provides a method of improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0032] In one aspect, the present disclosure provides a method of improving learning and working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0033] In one aspect, the present disclosure provides a method of treating mild dementia associated with Alzheimer's disease in a subject, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0034] In one aspect, the present disclosure provides a method of improving executive function in a subject with mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0035] In one aspect, the disclosure provides a method of improving working memory in a subject with mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0036] In one aspect, the disclosure provides a method of improving learning in a subject with mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0037] In one aspect, the disclosure provides a method of improving learning and working memory in a subject with mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) an NMDA receptor positive allosteric modulator, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0038] In one aspect, the present disclosure provides a method for treating or preventing Alzheimer's disease, comprising administering to a subject in need of treatment or prevention (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for treating Alzheimer's disease, comprising administering to a subject in need of treatment or prevention (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for treating Alzheimer's disease, comprising administering to a subject in need of treatment or prevention (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0039] In one aspect, the present disclosure provides a method for treating or preventing cognitive impairment in a subject with Alzheimer's disease, comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for treating cognitive impairment in a subject with Alzheimer's disease, comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for preventing cognitive impairment in a subject with Alzheimer's disease, comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0040] In one aspect, the present disclosure provides a method for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, the method comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for treating cognitive impairment caused by Alzheimer's disease in a subject, the method comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the present disclosure provides a method for preventing cognitive impairment caused by Alzheimer's disease in a subject, the method comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the cognitive impairment is mild cognitive impairment.

[0041] In one aspect, the disclosure provides a method for improving cognition in a subject with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0042] In one aspect, the present disclosure provides a method for delaying cognitive decline due to Alzheimer's disease in a subject, the method comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0043] In one aspect, the disclosure provides a method of treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0044] In one aspect, the disclosure provides a method for improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0045] In one aspect, the disclosure provides a method for improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0046] In one aspect, the disclosure provides a method for improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0047] In one aspect, the disclosure provides a method for improving learning and working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0048] In one aspect, the present disclosure provides a method for treating mild dementia associated with Alzheimer's disease in a subject, the method comprising administering to the subject (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0049] In one aspect, the present disclosure provides a method for improving executive function in a subject having mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0050] In one aspect, the present disclosure provides a method for improving working memory in a subject having mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0051] In one aspect, the disclosure provides a method for improving learning in a subject having mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0052] In one aspect, the disclosure provides a method for improving learning and working memory in a subject having mild dementia associated with Alzheimer's disease, the method comprising administering to the subject (a) a CYP46A1 inhibitor, and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0053] In some embodiments, the NMDA receptor positive allosteric modulator is 9-iodophenanthrene-3-carboxylic acid (UBP512), 6-(4-methylpentyl)naphthalene-2-carboxylic acid (UBP684), 4-cyclohexyl-N-(7-hydroxy-5-methyl-2-propyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)benzenesulfonamide (GNE-9278), 2-butyl-7-(((ethyl(phenyl)amino)methyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (GNE-3476), 4-(4-hydroxy-1-(2-(6-methyl-1H-indol-3-yl)ethyl)-3-nicotinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate methyl (PYD-111), 4-(3-acetyl-4-hydroxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate methyl (PYD-106), 3-chlorophenyl)(6,7-dimethoxy-1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinolin-2(1H)-yl) Selected from the group consisting of methanone (CIQ), NYX-458, and plazinemdor (5-(3-chloro-4-fluorophenyl)-7-cyclopropyl-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one), and pharmaceutically acceptable salts thereof.

[0054] In some embodiments, the NMDA receptor positive allosteric modulator is a neuroactive steroid, or a pharmaceutically acceptable salt thereof. In some embodiments, the neuroactive steroid is selected from any one of compounds B1-B543 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from any one of compounds B1-B140 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from any one of compounds B150-B245 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from any one of compounds B273-B349 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from any one of compounds B395-B432 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B433-B443 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B444-B451 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B452-B477 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B478-B530 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B531-B543 and pharmaceutically acceptable salts thereof.

[0055] In some embodiments, the CYP46A1 inhibitor is selected from the group consisting of TAK-935, any one of compounds A1-A182, and pharmaceutically acceptable salts thereof. In some embodiments, the CYP46A1 inhibitor is selected from the group consisting of TAK-935, any one of compounds A1-A125, and pharmaceutically acceptable salts thereof. In some embodiments, the CYP46A1 inhibitor is TAK-935 or a pharmaceutically acceptable salt thereof. In some embodiments, the CYP46A1 inhibitor is selected from the group consisting of any one of compounds A1-A125, and pharmaceutically acceptable salts thereof. In some embodiments, the CYP46A1 inhibitor is selected from the group consisting of any one of compounds A126-A182, and pharmaceutically acceptable salts thereof.

[0056] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is selected from the group consisting of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), aducanumab, and antigen-binding fragments thereof.

[0057] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (b) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 14, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; (c) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 21, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 24, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 26; (d) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 31, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 34, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 36; (e) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 41, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 43; and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 44, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 45, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 51, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 53, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 54, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 56, or (g) A heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 63, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 64, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 66.

[0058] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0059] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising: (a) the amino acid sequence of SEQ ID NO: 7, (b) the amino acid sequence of SEQ ID NO: 17, (c) the amino acid sequence of SEQ ID NO: 27, (d) the amino acid sequence of SEQ ID NO: 37, (e) the amino acid sequence of SEQ ID NO: 47, (f) the amino acid sequence of SEQ ID NO: 57, or (g) the amino acid sequence of SEQ ID NO: 67.

[0060] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising: (a) the amino acid sequence of SEQ ID NO: 8, (b) the amino acid sequence of SEQ ID NO: 18, (c) the amino acid sequence of SEQ ID NO: 28, (d) the amino acid sequence of SEQ ID NO: 38, (e) the amino acid sequence of SEQ ID NO: 48, (f) the amino acid sequence of SEQ ID NO: 58, or (g) the amino acid sequence of SEQ ID NO: 68.

[0061] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0062] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a human IgG1, IgG2, IgG3, or IgG4 constant domain, hi some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a human IgG1 constant region.

[0063] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is a human anti-amyloid beta antibody or antigen-binding fragment thereof.

[0064] In some embodiments, the antigen-binding fragment is a single-chain antibody, Fv, Fab, Fab', F(ab')2, Fd, single-chain Fv molecule (scFv), bispecific single-chain Fv dimer, diabody, domain-deleted antibody, or single-domain antibody (dAb).

[0065] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising (a) the amino acid sequence of SEQ ID NO: 9, (b) the amino acid sequence of SEQ ID NO: 19, (c) the amino acid sequence of SEQ ID NO: 29, (d) the amino acid sequence of SEQ ID NO: 39, (e) the amino acid sequence of SEQ ID NO: 49, (f) the amino acid sequence of SEQ ID NO: 59, or (g) the amino acid sequence of SEQ ID NO: 69.

[0066] In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising (a) the amino acid sequence of SEQ ID NO: 10, (b) the amino acid sequence of SEQ ID NO: 20, (c) the amino acid sequence of SEQ ID NO: 30, (d) the amino acid sequence of SEQ ID NO: 40, (e) the amino acid sequence of SEQ ID NO: 50, (f) the amino acid sequence of SEQ ID NO: 60, or (g) the amino acid sequence of SEQ ID NO: 70.

[0067] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9.

[0068] In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0069] In some embodiments, the anti-amyloid beta antibody is aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta that aducanumab binds.

[0070] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of aducanumab to amyloid beta. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to amyloid beta plaques, parenchymal amyloid, cerebrovascular amyloid, or diffuse amyloid beta deposits.

[0071] In some embodiments, the NMDA receptor positive allosteric modulator and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered simultaneously. In some embodiments, the NMDA receptor positive allosteric modulator and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered sequentially. In some embodiments, the NMDA receptor positive allosteric modulator and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered separately. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is administered before the NMDA receptor positive allosteric modulator. In some embodiments, the NMDA receptor positive allosteric modulator is administered before the anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the frequency of administration of the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA receptor positive allosteric modulator is the same. In some embodiments, the frequency of administration of the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA receptor positive allosteric modulator is different.

[0072] In some embodiments, the CYP46A1 inhibitor and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered simultaneously. In some embodiments, the CYP46A1 inhibitor and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered sequentially. In some embodiments, the CYP46A1 inhibitor and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered separately. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is administered before the CYP46A1 inhibitor. In some embodiments, the CYP46A1 inhibitor is administered before the anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the administration frequencies of the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor are the same. In some embodiments, the administration frequencies of the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor are different. [Brief explanation of the drawings]

[0073] [Figure 1] An overview of the study design is presented. [Figure 2] Figure 1 shows baseline executive function deficits in AD patients measured using the Digit Symbol Substitution Test. [Figure 3] 1 shows baseline learning and memory in AD patients as measured by pattern recognition memory (PRM). [Figure 4] 1 shows attention and psychomotor speed at baseline in AD patients as measured by reaction time (RT). [Figure 5] Figure 1 shows executive function in AD patients measured using the 2-back test. [Figure 6] 1 shows executive function in AD patients measured using MTT. [Figure 7] FIG. 1 shows learning and memory in AD patients measured using the VRM (free recall) test. [Figure 8] FIG. 1 shows learning and memory in AD patients measured using the PRM (% Latency Correct) test. DETAILED DESCRIPTION OF THE INVENTION

[0074] As generally described herein, the present invention provides compositions, kits and methods for treating a variety of CNS diseases and disorders in patients in need thereof.

[0075] definition The term "herein" means the entire application.

[0076] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the terminology used in connection with the compounds, compositions, and methods described herein is that which is well known and commonly used in the art.

[0077] It is understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different sections of this specification (including embodiments described by way of example only), can be combined with any one or more other embodiments of the invention unless expressly disclaimed or inappropriate, and that combinations of embodiments are not limited to those specific combinations claimed via the scope of multiple dependent claims.

[0078] All publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference in their entirety. In case of conflict, the present specification, including its specific definitions, will control.

[0079] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0080] Standard techniques may be used for chemical synthesis and antibody production. These and related techniques and procedures may generally be performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. Unless specific definitions are provided, the nomenclature utilized in connection with, and the laboratory procedures and techniques of, molecular biology, analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for recombinant technology, molecular biology, microbiology, chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and treatment of subjects.

[0081] Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated element (or component) or group of elements (or components), but not the exclusion of any other element (or component) or group of elements (or components).

[0082] Throughout this specification, when a composition is described as having, including, or comprising specific ingredients (or variations thereof), it is contemplated that the composition can also consist essentially of, or consist of, the listed ingredients. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process can also consist essentially of, or consist of, the listed processing steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0083] As used herein, the term "including" means "including but not limited to." "Comprises" and "including but not limited to" are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated element (or component) or group of elements (or components), but not the exclusion of any other element (or component) or group of elements (or components).

[0084] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0085] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0086] In the context of describing elements (particularly in the context of the claims which follow), the use of the terms "a," "an," and "the" and similar referents should be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context.

[0087] The term "or" as used herein should be understood to mean "and / or" unless the context clearly dictates otherwise.

[0088] Recitation of ranges of values ​​herein, unless otherwise indicated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually referenced herein. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges subsumed therein. For example, a stated range of "1 to 10" should be considered to include any and all subranges between (and including) the minimum value of 1 and the maximum value of 10, i.e., all subranges beginning with a minimum value of 1 or more, e.g., 1 to 6.1, and ending with a maximum value of 10 or less, e.g., 5.5 to 10. The disclosure of a range should also be considered to disclose the endpoints of that range.

[0089] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0090] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better illustrate embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0091] The terms "antibody" (Ab) and "immunoglobulin" (Ig) are used interchangeably herein and refer to a molecule (e.g., a complete antibody, an antibody fragment, or a modified antibody) that is capable of recognizing and binding to a specific target or antigen, such as a carbohydrate, polynucleotide, lipid, or polypeptide, through at least one antigen recognition site located in the variable region of the molecule. Antibodies can be either membrane-bound or secreted. As used herein, the term encompasses intact or "whole," polyclonal or monoclonal antibodies, as well as fragments thereof (single variable domain (VH, VL, or combinations thereof) antibodies, Fab, Fab', F(ab'), Fv), single chain (ScFv), synthetic variants thereof, naturally occurring variants, fusion proteins comprising an antibody portion having an antigen-binding fragment of the required specificity, humanized antibodies, chimeric antibodies, chimeric antigen receptors (CARs), and any other modified configuration of an immunoglobulin molecule that contains an antigen-binding site or fragment (epitope-recognition site) of the required specificity.

[0092] Antibodies, or Ig molecules, typically contain two heavy chains and two light chains linked together through disulfide bonds. Both the heavy (IgH) and light (IgL) chains contain a variable (V) region or domain and a constant (C) region or domain. The portion of the IgH locus that encodes the V region contains multiple copies of variable (V), diversity (D), and joining (J) gene segments. The portion of the IgL locus that encodes the V region contains multiple copies of V and J gene segments. The V region-encoding portions of the IgH and IgL loci undergo gene segment rearrangement, e.g., different combinations of V, (D), and J gene segments, to form IgH and IgL variable regions (VH and VL, respectively), resulting in diverse antigen specificities in antibodies. Each variable region contains three hypervariable complementarity-determining regions (CDRs) interspersed among less variable framework regions (FRs). A complete variable domain, if present, comprises four framework regions (FR) and three complementarity-determining regions (CDRs), arranged, starting from the amino terminus, in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Visual inspection and sequence analysis can be performed to identify the CDR boundaries.CDR sequences can be defined using the Kabat system or nomenclature (Kabat, EA et al., Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, US Government Printing Office (1991)), the Chothia system or nomenclature (Chothia & Lesk, Canonical Structures for the Hypervariable Regions of Immunoglobulins, J. Mol. Biol. 196:901-917 (1987)), and / or the IMGT system or nomenclature (Dondelinger et al., Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface / Residue Definition, Front Immunol, 9:2278 (2018)). The heavy chain comprises HCDR1, HCDR2, and HCDR3. The light chain comprises LCDR1, LCDR2, and LCDR3. The secreted form of the IgH C region of most antibodies consists of three C domains, CH1, CH2, CH3, and a hinge region, except for Cμ, which contains a CH4 region but lacks a hinge region. The membrane-bound form of the IgH C region also has membrane and intracellular domains. The IgH constant region determines the antibody's isotype, e.g., IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA, and IgE. It will be understood that non-human mammals encoding multiple Ig isotypes can undergo isotype class switching. There are two types of human IgL, Igκ, and Igλ.

[0093] As used herein, the term "monoclonal antibody" or "mAb" refers to an antibody produced by the same set of immune cells, each of which is a clone of a unique parent cell. Monoclonal antibodies have a monovalent affinity (i.e., they bind to the same epitope).

[0094] The term "antigen-binding fragment" as used herein refers to a polypeptide fragment comprising at least one CDR of an immunoglobulin heavy chain and / or immunoglobulin light chain that binds to amyloid beta. In this regard, an antigen-binding fragment of an antibody may comprise one, two, three, four, five, or all six CDRs of the VH and VL sequences shown herein from the anti-amyloid beta antibodies described herein. In some embodiments, an antigen-binding fragment of an anti-amyloid beta antibody comprises all six CDRs of the VH and VL sequences shown herein from the anti-amyloid beta antibodies disclosed herein. An antigen-binding fragment of an amyloid beta-specific antibody described herein is capable of binding to amyloid beta. In some embodiments, an anti-amyloid beta antibody or antigen-binding fragment thereof binds to amyloid beta plaques, parenchymal amyloid, cerebrovascular amyloid, or diffuse amyloid beta deposits.

[0095] In some embodiments, the antibodies and antigen-binding fragments thereof described herein each comprise a set of heavy and light chain CDRs interposed between a set of heavy and light chain framework regions (FRs) that provide conformational support for the CDRs and define the spatial relationship of the CDRs to one another. As used herein, the term "CDR set" refers to the three hypervariable regions of a heavy or light chain V region or V domain. Starting from the N-terminus of the heavy or light chain, these regions are designated "CDR1," "CDR2," and "CDR3," respectively. Thus, the antigen-binding site comprises six CDRs, including a set of CDRs from each of the heavy and light chain V regions or V domains.

[0096] The "Fab" domain or fragment contains the N-terminal portion of IgH, including the V region and CH1 domain of IgH, and the entire IgL. The "F(ab')2" domain contains the Fab domain and part of the hinge region, and two IgHs are linked together via a disulfide bond in the middle hinge region. Both Fab and F(ab')2 are "antigen-binding fragments."

[0097] The C-terminal portion of IgH, which is a crystallizable fragment of an antibody after papain digestion and includes the CH2 and CH3 domains, is referred to as the "Fc" domain. The Fc domain is the portion of Ig that is recognized by cellular receptors such as FcR and to which the complement-activating protein C1q binds. The lower hinge region, encoded in the 5' portion of the CH2 exon, provides flexibility within the antibody for binding to the FcR receptor. Although the boundaries of the Fc domain may vary, the human IgG heavy chain Fc domain as defined herein includes residue E216 at its carboxyl terminus of the CH3 domain (or the CH4 domain for IgM and IgE antibodies), numbered in the EU format as described by Edelman. The term "Fc domain" may refer to this sequence in isolation or in the context of an antibody, antibody fragment, or Fc fusion protein. The amino acid sequence of a non-naturally occurring Fc domain (also referred to herein as a "variant Fc domain") may include one or more amino acid modifications. Polymorphisms have been observed at several Fc domain positions, including but not limited to positions 270, 272, 312, 315, 356, and 358; therefore, slight differences between the presented sequence and those in the prior art may exist.

[0098] The term "EU format as described in Edelman" refers to the residue numbering of the human IgG1 EU antibody as described in Edelman GM et al., (1969) Proc. Natl. Acad. USA, 63, 78-85. The numbering of human IgG2 and human IgG4 residues is also in the EU format (see Dillon TM, et al., J Biol Chem. Jun 6;283(23):16206-15(2008); Aalberse RC et al., Immunology 105:9-19(2002); and Scholthauer T et al., Protein Engineering, Design and Selection, 29(10):457-466,(2016)). The EU numbering of residues can be determined by aligning the antibody with a "standard" EU-numbered sequence in regions of homology with the antibody's sequence.

[0099] An "Fv" fragment comprises a non-covalently linked VH::VL heterodimer comprising an antigen-binding site. In certain embodiments, single-chain Fv (scFv) antibodies are contemplated. scFvs are covalently linked VH::VL heterodimers expressed from a gene fusion comprising genes encoding VH and VL linked by a peptide-encoding linker (e.g., Huston et al. (1988) Proc. Nat. Acad. Sci. USA 85(16):5879-5883, incorporated herein by reference). As used herein, the term "linker" refers to a polypeptide sequence connecting two or more antibody domains. The properties of linkers and their suitability for particular purposes are known in the art. See, for example, Chen et al. Adv Drug Deliv Rev. October 15;65(10):1357-1369(2013) (disclosing various types of linkers, their properties, and related linker design tools and databases), which is incorporated herein by reference. Linkers can be flexible, rigid, or in vivo cleavable. Preferably, the linker is flexible. Flexible linkers typically contain small non-polar (e.g., Gly) or polar (e.g., Ser or Thr) amino acids. The most commonly used flexible linker has a sequence consisting primarily of a stretch of Gly and Ser residues ("GS" linker). Optionally, the flexible linker contains five repeats of Gly and Ser residues.

[0100] Where bispecific antibodies are used, they can be conventional bispecific antibodies which can be produced in a variety of ways, for example, prepared chemically or from hybrid hybridomas (see, e.g., Holliger, P. and Winter G. Current Opinion Biotechnol. 4, 446-449 (1993)), or can be any of the bispecific antibody fragments described above.

[0101] As used herein, the term "chimeric antibody" refers to an antibody encoded by a polynucleotide sequence that includes polynucleotide sequences from more than one species, e.g., human and mouse. Chimeric antibody as used herein can also refer to an antibody that contains regions from two or more different antibodies.

[0102] As used herein, the term "chimeric Ig chain" refers to an Ig heavy chain or an Ig light chain encoded by a polynucleotide sequence that includes polynucleotide sequences from two or more species, e.g., human and mouse. For example, a chimeric Ig heavy chain can include a human VH domain, DH domain, JH domain, CH1 domain, and upper hinge region, and mouse CH2 and CH3 domains. In some embodiments, the middle hinge region is mouse. In some embodiments, the middle hinge region is human. In some embodiments, the middle hinge region is chimeric.

[0103] As used herein, "human antibody" refers to an antibody having variable and constant regions derived from human germline immunoglobulin sequences. Humanized antibodies can, for example, contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" does not include antibodies in which CDR sequences are derived from the germline of another mammalian species, such as a mouse, and grafted onto human framework sequences (i.e., humanized antibodies). The term encompasses antibodies that have sequences derived from human genes but that have been modified, for example, to reduce potential immunogenicity, increase affinity, reduce effector function, or eliminate cysteines that may cause undesired folding. The term also encompasses such antibodies containing human amino acid sequences that have been recombinantly produced in non-human cells, which may confer glycosylation patterns that are not typical of human cells.

[0104] As used herein, the terms "polypeptide," "peptide," or "protein" are used interchangeably herein to describe a chain of amino acids linked together by chemical bonds. Non-limiting examples of polypeptides or proteins include IgH, IgL, a V domain, a C domain, or an antibody.

[0105] As used herein, the term "amino acid modification" refers to at least one amino acid substitution, insertion, deletion, or mutation in an amino acid sequence compared to the wild-type amino acid sequence. Such modifications are within the ordinary skill of one of ordinary skill in the art. Several modifications, including amino acid deletions, substitutions, and additions of the Fc region, have been shown to alter the binding of the Fc domain to its ligands and / or receptors, resulting in concomitant modification of effector function (e.g., Shields et al., J Biol Chem 276:6591-6604 (2001); Presta et al., Biochem Soc Trans 30:487-490 (2002); Escobar-Cabrera E et al. Antibodies. 6:7 (2017); Duncan AR et al. Nature. 1988;332:738-740 (1988); Duncan AR et al. Nature. 332:563-564 (1988); Hezareh M et al. J Virol. 75:12161-12168 (2001); Oganesyan V et al., each of which is incorporated herein by reference in its entirety). al.Acta Crystallogr D Biol Crystallogr;64:700-704(2008), Schlothauer T et al.Protein Eng Des Sel.Oct;29(10):457-466(2016), Tao MH et al.J.Immunol.143:2595-2601(1989), Von Kreudenstein TS et al.MAbs.5(5):646-654(2013), Wang X et al.Protein Cell. 9(1):63-73(2018); U.S. Patent Publication Nos. 2004 / 0132101, 2007 / 0111260, 2011 / 0287032, 2018 / 0194860, U.S. Patent No. 8,409,568, and International Publication No. WO2017 / 177337. Amino acid deletions are indicated by "Δ" and insertions are indicated by "In." For example, a deletion of the amino acid sequence from E216 to E222 is indicated as ΔE216-E222.For example, the insertion of an arginine (R) between amino acid residues 234 and 235 is designated as InR234 / 235.

[0106] A "conservative amino acid substitution" replaces an amino acid residue with a different amino acid residue having similar biochemical properties (e.g., charge, hydrophobicity, or size). Generally, conservative amino acid substitutions do not substantially change the functional properties of a protein. When comparing proteins containing conservative substitutions, the percent sequence identity or degree of similarity may be adjusted to take into account the conservative nature of the substitution. Such adjustments are well known in the art. See, e.g., Pearson, Methods Mol. Biol. 243:307-31 (1994).

[0107] The term "percent sequence identity" in the context of polypeptide (or polynucleotide) sequences is defined as the percentage of amino acid (or nucleic acid) residues in a candidate sequence that are identical with amino acid (or nucleic acid) residues in a reference polypeptide (or polynucleotide) sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, not counting any conservative substitutions as part of the sequence identity. Such conservative substitutions are taken into account (in addition to identical residues) when calculating the "percent sequence similarity" of the two sequences. Residue positions that are similar but not identical differ by conservative amino acid substitutions.

[0108] Sequence alignment (e.g., to determine amino acid sequence identity, sequence similarity, or percent sequence homology, such as between a wild-type protein and its mutant protein) can be accomplished in a variety of ways within the skill of one in the art using publicly available sequence analysis computer software, such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), Gap, BESTFIT®, and other programs in the Wisconsin Package Version 10.0 or the software of the Genetics Computer Group (GCG) (Madison, Wisconsin). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Polypeptide sequences can also be compared using FASTA using default or recommended parameters. In the context of polypeptide sequences, FASTA takes a query amino acid sequence and searches a sequence database using local sequence alignments to identify similar sequences within the database (Pearson, Methods Enzymol. 183:63-98 (1990); Pearson, Methods Mol. Biol. 132:185-219 (2000); Pearson Curr Protoc Bioinformatics. Mar 24;53:3.9.1-25 (2016) each incorporated herein by reference). BLAST, particularly blastp or tblastn, using default parameters can be used to compare a query sequence to a database containing sequences from different organisms. See, for example, Altschul et al., J. Mol. Biol. 215:403-410 (1990); Altschul et al., Nucleic Acids Res.25:3389-402(1997); Eser et al., PLoS One.22;9(12):e115445(2014).

[0109] Amino acids can be grouped based on their similar biochemical properties. Such groupings that can be used to define conservative substitutions include: 1) amino acid residues with aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) amino acid residues with aliphatic hydroxyl side chains: serine and threonine; 3) amino acid residues with amide-containing side chains: asparagine and glutamine; 4) amino acid residues with aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) amino acid residues with basic side chains: lysine, arginine, and histidine; 6) amino acid residues with acidic side chains: aspartic acid and glutamic acid; and 7) amino acid residues with sulfate-containing side chains: cysteine ​​and methionine. Non-limiting examples of preferred conservative amino acid substitutions include valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine.

[0110] The strength or affinity of an immunological binding interaction is determined by the dissociation constant (K D ) and smaller K D represents a greater affinity. The immunological binding properties of a selected polypeptide can be quantified using methods well known in the art. One such method involves measuring the rates of formation and dissociation of the antigen-binding site / antigen complex, which depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that affect the rate in both directions equally. Thus, the "on-rate constant" (K on ) and "off rate constant" (K off ) can be determined by calculation of the concentration and the actual rates of association and dissociation. off / K on The ratio of the two allows for the cancellation of all parameters not related to affinity and therefore the dissociation constant K D See generally Davies et al. (1990) Annual Rev. Biochem. 59:439-473. DA high affinity antibody is generally considered to specifically bind an antigen when its affinity is ≦1 mM, preferably ≦100 nM. -9 ) K in the range D and very high affinity antibodies generally have a picomolar (10 -12 ) K in the range D K D The binding affinity constant can be measured by surface plasmon resonance, for example, using the BIACORE® system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). See also Jonsson et al., Ann. Biol. Clin. 51:19-26 (1993); Jonsson et al., Biotechniques 11:620-627 (1991); Jonsson et al., J. Mol. Recognit. 8:125-131 (1995); Jonsson et al., Anal. Biochem. 198:268-277 (1991); Hearty S et al., Methods Mol Biol. 907:411-42 (2012), each of which is incorporated herein by reference. D can also be measured using the KinExA® system (Sapidyne Instruments, Hanover, Germany and Boise, ID). An antibody, or antigen-binding fragment thereof, is said to "specifically bind," "immunologically bind," and / or "immunologically reactive" with amyloid beta if it reacts detectably with amyloid beta (e.g., in an ELISA assay) and does not detectably react with unrelated polypeptides under similar conditions. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to amyloid beta plaques, parenchymal amyloid, cerebrovascular amyloid, or diffuse amyloid beta deposits.

[0111] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government, or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0112] "Pharmaceutically acceptable salts" refers to salts of compounds of the present invention that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoic acid)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbis(2-methyl- ... (2) acid addition salts formed with organic acids such as chloro[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylbutyric acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (3) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts further include, by way of example only, salts of non-toxic organic or inorganic acids such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, if the compound contains a basic functional group, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0113] The term "administering," as used herein, refers to any manner of transferring, delivering, introducing, or transporting a pharmaceutical composition or other agent described herein to a subject, including, but not limited to, oral administration, inhalation, topical contact, intravenous, intraperitoneal, intramuscular, intranasal, or subcutaneous administration.

[0114] As used herein, the term "unit dosage form" is defined to refer to the form in which the compounds disclosed herein are administered to a subject.

[0115] As used herein, the term "day" means a given period of 24 consecutive hours.

[0116] The terms "subject," "patient," and "individual" are used interchangeably herein and include, but are not limited to, humans and non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human (a "human subject"). In certain embodiments, the human subject is an infant, child, or adolescent (a "pediatric subject"). In other embodiments, the human subject is a young adult, middle-aged adult, or elderly adult (an "adult subject"). In certain embodiments, the subject is a non-human animal (a "non-human subject").

[0117] "Disease," "disorder," "condition," and "illness" are used interchangeably herein. In some embodiments, the disease is Alzheimer's disease. In some embodiments, the disease is cognitive impairment associated with Alzheimer's disease.

[0118] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" refer to measures (also "therapeutic treatment") that occur while a subject is afflicted with a specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition. The term refers to ameliorating at least one symptom of the disease or disorder in a subject. Treating includes curing, ameliorating, or at least partially ameliorating the disease or disorder, or any symptom of the disease or disorder.

[0119] As used herein, the terms "prevent," "preventing," and "prevention" refer to preventing or delaying the recurrence or onset of a coronavirus infection or alleviating one or more symptoms of a coronavirus infection in a subject as a result of administering a composition of the present disclosure. For example, in the context of administering a therapy to a subject, "prevent," "preventing," and "prevention" refer to inhibiting, alleviating, or delaying the onset of, or preventing or delaying the recurrence, onset, or onset of, one or more symptoms associated with Alzheimer's disease.

[0120] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0121] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, to delay or minimize one or more symptoms associated with a disease, disorder, or condition, or to improve cognitive function. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0122] A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount may be less than the therapeutically effective amount.

[0123] In some embodiments, administering a compound described herein, or a pharmaceutically acceptable salt thereof, improves cognitive function. In some embodiments, cognitive function refers to a range of mental tasks and functions, including, but not limited to, psychomotor performance, executive performance, emotional recognition, learning (e.g., visual, spatial), memory (e.g., semantic, episodic, procedural, priming, or task), orientation, language, problem-solving, visual perception, construction, and integration, planning, organizational skills, selective attention, inhibitory control, and the ability to mentally manipulate information. In some embodiments, cognitive function is one or more selected from the group consisting of psychomotor performance, executive performance, emotional recognition, learning (e.g., visual, spatial), memory (e.g., semantic, episodic, procedural, priming, or task), orientation, language, problem-solving, visual perception, construction, and integration, planning, organizational skills, selective attention, inhibitory control, and the ability to mentally manipulate information. In some embodiments, the compounds disclosed herein selectively target working memory and its improvement. In some embodiments, the compounds disclosed herein selectively target executive performance and its improvement. Measures of cognitive function include, for example, assessment tools designed to measure: (a) general intelligence, (b) nonverbal intelligence, (c) achievement, (d) attention / executive function, (e) memory and learning, (f) visual-motor and motor function, and (g) language.

[0124] Any change in cognitive function, for example, over time or through treatment, can be monitored by using one or more of these well-established tests at two or more time points and comparing the results.The phrase "improve cognitive function" as referred to herein refers to a favorable change in the subject's ability to perform symbolic operations, for example, perceive, remember, create mental images, have clarity of thought, be aware, reason, think, or judge.Favorable changes can be measured using any of the above-mentioned tests at two or more occasions, for example, at the first time to measure baseline cognitive function, and at the second time to measure cognitive function after a certain period of time (when treatment may be administered).Such assessment tools are well known in the art, and include, for example, the assessment tool described in Example 1 herein.

[0125] The term "memory" as used herein is defined as the biological processes of the brain that allow for the storage and retrieval of information.

[0126] The term "working memory" as used herein is defined as the combination of brain processes that provide the temporary storage and manipulation of information necessary to perform complex cognitive tasks such as learning and reasoning.

[0127] As used herein, the term "learning" refers to the brain processes involved in the acquisition of skills, knowledge, and information.

[0128] The terms "executive function" or "executive performance," as used interchangeably herein, refer to an umbrella term for cognitive processes that regulate, control, and manage other cognitive processes, including planning, working memory, attention, problem-solving, verbal reasoning, inhibition, mental flexibility, task switching, and initiating and monitoring actions. The prefrontal regions of the frontal lobe are necessary, but not sufficient, to carry out these functions.

[0129] "Improve," "improving," or "improvement," or grammatical variations thereof, when used in connection with working memory or executive function, refers to the ability to achieve a measurable increase in performance related to a task used to test working memory or executive function in a subject.

[0130] As used herein, the term "pharmaceutically acceptable carrier" is used interchangeably and refers to any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Pharmaceutically acceptable carriers are well known in the art. See, for example, Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984), incorporated herein by reference. Some examples of pharmaceutically acceptable carriers are water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof. In many cases, it is preferable to include an isotonic agent, such as a sugar, a polyalcohol such as mannitol, sorbitol, or sodium chloride, in the composition. Additional examples of pharmaceutically acceptable carriers are wetting agents, or minor amounts of auxiliary substances such as wetting agents or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the antibody.Pharmaceutical compositions can be prepared by mixing the compounds, antibodies, or antigen-binding fragments thereof disclosed herein with acceptable carriers, excipients, or stabilizers, for example, in the form of a lyophilized powder, a slurry, an aqueous solution, or a suspension (see, for example, Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY).

[0131] General Disclosed herein are pharmaceutical compositions, kits, and methods of treatment that include (a) an NMDA receptor positive allosteric modulator (NMDA PAM), (b) an anti-amyloid beta antibody or antigen-binding fragment thereof, and (c) a pharmaceutically acceptable carrier. Also disclosed herein are pharmaceutical compositions, kits, and methods of treatment that include (a) a CYP46A1 inhibitor, (b) an anti-amyloid beta antibody or antigen-binding fragment thereof, and (c) a pharmaceutically acceptable carrier.

[0132] CYP46A1 inhibitors CYP46A1 inhibitors useful in the compositions, kits, and methods of the present disclosure are compounds that inhibit the enzyme cholesterol 24-hydroxylase (also known as CYP46A1 and CH24H), which converts cholesterol into 24S-hydroxycholesterol (24-HC) and, when administered in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof, exhibit beneficial effects for treating or preventing Alzheimer's disease as disclosed herein. CYP46A1 inhibitors are known to those skilled in the art. Therefore, any CYP46A1 inhibitor may be useful in the compositions, kits, and methods of the present disclosure.

[0133] In some embodiments, the CYP46A1 inhibitor is any compound disclosed in WO2020 / 243027, WO2013 / 054822, US9193709, WO2014 / 092100, US9643957, WO2014 / 163162, US9624184, WO2014 / 061676, US9296746, WO2017 / 065287, the disclosures of each of which are incorporated herein by reference in their entirety.

[0134] In some embodiments, the CYP46A1 inhibitor is selected from the group consisting of TAK-935 and any of compounds A1-A182, and pharmaceutically acceptable salts thereof. In some embodiments, the CYP46A1 inhibitor is any one of compounds A1-A182 (see Table 1), or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0135] In some embodiments, the CYP46A1 inhibitor is any single compound shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0136] The synthesis of compounds A1-A125 is described in WO2020 / 243027, and the synthesis of compounds A126-A182 is described in WO2022 / 115620, the disclosures of each of the foregoing applications being incorporated herein by reference in their entirety.

[0137] NMDA receptor positive allosteric modulators The NMDA PAM useful in the compositions, kits and methods of the present disclosure is a compound that is a modulator of synaptic and / or extrasynaptic NMDA receptor, and when administered in combination with anti-amyloid beta antibody or its antigen-binding fragment, shows the beneficial effect of treating or preventing Alzheimer's disease as disclosed herein.NMDA PAM is known to those skilled in the art.Therefore, any NDMA PAM can be useful in the compositions, kits and methods of the present disclosure.

[0138] In some embodiments, the NDMA PAM is a neuroactive steroid. In some embodiments, the neuroactive steroid is any one of compounds B1-B543, or a pharmaceutically acceptable salt thereof. In some embodiments, the neuroactive steroid is any one of compounds B1-B543 (see Table 2): [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

[0139] In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B1-B140 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B141-B149 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B150-B245 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B246-B272 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B273-B349 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B395-B432 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B433-B443 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B444-B451 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B452-B477 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B478-B530 and pharmaceutically acceptable salts thereof. In some embodiments, the neuroactive steroid is selected from the group consisting of any one of compounds B531-B543 and pharmaceutically acceptable salts thereof.

[0140] In some embodiments, the neuroactivity of any single compound shown in Table 2 or a pharmaceutically acceptable salt thereof.

[0141] The synthesis of compounds B1 to B140 is described in WO2013 / 036835, the synthesis of B141 to B149 is described in WO2015 / 195967, the synthesis of compounds B150 to B245 is described in WO2014 / 160480, the synthesis of B246 to B272 is described in WO2017 / 007832, the synthesis of B273 to B394 is described in WO2017 / 007840, and the synthesis of B395 to B432 is described in WO2017 / 007840. The synthesis of B433 to B443 is described in WO2017 / 007836, the synthesis of B433 to B443 in WO2018 / 009867, the synthesis of B444 to B451 in WO2017 / 193046, the synthesis of B452 to B477 in WO2017 / 173358, the synthesis of B478 to B530 in WO2018 / 075699, and the synthesis of B531 to B543 in WO2018 / 064659. The disclosures of each of the foregoing applications are incorporated herein by reference in their entirety.

[0142] In some embodiments, NMDA PAMs include 9-iodophenanthrene-3-carboxylic acid (UBP512), 6-(4-methylpentyl)naphthalene-2-carboxylic acid (UBP684), 4-cyclohexyl-N-(7-hydroxy-5-methyl-2-propyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)benzenesulfonamide (GNE-9278), 2-butyl-7-(((ethyl(phenyl)amino)methyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (GNE-3476), 4-(4-hydroxy-1-(2-(6-methyl-1H-indol-3-yl)ethyl)-3-nicotinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate methyl ester (PYD-111), 4-( 3-acetyl-4-hydroxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate methyl (PYD-106), 3-chlorophenyl)(6,7-dimethoxy-1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), NYX-458, plazinemdor (5-(3-chloro-4-fluorophenyl)-7-cyclopropyl-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one), and pharmaceutically acceptable salts thereof. In some embodiments, the NMDA PAM is BP512 or a pharmaceutically acceptable salt thereof. In some embodiments, the NMDA PAM is UBP684 or a pharmaceutically acceptable salt thereof. In some embodiments, the NMDA PAM is GNE-9278 or a pharmaceutically acceptable salt thereof. In some embodiments, the NMDA PAM is GNE-3476 or a pharmaceutically acceptable salt thereof. In some embodiments, the NMDA PAM is PYD-111 or a pharmaceutically acceptable salt thereof. In some embodiments, the NMDA PAM is PYD-106 or a pharmaceutically acceptable salt thereof. In some embodiments, the NMDA PAM is CIQ or a pharmaceutically acceptable salt thereof.In some embodiments, the NMDA PAM is NYX-458 or a pharmaceutically acceptable salt thereof. In some embodiments, the NMDA PAM is prazinemdor (5-(3-chloro-4-fluorophenyl)-7-cyclopropyl-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one) or a pharmaceutically acceptable salt thereof.

[0143] Anti-amyloid beta antibodies The anti-amyloid beta antibody or antigen-binding fragment thereof useful in the compositions, kits, and methods of the present disclosure is an antibody or fragment thereof that binds to amyloid beta and, when administered in combination with an NMDA PAM or CYP inhibitor, exhibits beneficial effects for treating or preventing Alzheimer's disease as disclosed herein. Any anti-amyloid beta antibody or antigen-binding fragment thereof, including those disclosed in U.S. Patent Nos. 10,842,871, 10,131,708, 9,828,420, and 8,906,367, and U.S. Patent Publication No. 2015 / 013155267 (the disclosures of all of which are incorporated herein by reference), can be used in the pharmaceutical compositions, kits, and methods disclosed herein.

[0144] More specifically, the pharmaceutical compositions, kits, and methods disclosed herein include anti-amyloid beta antibodies, antigen-binding fragments (or portions) thereof, antibody light chains, antibody heavy chains, and fragments of these light or heavy chains. The anti-amyloid beta antibodies and antigen-binding fragments thereof disclosed herein also include antibodies lacking a heavy chain signal sequence and / or a light chain signal sequence, and glycosylated antibodies. The anti-amyloid beta antibodies and antigen-binding fragments thereof disclosed herein also include precursor antibodies, non-glycosylated antibodies, and antibodies whose heavy and / or light chains contain signal sequences.

[0145] The antibodies and antigen-binding fragments thereof described herein can be purified and / or isolated using known techniques. "Purified" or "isolated" antibodies or portions have been at least partially separated from the molecules (e.g., peptides) of their source (e.g., in a mixture, such as a cell supernatant or a mixture of antibodies in a library) and include antibodies obtained by any other suitable method. Isolated antibodies include substantially pure (e.g., essentially pure) antibodies, as well as antibodies produced by chemical synthesis, recombinant techniques, and combinations thereof.

[0146] The anti-amyloid beta antibody or antigen-binding fragment thereof may be human. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof of the present disclosure is chimeric. In some embodiments, the chimeric anti-amyloid beta antibody or antigen-binding fragment thereof comprises a chimeric IgH chain and a human Igκ chain. In some embodiments, the chimeric anti-amyloid beta antibody or antigen-binding fragment thereof comprises a chimeric IgH chain and a human Igλ chain. In some embodiments, the chimeric anti-S1 antibody comprises human and mouse sequences.

[0147] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises one to six complementarity determining regions (CDRs) disclosed herein.

[0148] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is selected from the group consisting of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), aducanumab, and antigen-binding fragments thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is bapineuzumab or an antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is solanezumab or an antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is gantenerumab or an antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is crenezumab or an antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is ponezumab or an antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is lecanemab (BAN2401) or an antigen-binding fragment thereof. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is aducanumab or an antigen-binding fragment thereof.

[0149] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), or aducanumab binds. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as bapineuzumab binds. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as solanezumab binds. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as gantenerumab binds. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as crenezumab binds. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as bound by ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as bound by lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to the same conformational epitope of amyloid beta as bound by aducanumab.

[0150] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), or aducanumab to amyloid beta. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of bapineuzumab to amyloid beta. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of solanezumab to amyloid beta. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of gantenerumab to amyloid beta. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of ponezumab to amyloid beta. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of lecanemab (BAN2401) to amyloid beta. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof competitively inhibits the binding of aducanumab to amyloid beta.

[0151] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises six CDRs of any one of the anti-amyloid beta antibodies disclosed herein as determined by the Kabat, Chothia, or IMTG nomenclature systems. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises six CDRs of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises six CDRs of bapineuzumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises six CDRs of solanezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises six CDRs of gantenerumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises six CDRs of crenezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the six CDRs of ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the six CDRs of lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the six CDRs of aducanumab.

[0152] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (b) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 14, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; (c) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 21, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 24, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 26; (d) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 31, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 33, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 34, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 36; (e) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 41, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 43; and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 44, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 45, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; (f) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 51, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 53, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 54, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 56, or (g) A heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 63, and a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 64, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 66.

[0153] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0154] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 11, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 13; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 14, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.

[0155] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 21, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 23; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 24, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 26.

[0156] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 31, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 33; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 34, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 36.

[0157] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 41, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 43; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 44, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 45, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46.

[0158] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 51, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 53; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 54, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 56.

[0159] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable domain (VH) comprising (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 63; and (b) a light chain variable domain (VL) comprising (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 64, (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 66.

[0160] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and / or a light chain variable domain (VL) of any one of the anti-amyloid beta antibodies disclosed herein, hi some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a VH domain of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab.

[0161] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of bapineuzumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of solanezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of gantenerumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of crenezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain of aducanumab.

[0162] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of bapineuzumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of solanezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of gantenerumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of crenezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VL domain of aducanumab.

[0163] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of bapineuzumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of solanezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of gantenerumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of crenezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the VH domain and VL domain of aducanumab.

[0164] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising: (a) the amino acid sequence of SEQ ID NO: 7, (b) the amino acid sequence of SEQ ID NO: 17, (c) the amino acid sequence of SEQ ID NO: 27, (d) the amino acid sequence of SEQ ID NO: 37, (e) the amino acid sequence of SEQ ID NO: 47, (f) the amino acid sequence of SEQ ID NO: 57, or (g) the amino acid sequence of SEQ ID NO: 67.

[0165] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising: (a) the amino acid sequence of SEQ ID NO: 8, (b) the amino acid sequence of SEQ ID NO: 18, (c) the amino acid sequence of SEQ ID NO: 28, (d) the amino acid sequence of SEQ ID NO: 38, (e) the amino acid sequence of SEQ ID NO: 48, (f) the amino acid sequence of SEQ ID NO: 58, or (g) the amino acid sequence of SEQ ID NO: 68.

[0166] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0167] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 17, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 18.

[0168] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 27, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 28.

[0169] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 38.

[0170] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 47, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 48.

[0171] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 57, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 58.

[0172] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 67. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 68. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 67, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 68.

[0173] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain and / or light chain of any one of the anti-amyloid beta antibodies disclosed herein.

[0174] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of bapineuzumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of solanezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of gantenerumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of crenezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy chain of aducanumab.

[0175] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of bapineuzumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of solanezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of gantenerumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of crenezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the light chain of aducanumab.

[0176] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chains of any one of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), and aducanumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chains of bapineuzumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chains of solanezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chains of gantenerumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chains of crenezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chains of ponezumab. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chain domains of lecanemab (BAN2401). In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises the heavy and light chain domains of aducanumab.

[0177] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0178] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0179] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 and a light chain comprising the amino acid sequence of SEQ ID NO: 30.

[0180] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 and a light chain comprising the amino acid sequence of SEQ ID NO: 40.

[0181] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 49. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 50. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 49 and a light chain comprising the amino acid sequence of SEQ ID NO: 50.

[0182] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 59 and a light chain comprising the amino acid sequence of SEQ ID NO: 60.

[0183] In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69. In some embodiments, the anti-amyloid beta antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 70. In some embodiments, the anti-amyloid beta antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 69 and a light chain comprising the amino acid sequence of SEQ ID NO: 70.

[0184] The anti-amyloid beta antibody or antigen-binding fragment thereof may comprise any of the complementarity determining regions (CDRs) (i.e., HCDRs, LCDRs), VH, VL, heavy chain sequences, or light chain sequences shown in Tables 3 to 9. Tables 3 to 9 provide details of the VH, VL, and various anti-amyloid beta antibodies. [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0185] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a human IgG1, IgG2, IgG3, or IgG4 constant domain. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a human IgG1 constant region. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a human IgG2 constant region. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a human IgG3 constant region. In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof comprises a human IgG4 constant region.

[0186] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof is a human anti-amyloid beta antibody or antigen-binding fragment thereof.

[0187] In some embodiments, the antigen-binding fragment is a single-chain antibody, Fv, Fab, Fab', F(ab')2, Fd, single-chain Fv molecule (scFv), bispecific single-chain Fv dimer, diabody, domain-deleted antibody, or single-domain antibody (dAb). In some embodiments, the anti-amyloid beta antibody is a whole antibody. In some embodiments, the anti-amyloid beta antibody is a single-chain antibody. In some embodiments, the anti-amyloid beta antibody is an scFv. In some embodiments, the anti-amyloid beta antibody is a Fab. In some embodiments, the anti-amyloid beta antibody is a F(ab')2. In some embodiments, the anti-amyloid beta antibody is an Fv. In some embodiments, the anti-amyloid beta antibody is an Fd. In some embodiments, the anti-amyloid beta antibody is a bispecific single-chain Fv dimer. In some embodiments, the anti-amyloid beta antibody is a diabody. In some embodiments, the anti-amyloid beta antibody is a single-domain antibody (dAb). In some embodiments, the anti-amyloid beta antibody is a bispecific antibody.

[0188] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof of the present disclosure is human. In some embodiments, the human anti-amyloid beta or antigen-binding fragment thereof comprises a human IgH chain and a human Igκ chain. In some embodiments, the human anti-amyloid beta or antigen-binding fragment thereof comprises a human IgH chain and a human Igλ chain. In some embodiments, the isotype of the anti-amyloid beta antibody is selected from IgM, IgD, IgG (such as IgG1, IgG2, IgG3, and IgG4), IgA, and IgE. In some embodiments, the isotype of the anti-amyloid beta antibody is selected from IgG1, IgG2, IgG3, and IgG4.

[0189] In some embodiments, the anti-amyloid beta antibody binds to an Fc receptor (FcR) selected from FcγR, FcεR, and FcαR. In some embodiments, the anti-amyloid beta antibody binds to an FcγR selected from FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16), including their isoforms. In some embodiments, the Fc region of the anti-amyloid beta antibody is mutated to preferentially bind to a particular FcγR.

[0190] In some embodiments, the anti-amyloid beta antibody or antigen-binding fragment thereof binds to amyloid beta plaques, parenchymal amyloid, cerebrovascular amyloid, or diffuse amyloid beta deposits.

[0191] Pharmaceutical Compositions In one aspect, the disclosure provides a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the pharmaceutical composition comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1.

[0193] In some embodiments, the pharmaceutical composition comprises 0.1-1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 0.1-1.0 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 0.5 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutical composition comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 1.0 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1.

[0194] In one aspect, provided herein is a pharmaceutical composition comprising: (a) an NMDA receptor positive allosteric modulator; (b) an anti-amyloid beta antibody or antigen-binding fragment thereof; and (c) a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises: (a) an effective amount of an NMDA receptor positive allosteric modulator; (b) an effective amount of anti-amyloid beta or antigen-binding fragment thereof; and (c) a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises: (a) a therapeutically effective amount of an NMDA receptor positive allosteric modulator; (b) a therapeutically effective amount of anti-amyloid beta or antigen-binding fragment thereof; and (c) a pharmaceutically acceptable carrier.

[0195] In one aspect, provided herein is a pharmaceutical composition comprising (a) a CYP46A1 inhibitor, (b) an anti-amyloid beta antibody or antigen-binding fragment thereof, and (c) a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises (a) an effective amount of CYP46A1, (b) an effective amount of anti-amyloid beta or antigen-binding fragment thereof, and (c) a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises (a) a therapeutically effective amount of CYP46A1, (b) a therapeutically effective amount of anti-amyloid beta or antigen-binding fragment thereof, and (c) a pharmaceutically acceptable carrier.

[0196] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration. In some embodiments, a compound or pharmaceutical composition is administered to a subject orally. In some embodiments, a compound or pharmaceutical composition is administered to a subject parenterally. In some embodiments, a compound or pharmaceutical composition is administered to a subject rectally. In some embodiments, a compound or pharmaceutical composition is administered to a subject transdermally. In some embodiments, a compound or pharmaceutical composition is administered to a subject intradermally. In some embodiments, a compound or pharmaceutical composition is administered to a subject intrathecally. In some embodiments, a compound or pharmaceutical composition is administered to a subject subcutaneously. In some embodiments, a compound or pharmaceutical composition is administered to a subject intravenously. In some embodiments, a compound or pharmaceutical composition is administered to a subject intramuscularly. In some embodiments, a compound or pharmaceutical composition is administered to a subject intranasally.

[0197] Generally, the compounds provided herein (i.e., Compound 1, CYP46A1 inhibitors, NMDA PAM, and anti-amyloid beta or antigen-binding fragments thereof) are administered in effective amounts. The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0198] The pharmaceutical compositions of the present invention can also be delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the active ingredient throughout the body; for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., via an IV infusion) allows for a much faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition can be initially administered as a bolus dose, followed by continuous infusion.

[0199] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosage forms for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that serve to form the desired dosage form. The above-described components of orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, as well as processing techniques and equivalents, are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0200] The compositions can be in sustained release form or derived from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0201] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present disclosure (i.e., Compound 1, CYP46A1 inhibitors, and NMDA PAMs). Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, paratoluenesulfonate, and the like.

[0202] When used to prevent the development of a CNS disorder, the compounds provided herein will typically be administered at dosage levels described herein under the advice and supervision of a physician to a subject at risk of developing the condition. Subjects at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0203] kit In one aspect, provided herein is a kit comprising a composition comprising an NMDA receptor positive allosteric modulator disclosed herein, a composition comprising an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein, and a package insert. In some embodiments, provided herein is a kit comprising a first container, a second container, and a package insert, wherein the first container contains a composition comprising an NMDA receptor positive allosteric modulator disclosed herein, the second container contains a composition comprising an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein, and the package insert contains instructions for treating Alzheimer's disease in a subject. It is understood that the kit may contain one distinct composition or two or more distinct compositions, wherein the first composition comprises an NMDA PAM and the second composition comprises an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0204] It is understood that the NMDA PAM composition and the anti-amyloid beta antibody or antigen-binding fragment thereof composition can independently have any dosage form. For example, the anti-amyloid beta antibody or antigen-binding fragment thereof composition can be in a liquid dosage form, while the NMDA PAM composition can be in a solid dosage form.

[0205] In one aspect, provided herein is a kit comprising a composition comprising a CYP46A1 inhibitor disclosed herein, a composition comprising an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein, and a package insert. In some embodiments, provided herein is a kit comprising a first container, a second container, and a package insert, wherein the first container contains a composition comprising a CYP46A1 inhibitor disclosed herein, the second container contains a composition comprising an anti-amyloid beta antibody or antigen-binding fragment thereof disclosed herein, and the package insert contains instructions for treating Alzheimer's disease in a subject. It is understood that the kit may contain one distinct composition or two or more distinct compositions, wherein the first composition comprises a CYP46A1 inhibitor and the second composition comprises an anti-amyloid beta antibody or antigen-binding fragment thereof.

[0206] It is understood that the CYP46A1 inhibitor composition and the anti-amyloid beta antibody or antigen-binding fragment thereof composition can independently have any dosage form. For example, the anti-amyloid beta antibody or antigen-binding fragment thereof composition can be in a liquid dosage form, while the CYP46A1 inhibitor composition can be in a solid dosage form.

[0207] It is understood that the package insert includes instructions for treating any of the conditions disclosed herein. In some embodiments, the instructions are for treating Alzheimer's disease. In some embodiments, the instructions are for preventing Alzheimer's disease. In some embodiments, the instructions are for treating cognitive impairment in a subject with Alzheimer's disease. In some embodiments, the instructions are for preventing Alzheimer's disease. In some embodiments, the instructions are for preventing cognitive impairment in a subject with Alzheimer's disease. In some embodiments, the instructions are for treating cognitive impairment due to Alzheimer's disease in a subject. In some embodiments, the instructions are for preventing cognitive impairment due to Alzheimer's disease in a subject. In some embodiments, the instructions are for treating mild cognitive impairment due to Alzheimer's disease in a subject. In some embodiments, the instructions are for preventing mild cognitive impairment due to Alzheimer's disease in a subject. In some embodiments, the instructions are for improving cognition in a subject with Alzheimer's disease. In some embodiments, the instructions are for slowing cognitive decline due to Alzheimer's disease in a subject. In some embodiments, the instructions are for reducing amyloid beta plaques in the brain of a subject with Alzheimer's disease. In some embodiments, the instructions are for reducing amyloid beta plaque deposition in the brain of a subject with Alzheimer's disease. In some embodiments, the instructions are for treating mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, the instructions are for improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, the instructions are for improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, the instructions are for improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease.In some embodiments, the instructions are for improving learning and working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, the instructions are for treating mild dementia associated with Alzheimer's disease in a subject. In some embodiments, the instructions are for improving executive function in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, the instructions are for improving working memory in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, the instructions are for improving learning in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, the instructions are for improving learning and working memory in a subject with mild dementia associated with Alzheimer's disease.

[0208] In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA PAM simultaneously. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA PAM sequentially. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA PAM separately. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof before the NMDA PAM. In some embodiments, the kit includes instructions for administering the NMDA PAM before the anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA PAM at the same frequency. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA PAM at different frequencies.

[0209] In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor simultaneously. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor sequentially. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor separately. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof before the CYP46A1 inhibitor. In some embodiments, the kit includes instructions for administering the CYP46A1 inhibitor before the anti-amyloid beta antibody or antigen-binding fragment thereof. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor at the same frequency. In some embodiments, the kit includes instructions for administering the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor at different frequencies.

[0210] The kits of the present disclosure may be in any suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, ampoules, jars, syringes, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretive information.

[0211] The first and second containers can be the same or different shapes (e.g., vials, syringes, and bottles) and / or materials (e.g., plastic or glass). The kit can further include other materials that may be useful in administering the medication, such as diluents, filters, IV bags and lines, needles and syringes.

[0212] In some embodiments, the present invention provides an article of manufacture comprising the contents of a kit described herein.

[0213] Methods of Treatment and Use The compounds, pharmaceutical compositions, and kits disclosed herein are useful for treating or preventing Alzheimer's disease.

[0214] Alzheimer's disease (AD) comprises dementia primarily identified by clinical diagnosis and established by disease markers. It is a continuum with specific operationally defined stages of disease progression. AD pathology begins before the onset of clinical symptoms. For example, amyloid plaques, one marker of AD pathology, form 10 to 20 years before the onset of AD dementia. Currently recognized stages of AD include preclinical, prodromal, mild, moderate, and severe. These stages can be further divided into subcategories based on the severity of symptoms and measures of AD progression.

[0215] Those skilled in the art will recognize that differences between patient groups may not be clearly distinct in certain clinical settings. Nevertheless, clinical disease stage can be characterized by measuring various traits or markers and their changes over time, such as amyloid beta accumulation (CSF / PET), synaptic dysfunction (FDG-PET / fMRI), tau-mediated neuronal damage (CSF), brain structure (volumetric MRI), cognition, and clinical function. Clifford Jack et al. Lancet. Neurol. 2010 January;9(1):119.

[0216] The current core clinical criteria for all dementias, referred to as the NINCDS-ADRDA criteria (McKhann GM, V. Diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia 7 (2011) 263-269), are known in the art and can be employed in practicing the present invention. They include cognitive or behavioral impairments, including a decline in the ability to acquire and remember new information, decline in reasoning and handling complex tasks, decline in visuospatial abilities, decline in language function (speaking, reading, writing), and changes in personality, behavior, or attitude. Id. Alzheimer's disease is currently diagnosed using the core criteria and is typically characterized by symptoms that develop gradually over months to years (insidious onset) rather than suddenly over hours or days. Typically, subjects with Alzheimer's disease have a clear history of reported or observed cognitive deterioration. As new information about AD becomes available, other diagnostic classification systems have evolved. These systems include the International Working Group (IWG) New Research Criteria for the Diagnosis of AD (Dubois B et al. Lancet Neurol 2007;6(8):734-736), the IWG Research Criteria (Dubois et al. Lancet Neurol 2010;9(11):1118-27), the NIA / AA Criteria (Jack CR et al. Alzheimer's Dement 2011;7(3):257-62), and the DSM-5 Criteria (American Psychiatric Association, DSM-5, 2013). These classification systems can also be used to diagnose AD subjects for treatment using the methods of the present invention.

[0217] Subjects with Alzheimer's disease referred to in the methods herein include, but are not limited to, patients with preclinical, prodromal, mild, moderate, or severe Alzheimer's disease.

[0218] Subjects with Alzheimer's disease who require treatment range from those with amyloid pathology and early neurodegeneration, to those with widespread neurodegeneration and irreversible neuronal loss accompanied by progressive cognitive and functional impairment, to those with dementia. Subjects with preclinical Alzheimer's disease can be identified by an asymptomatic stage with or without memory complaints, and emerging episodic memory and executive function deficits. This stage is typically characterized by the appearance of in vivo molecular biomarkers of Alzheimer's disease and the absence of clinical symptoms.

[0219] Prodromal Alzheimer's disease patients are in a pre-dementia stage characterized primarily by cognitive impairment and newly emerging functional impairments associated with disease progression. Prodromal AD patients typically have an MMSE score of 24-30 (inclusive), spontaneous memory complaints, objective memory loss defined as a free recall score of ≤27 on the FCSRT, a global CDR score of 0.5, the absence of significant levels of impairment in other cognitive domains, and essentially preserved activities of daily living, as well as the absence of dementia.

[0220] Patients with mild AD typically have an MMSE score of 20-26 (inclusive), an overall CDR of 0.5 or 1.0, and meet the National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD (see Section 22).

[0221] When AD is diagnosed based on clinical symptoms, patients with mild AD will exhibit significant behavior at work, forgetfulness, mood swings, and attention disorders. Patients with moderate AD will exhibit cognitive impairment, restricted daily activities, disorientation, asthenia, agnosia, aphasia, and behavioral abnormalities. Patients with severe AD are characterized by loss of independence, deterioration of memory and speech, and incontinence.

[0222] In some embodiments, the present disclosure provides: 18 The present disclosure provides for the treatment of early-stage patients who are amyloid-positive as assessed by F-AV-45 PET scan. Patients may be asymptomatic or exhibit only transient symptoms of headache, confusion, difficulty walking, or visual impairment. Patients may or may not be ApoE4 carriers as determined by ApoE genotyping. In other embodiments, the present disclosure provides for the treatment of patients with any medical or neurological condition (other than AD) that may be a precipitating factor in the subject's cognitive impairment, such as stroke or other cerebrovascular disease, other neurodegenerative disease, a history of clinically significant psychiatric illness, acute or subacute micro- or macro-bleeding, previous macro-bleeding, or superficial siderosis, although even these patients can be treated after screening and selection by a competent clinician.

[0223] Accordingly, in one aspect, there is provided a method of treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, comprising administering to the subject Compound 1. [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, comprising administering Compound 1 to the subject. In some embodiments, provided herein are methods of treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, comprising administering a pharmaceutically acceptable salt of Compound 1 to the subject. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0224] In one aspect, provided herein is a method of treating mild dementia associated with Alzheimer's disease in a subject, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating mild dementia associated with Alzheimer's disease in a subject, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of treating mild dementia associated with Alzheimer's disease in a subject, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0225] In another aspect, provided herein are methods of treating mild cognitive impairment (MCI) due to Alzheimer's disease in a subject, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating mild cognitive impairment (MCI) due to Alzheimer's disease in a subject, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of treating mild cognitive impairment (MCI) due to Alzheimer's disease in a subject, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0226] In another aspect, provided herein are methods for treating mild dementia caused by Alzheimer's disease in a subject, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating mild dementia caused by Alzheimer's disease in a subject, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods for treating mild dementia caused by Alzheimer's disease in a subject, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0227] In another aspect, provided herein are methods of treating mild cognitive impairment (MCI) in a subject with Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating mild cognitive impairment (MCI) in a subject with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of treating mild cognitive impairment (MCI) in a subject with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0228] In another aspect, provided herein are methods of treating mild dementia in a subject with Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating mild dementia in a subject with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of treating mild dementia in a subject with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0229] In one aspect, provided herein is a method of improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0230] In one aspect, provided herein is a method of improving executive function in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving executive function in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving executive function in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0231] In another aspect, provided herein are methods of improving executive function in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving executive function in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving executive function in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0232] In another aspect, provided herein are methods of improving executive function in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving executive function in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving executive function in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0233] In another aspect, provided herein are methods of improving executive function in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving executive function in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving executive function in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0234] In another aspect, provided herein are methods of improving executive function in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving executive function in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving executive function in an Alzheimer's disease subject with mild dementia, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0235] In one aspect, provided herein is a method of improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0236] In one aspect, provided herein is a method of improving working memory in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving working memory in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving working memory in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0237] In another aspect, provided herein are methods of improving working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0238] In another aspect, provided herein are methods of improving working memory in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving working memory in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving working memory in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0239] In another aspect, provided herein are methods of improving working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0240] In another aspect, provided herein are methods of improving working memory in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving working memory in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving working memory in an Alzheimer's disease subject with mild dementia, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0241] In one aspect, provided herein is a method of improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0242] In one aspect, provided herein is a method of improving learning in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving learning in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving learning in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0243] In another aspect, provided herein are methods of improving learning in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0244] In another aspect, provided herein are methods of improving learning in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0245] In another aspect, provided herein are methods of improving learning in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0246] In another aspect, provided herein are methods of improving learning in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning in an Alzheimer's disease subject with mild dementia, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0247] In one aspect, provided herein is a method of improving learning and working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving learning and working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving learning and working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0248] In one aspect, provided herein is a method of improving learning and working memory in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving learning and working memory in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein is a method of improving learning and working memory in a subject with mild dementia associated with Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0249] In another aspect, provided herein are methods of improving learning and working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning and working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning and working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally.In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0250] In another aspect, provided herein are methods of improving learning and working memory in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning and working memory in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning and working memory in a subject with mild dementia due to Alzheimer's disease, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0251] In another aspect, provided herein are methods of improving learning and working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning and working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning and working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI), comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0252] In another aspect, provided herein are methods of improving learning and working memory in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of improving learning and working memory in an Alzheimer's disease subject with mild dementia, comprising administering to the subject Compound 1. In some embodiments, provided herein are methods of improving learning and working memory in an Alzheimer's disease subject with mild dementia, comprising administering to the subject a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is administered to the subject daily. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to the subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is administered orally. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0253] In one aspect, provided herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0254] In some embodiments, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mild dementia associated with Alzheimer's disease in a subject. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for treating mild dementia associated with Alzheimer's disease in a subject. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild dementia associated with Alzheimer's disease in a subject. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0255] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mild cognitive impairment (MCI) due to Alzheimer's disease in a subject. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) due to Alzheimer's disease in a subject. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) due to Alzheimer's disease in a subject. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) due to Alzheimer's disease in a subject. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0256] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mild dementia caused by Alzheimer's disease in a subject. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for treating mild dementia caused by Alzheimer's disease in a subject. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild dementia caused by Alzheimer's disease in a subject. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0257] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mild cognitive impairment (MCI) in a subject with Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) in a subject with Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild cognitive impairment (MCI) in a subject with Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0258] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating mild dementia in a subject with Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for treating mild dementia in a subject with Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for treating mild dementia in a subject with Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0259] In one aspect, provided herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0260] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving executive function in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0261] In one aspect, provided herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for improving executive function in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0262] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving executive function in a subject with mild dementia due to Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild dementia due to Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving executive function in a subject with mild dementia due to Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0263] In one aspect, provided herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for improving executive function in an Alzheimer's disease subject with mild cognitive impairment (MCI). In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving executive function in an Alzheimer's disease subject with mild cognitive impairment (MCI). In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving executive function in an Alzheimer's disease subject with mild cognitive impairment (MCI). In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0264] In one aspect, provided herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for improving executive function in an Alzheimer's disease subject with mild dementia. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving executive function in an Alzheimer's disease subject with mild dementia. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving executive function in an Alzheimer's disease subject with mild dementia. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0265] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0266] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving working memory in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild dementia associated with Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0267] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild cognitive impairment (MCI) due to Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0268] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving working memory in a subject with mild dementia due to Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild dementia due to Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving working memory in a subject with mild dementia due to Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3 to 6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 0.1 to about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 0.5 mg of Compound 1. In some embodiments, the medicament comprises about 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises about 1.0 mg of Compound 1. In some embodiments, the medicament comprises about 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.1 to 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.1-1.0 mg of Compound 1. In some embodiments, the medicament comprises 0.1-1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 0.5 mg of Compound 1. In some embodiments, the medicament comprises 0.5 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the medicament comprises 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises 1.0 mg of Compound 1. In some embodiments, the medicament comprises 1.0 mg of a pharmaceutically acceptable salt of Compound 1. In some embodiments, Compound 1 is for oral administration. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0269] In one aspect, provided herein is the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for improving working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI). In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI). In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving working memory in an Alzheimer's disease subject with mild cognitive impairment (MCI). In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.

[0270] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving working memory in an Alzheimer's disease subject with mild dementia. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving working memory in an Alzheimer's disease subject with mild dementia. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving working memory in an Alzheimer's disease subject with mild dementia. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of about 3 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 0.3-6 mg / day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is for administration to a subject at a dose of 3 mg / day. In some embodiments, Compound 1 is for administration to a subject at a dose of 3 mg / day. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for administration to a subject at a dose of 3 mg / day.In some embodiments, Compound 1 is for oral administration. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for oral administration.

[0271] In one aspect, provided herein is the use of Compound 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, provided herein is the use of Compound 1 for the manufacture of a medicament for improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, provided herein is the use of a pharmaceutically acceptable salt of Compound 1 for the manufacture of a medicament for improving learning in a subject with mild cognitive impairment (MCI) associated with Alzheimer's disease. In some embodiments, Compound 1 is for daily administration to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is for daily administration to a subject. In some embodiments, Compound 1 or a pharmaceutically acceptable...

Claims

1. A composition for treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, comprising a compound having the formula 【Chemical 33】 or a pharmaceutically acceptable salt thereof.

2. A composition for improving executive function in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising a compound having the formula 【Chemical 34】 or a pharmaceutically acceptable salt thereof.

3. A composition for improving working memory in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising a compound having the formula 【Chemical Formula 35】 or a pharmaceutically acceptable salt thereof.

4. A composition for improving learning in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising a compound having the formula 【Chemical 36】 or a pharmaceutically acceptable salt thereof.

5. A composition for improving learning and working memory in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease, comprising a compound having the formula 【Chemical 37】 or a pharmaceutically acceptable salt thereof.

6. A composition for treating mild dementia associated with Alzheimer's disease in a subject, comprising a compound having the formula 【Chemical Formula 38】 or a pharmaceutically acceptable salt thereof.

7. A composition for improving executive function in a subject having mild dementia associated with Alzheimer's disease, comprising a compound having the formula 【Chemical Formula 39】 or a pharmaceutically acceptable salt thereof.

8. A composition for improving working memory in a subject having mild dementia associated with Alzheimer's disease, comprising a compound having the formula 【Chemical 40】 or a pharmaceutically acceptable salt thereof.

9. A composition for improving learning in a subject having mild dementia associated with Alzheimer's disease, comprising a compound having the formula 【Chemical Formula 41】 or a pharmaceutically acceptable salt thereof.

10. A composition for improving learning and working memory in a subject having mild dementia associated with Alzheimer's disease, comprising a compound having the formula 【Chemical 42】 or a pharmaceutically acceptable salt thereof.

11. The composition according to any one of claims 1 to 10, wherein the composition is administered to the subject daily.

12. The composition according to any one of claims 1 to 10, wherein the composition is administered to the subject at a dose of about 3 mg / day of Compound 1 or a pharmaceutically acceptable salt thereof.

13. The composition according to claim 12, wherein the composition is administered to the subject at about 3 mg of Compound 1 per day.

14. The composition according to any one of claims 1 to 10, wherein the composition is administered orally.

15. The composition according to any one of claims 1 to 10, wherein the subject is an adult.

16. A compound having the formula 【Chemical 53】 or a pharmaceutically acceptable salt thereof, for use in a) treating mild cognitive impairment (MCI) associated with Alzheimer's disease in a subject, b) improving executive function in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease, c) improving working memory in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease, d) improving learning in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease, or e) the manufacture of a medicament for improving learning and working memory in a subject having mild cognitive impairment (MCI) associated with Alzheimer's disease.

17. A compound having the formula 【Chemical 54】 or a pharmaceutically acceptable salt thereof, for use in a) treating mild dementia associated with Alzheimer's disease in a subject, b) improving executive function in a subject having mild dementia associated with Alzheimer's disease, c) improving working memory in a subject having mild dementia associated with Alzheimer's disease, d) improving learning in a subject having mild dementia associated with Alzheimer's disease, or e) the manufacture of a medicament for improving learning and working memory in a subject having mild dementia associated with Alzheimer's disease.

18. The use according to any one of claims 16 to 17, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject daily.

19. The use according to any one of claims 16 to 17, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 3 mg / day.

20. The use according to claim 19, wherein about 3 mg of Compound 1 per day is administered to the subject.

21. The use according to any one of claims 16 to 17, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

22. A pharmaceutical composition comprising: (a) an NMDA receptor positive allosteric modulator; (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof; (c) a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising: (a) a CYP46A1 inhibitor; (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof; (c) a pharmaceutically acceptable carrier.

24. The pharmaceutical composition according to any one of claims 22 to 23, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof is selected from the group consisting of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponesimod, lecanemab (BAN2401), aducanumab, and antigen-binding fragments thereof.

25. The pharmaceutical composition according to any one of claims 22 to 23, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof comprises a constant domain of human IgG1, IgG2, IgG3, or IgG4.

26. The pharmaceutical composition according to claim 25, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof comprises a human IgG1 constant region.

27. The pharmaceutical composition according to any one of claims 22 to 23, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof is a human anti-amyloid beta antibody or an antigen-binding fragment thereof.

28. The antigen-binding fragment is a single-chain antibody, Fv, Fab, Fab', F(ab'), ２ , Fd, single-chain Fv molecule (scFv), bispecific single-chain Fv dimer, diabody, domain-deleted antibody, or single-domain antibody (dAb), and the pharmaceutical composition according to any one of claims 22 to 23.

29. The pharmaceutical composition according to any one of claims 22 to 23, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof binds to amyloid beta plaques, parenchymal amyloid, cerebrovascular amyloid, or diffuse amyloid beta deposits.

30. The NMDA receptor positive allosteric modulator is selected from the group consisting of 9-iodophenanthrene-3-carboxylic acid (UBP512), 6-(4-methylpentyl)naphthalene-2-carboxylic acid (UBP684), 4-cyclohexyl-N-(7-hydroxy-5-methyl-2-propyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)benzenesulfonamide (GNE-9278), 2-butyl-7-(((ethyl(phenyl)amino)methyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (GNE-3476), methyl 4-(4-hydroxy-1-(2-(6-methyl-1H-indol-3-yl)ethyl)-3-nicotinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (PYD-111), methyl 4-(3-acetyl-4-hydroxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (PYD-106), 3-chlorophenyl)(6,7-dimethoxy-1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), NYX-458, and plazinemdor (5-(3-chloro-4-fluorophenyl)-7-cyclopropyl-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one), and pharmaceutically acceptable salts thereof, the pharmaceutical composition according to claim 22.

31. The NMDA receptor positive allosteric modulator is a neuroactive steroid or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 22.

32. The neuroactive steroid is selected from any one of Compounds B1 to B543 and pharmaceutically acceptable salts thereof, the pharmaceutical composition according to claim 31.

33. The CYP46A1 inhibitor is selected from the group consisting of TAK-935, any one of Compounds A1 to A182, and pharmaceutically acceptable salts thereof, the pharmaceutical composition according to claim 23.

34. The pharmaceutical composition according to claim 33, wherein the CYP46A1 inhibitor is TAK-935 or a pharmaceutically acceptable salt thereof.

35. The pharmaceutical composition according to claim 33, wherein the CYP46A1 inhibitor is selected from the group consisting of any one of Compounds A1 to A182 and a pharmaceutically acceptable salt thereof.

36. A kit comprising a first container, a second container, and an accompanying document, wherein the first container contains a composition comprising a positive allosteric modulator of the NMDA receptor, the second container contains a composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, and the accompanying document contains instructions for treating Alzheimer's disease in a subject.

37. A kit comprising a first container, a second container, and an accompanying document, wherein the first container contains a composition comprising a CYP46A1 inhibitor, the second container contains a composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, and the accompanying document contains instructions for treating Alzheimer's disease in a subject.

38. A combination for treating or preventing Alzheimer's disease in a subject in need thereof, comprising (a) a positive allosteric modulator of the NMDA receptor, and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

39. A combination for treating or preventing cognitive impairment in a subject having Alzheimer's disease, comprising (a) a positive allosteric modulator of the NMDA receptor, and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

40. A combination for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, comprising (a) a positive allosteric modulator of the NMDA receptor, and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

41. A combination for improving cognition in a subject having Alzheimer's disease, comprising (a) a positive allosteric modulator of the NMDA receptor, and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

42. A combination for delaying cognitive decline caused by Alzheimer's disease in a subject, comprising (a) a positive allosteric modulator of the NMDA receptor, and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

43. A combination for treating or preventing Alzheimer's disease in a subject in need thereof, comprising: (a) a CYP46A1 inhibitor; and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

44. A combination for treating or preventing cognitive impairment in a subject having Alzheimer's disease, comprising: (a) a CYP46A1 inhibitor; and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

45. A combination for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, comprising: (a) a CYP46A1 inhibitor; and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

46. A combination for improving cognition in a subject having Alzheimer's disease, comprising: (a) a CYP46A1 inhibitor; and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

47. A combination for delaying cognitive decline caused by Alzheimer's disease in a subject, comprising: (a) a CYP46A1 inhibitor; and (b) an anti-amyloid beta antibody or an antigen-binding fragment thereof.

48. The combination according to any one of claims 38 to 47, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof is selected from the group consisting of bapineuzumab, solanezumab, gantenerumab, crenezumab, ponezumab, lecanemab (BAN2401), aducanumab, and antigen-binding fragments thereof.

49. The combination according to any one of claims 38 to 47, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof comprises a constant domain of human IgG1, IgG2, IgG3, or IgG4.

50. The combination according to claim 49, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof comprises a human IgG1 constant region.

51. The combination according to any one of claims 38 to 47, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof is a human anti-amyloid beta antibody or an antigen-binding fragment thereof.

52. The antigen-binding fragment is a single-chain antibody, Fv, Fab, Fab', F(ab'), ２ , Fd, single-chain Fv molecule (scFv), bispecific single-chain Fv dimer, diabody, domain-deleted antibody, or single-domain antibody (dAb), and the combination according to any one of claims 38 to 47.

53. The combination according to any one of claims 38 to 47, wherein the anti-amyloid beta antibody or an antigen-binding fragment thereof binds to amyloid beta plaques, parenchymal amyloid, cerebrovascular amyloid, or diffuse amyloid beta deposits.

54. The NMDA receptor positive allosteric modulator is selected from the group consisting of 9-iodophenanthrene-3-carboxylic acid (UBP512), 6-(4-methylpentyl)naphthalene-2-carboxylic acid (UBP684), 4-cyclohexyl-N-(7-hydroxy-5-methyl-2-propyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)benzenesulfonamide (GNE-9278), 2-butyl-7-(((ethyl(phenyl)amino)methyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (GNE-3476), 4-(4-hydroxy-1-(2-(6-methyl-1H-indol-3-yl)ethyl)-3-nicotinotinoyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate methyl (PYD-111), 4-(3-acetyl-4-hydroxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate methyl (PYD-106), 3-chlorophenyl)(6,7-dimethoxy-1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), NYX-458, and plazinemdor (5-(3-chloro-4-fluorophenyl)-7-cyclopropyl-3-(2-(3-fluoro-3-methylazetidin-1-yl)-2-oxoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one), and pharmaceutically acceptable salts thereof, the combination according to any one of claims 38 to 42.

55. The combination according to any one of claims 38 to 42, wherein the NMDA receptor positive allosteric modulator is a neuroactive steroid or a pharmaceutically acceptable salt thereof.

56. The combination according to claim 55, wherein the neuroactive steroid is selected from any one of Compounds B1 to B543 and pharmaceutically acceptable salts thereof.

57. The combination according to any one of claims 38 to 42, wherein the NMDA receptor positive allosteric modulator and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered simultaneously.

58. The combination according to any one of claims 38 to 42, wherein the NMDA receptor positive allosteric regulator and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered continuously.

59. The combination according to any one of claims 38 to 42, wherein the NMDA receptor positive allosteric regulator and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered separately.

60. The combination according to any one of claims 38 to 42, wherein the anti-amyloid beta antibody or antigen-binding fragment thereof is administered before the NMDA receptor positive allosteric regulator.

61. The combination according to any one of claims 38 to 42, wherein the NMDA receptor positive allosteric regulator is administered before the anti-amyloid beta antibody or antigen-binding fragment thereof.

62. The combination according to any one of claims 38 to 42, wherein the frequencies of administration of the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA receptor positive allosteric regulator are the same.

63. The combination according to any one of claims 38 to 42, wherein the frequencies of administration of the anti-amyloid beta antibody or antigen-binding fragment thereof and the NMDA receptor positive allosteric regulator are different.

64. The combination according to any one of claims 43 to 47, wherein the CYP46A1 inhibitor is selected from the group consisting of TAK-935, any one of compounds A1 to A182, and pharmaceutically acceptable salts thereof.

65. The combination according to claim 64, wherein the CYP46A1 inhibitor is TAK-935 or a pharmaceutically acceptable salt thereof.

66. The combination according to claim 64, wherein the CYP46A1 inhibitor is selected from the group consisting of any one of compounds A1 to A182 and pharmaceutically acceptable salts thereof.

67. The combination according to any one of claims 43 to 47, wherein the CYP46A1 inhibitor and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered simultaneously.

68. The combination according to any one of claims 43 to 47, wherein the CYP46A1 inhibitor and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered continuously.

69. The combination according to any one of claims 43 to 47, wherein the CYP46A1 inhibitor and the anti-amyloid beta antibody or antigen-binding fragment thereof are administered separately.

70. The combination according to any one of claims 43 to 47, wherein the anti-amyloid beta antibody or antigen-binding fragment thereof is administered before the CYP46A1 inhibitor.

71. The combination according to any one of claims 43 to 47, wherein the CYP46A1 inhibitor is administered before the anti-amyloid beta antibody or antigen-binding fragment thereof.

72. The combination according to any one of claims 43 to 47, wherein the frequencies of administration of the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor are the same.

73. The combination according to any one of claims 43 to 47, wherein the frequencies of administration of the anti-amyloid beta antibody or antigen-binding fragment thereof and the CYP46A1 inhibitor are different.

74. Use of (a) an NMDA receptor positive allosteric modulator and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof for (i) treating or preventing Alzheimer's disease in a subject, (ii) treating or preventing cognitive impairment in a subject having Alzheimer's disease, (iii) treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, (iv) improving cognition in a subject having Alzheimer's disease, or (v) manufacturing a medicament for delaying cognitive decline caused by Alzheimer's disease in a subject.

75. Use of (a) a CYP46A1 inhibitor and (b) an anti-amyloid beta antibody or antigen-binding fragment thereof for (i) treating or preventing Alzheimer's disease in a subject, (ii) treating or preventing cognitive impairment in a subject having Alzheimer's disease, (iii) treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, (iv) improving cognition in a subject having Alzheimer's disease, or (v) manufacturing a medicament for delaying cognitive decline caused by Alzheimer's disease in a subject. **Claim 76**: A composition for treating or preventing Alzheimer's disease in a subject in need thereof, the composition comprising an NMDA receptor positive allosteric modulator, wherein the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 77**: A composition for treating or preventing Alzheimer's disease in a subject in need thereof, the composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, wherein the composition is for use in combination with an NMDA receptor positive allosteric modulator. **Claim 78**: A composition for treating or preventing cognitive impairment in a subject having Alzheimer's disease, the composition comprising an NMDA receptor positive allosteric modulator, wherein the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 79**: A composition for treating or preventing cognitive impairment in a subject having Alzheimer's disease, the composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, wherein the composition is for use in combination with an NMDA receptor positive allosteric modulator. **Claim 80**: A composition for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, the composition comprising an NMDA receptor positive allosteric modulator, wherein the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 81**: A composition for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, the composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, wherein the composition is for use in combination with an NMDA receptor positive allosteric modulator. **Claim 82**: A composition for improving cognition in a subject having Alzheimer's disease, the composition comprising an NMDA receptor positive allosteric modulator, wherein the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 83**: A composition for improving cognition in a subject having Alzheimer's disease, the composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, wherein the composition is for use in combination with an NMDA receptor positive allosteric modulator. **Claim 84**: A composition for delaying cognitive decline caused by Alzheimer's disease in a subject, the composition comprising an NMDA receptor positive allosteric modulator, wherein the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 85**: A composition for delaying cognitive decline caused by Alzheimer's disease in a subject, the composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, wherein the composition is for use in combination with an NMDA receptor positive allosteric modulator. **Claim 86**: A composition for treating or preventing Alzheimer's disease in a subject in need thereof, the composition comprising a CYP46A1 inhibitor, wherein the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 87**: A composition for treating or preventing Alzheimer's disease in a subject in need thereof, the composition comprising an anti-amyloid beta antibody or an antigen-binding fragment thereof, wherein the composition is for use in combination with a CYP46A1 inhibitor. **Claim 88**: A composition for treating or preventing cognitive impairment in a subject having Alzheimer's disease, the composition comprising a CYP46A1 inhibitor, wherein the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 89**: A composition for treating or preventing cognitive impairment in a subject having Alzheimer's disease, wherein the composition comprises an anti-amyloid beta antibody or an antigen-binding fragment thereof, and the composition is for use in combination with a CYP46A1 inhibitor. **Claim 90**: A composition for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, wherein the composition comprises a CYP46A1 inhibitor, and the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 91**: A composition for treating or preventing cognitive impairment caused by Alzheimer's disease in a subject, wherein the composition comprises an anti-amyloid beta antibody or an antigen-binding fragment thereof, and the composition is for use in combination with a CYP46A1 inhibitor. **Claim 92**: A composition for improving cognition in a subject having Alzheimer's disease, wherein the composition comprises a CYP46A1 inhibitor, and the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 93**: A composition for improving cognition in a subject having Alzheimer's disease, wherein the composition comprises an anti-amyloid beta antibody or an antigen-binding fragment thereof, and the composition is for use in combination with a CYP46A1 inhibitor. **Claim 94**: A composition for delaying cognitive decline caused by Alzheimer's disease in a subject, wherein the composition comprises a CYP46A1 inhibitor, and the composition is for use in combination with an anti-amyloid beta antibody or an antigen-binding fragment thereof. **Claim 95**: A composition for delaying cognitive decline caused by Alzheimer's disease in a subject, wherein the composition comprises an anti-amyloid beta antibody or an antigen-binding fragment thereof, and the composition is for use in combination with a CYP46A1 inhibitor.

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