Biomarkers and treatments for Alzheimer's disease and mild cognitive impairment

Abstract

To provide immunogenic peptides, compositions, means, and methods for treating Alzheimer's disease or mild cognitive impairment. [Solution] This disclosure further provides means and methods for diagnosing a patient with Alzheimer's disease or mild cognitive impairment, selecting a patient for treatment therefor, and / or determining the effectiveness of treatment therefor. In some embodiments, the patient has a diagnosis of Alzheimer's disease. In some embodiments, the patient has Alzheimer's disease. In some embodiments, the patient has a diagnosis of mild cognitive impairment. In some embodiments, the patient has mild cognitive impairment.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 897,940, filed on September 9, 2019, and to U.S. Provisional Patent Application No. 63 / 003,585, filed on April 1, 2020, the entire contents of each of these applications incorporated herein by reference.

[0002] This disclosure relates to immunogenic peptides, compositions, means, and methods for treating Alzheimer's disease or mild cognitive impairment. This disclosure further features means and methods for diagnosing and / or selecting a patient for Alzheimer's disease or mild cognitive impairment, and for evaluating the effectiveness of treatments for Alzheimer's disease or mild cognitive impairment. [Background technology]

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disorder that can destroy higher brain structures, including those involved in memory and cognition. This disease leads to cognitive impairments, as well as a decline in memory, learning, language, and the ability to perform intentional, purposeful actions. Effective methods and compositions for the treatment and prevention of AD are needed.

[0004] Alzheimer's disease (AD) is typically histologically characterized by the presence of extracellular plaques and tangles of intracellular and extracellular neurofibrillary fibers in the brain. While the plaques are primarily composed of β-amyloid (Aβ), the tangles contain pathological forms of tau, including pathological tau conformations and aggregates. The recognized role of tau in AD pathology has been demonstrated in numerous studies. For example, Braak revealed that the most closely correlated factor with AD neurodegeneration is not the presence of amyloid plaques, but the presence of tau tangles (Braak, H., et al. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239-259 (1991)). The recognized role of tau in AD pathology has been demonstrated in numerous studies.

[0005] Tau belongs to the intrinsically disordered protein family and is characterized by its lack of a robust three-dimensional structure under its physiological conditions (Zilka et al., 2008). However, cleavage and hyperphosphorylation of tau can lead to pathological transformations from its intrinsically disordered state to multiple soluble and insoluble misdisordered structures, including paired helical fibrils (PHFs) and other aggregates (Wischik et al., 1988a; Wischik et al., 1988b; Novak et al., 1993; Skrabana et al., 2006; Zilka et al., 2008; Kovacech et al., 2010). Such structural changes can lead to the acquisition of toxic function, loss of physiological function of the intrinsic protein, or both (Zilka et al., 2008; Kovacech et al., 2010).

[0006] Although tau appears to play a pathological role in the clinical symptoms of Alzheimer's disease (AD), the development of drugs that counteract tau has been slow, partly due to its importance in physiological microtubule dynamics and its complex biology (Dickey and Petrucelli, 2006). However, as our understanding of the molecular mechanisms underlying tau pathogenesis deepens, the possibility of specifically targeting tau pathological modifications for therapeutic purposes has opened up. As a result, several therapeutic approaches have emerged that directly or indirectly target the tau cascade (see, for example, Dickey and Petrucelli, 2006; Schneider and Mandelkow, 2008; Zilka et al., 2008 for review articles), such as compounds that prevent or reverse tau aggregation (Wischik et al., 1996; Necula et al., 2005; Pickhardt et al., 2005; Taniguchi et al., 2005a; Larbig et al., 2007), small molecule drugs that inhibit tau kinase or activate tau phosphatase (Iqbal and Grundke-Iqbal, 2004; Noble et al., 2005; Iqbal and Grundke-Iqbal, 2007), and microtubule stabilizing drugs (Zhang et al. Drugs that promote the proteolysis of misfolded tau proteins (Dickey et al., 2005, Dickey et al. 2006; Dickey and Petrucelli, 2006), immunosuppressants (Zilka et al., 2008), and immunotherapy strategies including active and passive immunization (Schneider and Mandelkow et al., 2008; Zilka et al. One example is al., 2008: Tabira, T. Immunization Therapy for Alzheimer disease: A Comprehensive Review of Active Immunization Strategie. Tohoku J. Exp. Med., 220: 95-106 (2010).

[0007] Novak et al.'s International Publication No. 2013 / 041962 (referred to herein by reference in its entirety) describes the discovery of four regions of tau that promote intertau aggregation in AD, and vaccines and antibodies that prevent tau aggregation by binding to these four regions. Several AD studies using APP transgenic mice have shown that active immunization techniques (i.e., techniques in which the patient's own body generates immunity against the target) are effective in removing Aβ deposition and improving neuropathological lesions (see, for example, Schenk et al., 1999; Janus et al., 2000; Morgan et al., 2000; Sigurdsson et al., 2001). More recently, active immunotherapy with phosphorylated tau epitopes (Tau379-408 [P-Ser396,404]) has reduced the spread of aggregated tau in the brain and slowed the progression of behavioral phenotypes in a mouse model of tau entanglement lesions (Asuni et al., 2007; Boutajangout et al. 2010; U.S. Patent Application Publication No. 2008 / 0050383; U.S. Patent Application Publication No. 2010 / 00316564). The treated animals produced anti-tau antibodies, which were detected in the brain and co-localized with antibodies that recognized pathological tau (Asuni et al., 2007). This immunotherapy approach was substantially more effective in these animals in the early stages of functional impairment (5 months) than in the later stages (8 months), suggesting that early clearance of pathological tau may have therapeutic benefits (Asuni et al., 2007; Zilka et al., 2008). In fact, there is a recognition that not all tau is easily destroyed and cleared, or may even be unsuitable. Some studies suggest that destroying tau aggregates may increase the abundance of toxic intermediate species, while others suggest that detectable tau aggregates are not necessarily toxic and may even play a protective role (Lee et al., 2005). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2013 / 041962 [Patent Document 2] Specification of US Patent Application Publication No. 2008 / 0050383 [Patent Document 3] Specification of US Patent Application Publication No. 2010 / 00316564 [Non-Patent Document]

[0009] [Non-Patent Document 1] Braak, H., et al. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239-259 (1991) [Non-Patent Document 2] Tabira, T. Immunization Therapy for Alzheimer disease: A Comprehensive Review of Active Immunization Strategie. Tohoku J. Exp. Med., 220:95-106 (2010) [Summary of the Invention] [Means for Solving the Problems] [[ID=Q3]]

[0010] Therefore, although immunotherapy approaches targeting tau have been shown to be promising preclinically, there is still a need for validated therapeutic agents and methods that produce improved, sustained benefits. In some embodiments, the present disclosure is a method for diagnosing a patient having Alzheimer's disease (AD) or mild cognitive impairment, wherein a) the presence of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, and hsa-miR-374a-5p in a sample from or of the patient. a) detecting the presence and / or quantity of one or more of hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p, b) where hs The present invention relates to a method in which the presence of one or more of a-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p and / or a change in the amount in a control sample or a threshold is an indicator of Alzheimer's disease in the subject, and c) a method for diagnosing the presence or absence of Alzheimer's disease in a patient based on step (b).In some embodiments, detecting the presence and / or amount of one or more of the above mRNA biomarkers involves: a) obtaining cerebrospinal fluid (CSF), serum, or plasma samples from a patient; and b) optionally detecting hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-mi from the patient's CSF, serum, or plasma. c) Extract one or more of R-21-5p, and d) perform cDNA synthesis at the discretion of the recipient, and hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR- The method includes detecting the presence and / or amount of one or more of hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p, for example, using quantitative polymerase chain reaction (qPCR). In some embodiments, the control sample is from a healthy person or a patient with Alzheimer's disease.

[0011] In some embodiments, the amount of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, or hsa-miR-21-5p in the patient differs from that in the control sample by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more. In some embodiments, the amount of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, or hsa-miR-21-5p in the patient is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than in the control sample. In some embodiments, the patient has HSA-LET-7A-5P, HSA-MIR-10A-5P, HSA-MIR-145-5P, HSA-MIR-103A-3P, HSA-MIR-191-5P, HSA-MIR-374A-5P, HSA-MIR-26A-5P, HSA-MIR-107, HSA-MIR-15A-5P, HSA- The amounts of miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, or hsa-miR-21-5p are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 500% higher than in the control sample. In some embodiments, patient diagnosis is performed in vitro.

[0012] In some embodiments, compared to a control sample or threshold, hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126- The presence and / or changes in the amounts of at least two, at least three, at least four, at least five, at least six, or at least seven or more of the following: 3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p, are indicators of Alzheimer's disease in the subject. In some embodiments, the presence and / or amount of one or more of the following: hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p are detected. In some embodiments, patients diagnosed with Alzheimer's disease or mild cognitive impairment are administered one or more doses of an immunogenic composition containing an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0013] In some embodiments, the Disclosure relates to a method for diagnosing a patient having Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) detecting the presence and / or amount of one or more metabolites, e.g., 2,4-dihydroxybutanoic acid, phospholipids, phosphatidylcholine, sphingomyelin, or sterols, in the patient's plasma, serum, or cerebrospinal fluid (CSF); b) where the presence and / or change in the amount of one or more metabolites compared to the amount in a control sample or a threshold is an indicator of the Alzheimer's disease in question; and c) diagnosing the presence or absence of Alzheimer's disease in the patient based on step (b). In some embodiments, detecting the presence and / or amount of one or more metabolites comprises: a) obtaining a cerebrospinal fluid (CSF), serum, or plasma sample from the patient; b) extracting one or more metabolites from the patient's CSF, serum, or plasma; and c) determining the amount of one or more metabolites, for example, using mass spectrometry. In some embodiments, the mass spectrometry is time-of-flight mass spectrometry or tandem mass spectrometry / mass spectrometry. In some embodiments, the control sample is from a healthy individual or a patient with Alzheimer's disease.

[0014] In some embodiments, the amount of metabolites in patient samples differs from that in control samples by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more. In some embodiments, the amount of metabolites in patient samples is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 500% more than that in control samples. In some embodiments, the amount of metabolites in patient samples is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than that in control samples. In some embodiments, patient diagnosis is performed in vitro.

[0015] In some embodiments, the presence and / or changes in the amount of at least two, at least three, at least four, at least five, at least six, or at least seven or more metabolites compared to a control sample or threshold are indicators of the Alzheimer's disease in question. In some embodiments, patients diagnosed with Alzheimer's disease or mild cognitive impairment are administered one or more doses of an immunogenic composition containing an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0016] In some embodiments, the Disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) detecting the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p in a sample from a patient; and b) adding hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-m The present invention relates to a method for selecting a patient for treatment when one or more of iR-23a-3p are present, or when there is a change in the level of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p compared to a control sample or threshold, and a) selecting a patient for treatment by administering one or more doses of an immunogenic composition containing an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0017] In some embodiments, the amounts of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in patient samples differ from those in control samples by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more. In some embodiments, the amounts of hsa-let-7a-5p and / or hsa-miR-15a-5p in patient samples are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or less than those in control samples. In some embodiments, the amount of hsa-miR-15a-5p in patient samples is 1 / 2 / 3 / 4 / 5 / 6 / 7 / 8 / 9 / 10 / 15 / 20 / 25 / 50 / 100 or less of that in control samples. In some embodiments, the amount of hsa-miR191-5p and / or hsa-miR-23a-3p in patient samples is 1 / 2 / 3 / 4 / 5 / 6 / 7 / 8 / 9 / 10 / 15 / 20 / 25 / 50 / 100 or more of that in control samples. In some embodiments, the amount of hsa-miR-23a-3p in patient samples is 1 / 2 / 3 / 4 / 5 / 6 / 7 / 8 / 9 / 10 / 15 / 20 / 25 / 50 / 100 or more of that in control samples. In some embodiments, the presence and / or change in the amount of at least two, at least three, or at least four of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p compared to a control sample or threshold is an indicator of Alzheimer's disease in the subject. In some embodiments, the presence and / or change in the amount of at least two, at least three, or at least four of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p compared to a control sample or threshold is an indicator that the subject is selected for treatment with one or more doses of an immunogenic composition containing an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0018] In some embodiments, the present disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) detecting the presence and / or amount of neurofilament light chains (NfLs) in a sample from a patient; b) selecting a patient for treatment when the sample from the patient contains NfLs and / or a changed (e.g., increased) amount of NfLs compared to a control sample or threshold; and c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0019] In some embodiments, the amount of NfL in the patient is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times, or more, than in the control sample. In some embodiments, the amount of NfL in the sample from the patient exceeds a threshold of approximately 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 pg / ml. In some embodiments, the amount of NfL in the patient is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% more than in the control sample. In some embodiments, the control sample is a plasma sample. In some embodiments, the sample from the patient is a plasma sample. In some embodiments, the present disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the patient's Mini-Mental State Examination (MMSE) score; b) comparing the score from step a) to a threshold score; b) selecting the patient for treatment if the patient's MMSE score is above the threshold; and d) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0020] In some embodiments, the patient's MMSE score is at least 29, at least 28, at least 27, at least 26, at least 25, at least 24, at least 23, at least 22, at least 21, at least 20, at least 19, at least 18, at least 17, at least 16, at least 15, at least 14, at least 13, or at least 12. In some embodiments, the patient's MMSE score is above the threshold of 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, or 12. In some embodiments, the patient's MMSE score is between 24 and 26. In some embodiments, the Disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the genotype of each of two alleles of the ApoE gene present in the patient; b) selecting the patient for treatment if the patient has at least one ApoE-ε4 allele; and c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the patient has two ε4 alleles. In some embodiments, the Disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) detecting the presence and / or amount of neurogranin in a sample from the patient; b) selecting the patient for treatment if the patient or a sample from the patient contains neurogranin and / or contains an increased amount compared to a control sample or threshold; and c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2.

[0021] In some embodiments, the amount of neurogranin in patient samples differs from that in control samples by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more. In some embodiments, the amount of neurogranin in patient samples is greater than a threshold of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 100 pg / ml. In some embodiments, the amount of neurogranin in patient samples is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than that in control samples. In some embodiments, the amount of neurogranin in patient samples is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% more than that in control samples.

[0022] In some embodiments, the Disclosure relates to a method for treating a patient suffering from Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p in a sample from the patient; b) administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2; c) after administering one or more doses, the patient's hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191- The method comprises: d) determining the presence and / or amount of one or more of 5p and hsa-miR-23a-3p; d) comparing the presence and / or amount from the post-treatment step (c) with the presence and / or amount from the pre-treatment step (a), wherein a change in the amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p is an indicator of therapeutic efficacy; and e) administering one or more additional doses of the immunogenic composition when the patient demonstrates therapeutic efficacy in step (d).

[0023] In some embodiments, a decrease in the amount of hsa-let-7a-5p and / or hsa-miR-15a-5p after treatment is an indicator of effectiveness. In some embodiments, a decrease in hsa-let-7a-5p and / or hsa-miR-15a-5p to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or less after treatment is an indicator of effectiveness. In some embodiments, an increase in the amount of hsa-miR191-5p and / or hsa-miR-23a-3p after treatment is an indicator of effectiveness. In some embodiments, an increase in hsa-miR191-5p and / or hsa-miR-23 to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more after treatment is an indicator of effectiveness.

[0024] In some embodiments, in step (b), the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of immunogenic peptide. In some embodiments, in step (e), the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of immunogenic peptide.

[0025] In some embodiments, treating a patient involves administering doses at intervals of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, or 40 weeks.

[0026] In some embodiments, the present disclosure relates to a method for treating a patient suffering from Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the presence and / or amount of NfL in the patient; b) administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2; c) determining the presence and / or amount of NfL in the patient after administering one or more doses; d) comparing the presence and / or amount from step (c) after treatment with the presence and / or amount from step (a) before treatment, wherein the change in the amount of NfL is an indicator of therapeutic efficacy; and e) administering one or more additional doses of the immunogenic composition when the patient demonstrates therapeutic efficacy in step (d).

[0027] In some embodiments, a stable or decreasing amount of NfL after treatment is an indicator of effectiveness. In some embodiments, a non-increase in the amount of NfL after treatment by more than approximately 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% is an indicator of effectiveness. In some embodiments, a decrease in the amount of NfL after treatment by more than approximately 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% is an indicator of effectiveness. In some embodiments, an indicator of efficacy is that the amount of NfL does not increase by more than approximately 6 pg / mL, 5 pg / mL, 4 pg / mL, 3 pg / mL, or 2 pg / mL after treatment. In some embodiments, the amount of NfL in patients does not increase by more than approximately 3.2 pg / mL compared to baseline two years after administration of one or more doses of immunogenic composition. In some embodiments, the amount of NfL in patients increases by approximately 1 to approximately 3.2 pg / mL compared to baseline two years after administration of one or more doses of immunogenic composition. In some embodiments, two years after administration of one or more doses of immunogenic composition, the increase in NfL levels in patients who received one or more doses of immunogenic composition is approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, or approximately 100% less than the increase in NfL levels in age-appropriate patients who did not receive one or more doses of immunogenic composition. In some embodiments, two years after administration of one or more doses of the immunogenic composition, the increase in NfL levels in patients who received one or more doses of the immunogenic composition was about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than the increase in NfL levels in age-appropriate patients who received placebo.

[0028] In some embodiments, in step (b), the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of immunogenic peptide. In some embodiments, in step (e), the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of immunogenic peptide. In some embodiments, one or more doses of immunogenic composition comprise at least 6 doses. In further embodiments, one or more doses of immunogenic composition comprise 6 monthly doses followed by at least 5 boosters.

[0029] In some embodiments, treating a patient involves administering doses at intervals of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, or 40 weeks.

[0030] In some embodiments, the present disclosure relates to a method for treating a patient suffering from Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the presence and / or amount of neurogranin in the patient; b) administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2; c) determining the presence and / or amount of neurogranin in the patient after administering one or more doses; d) comparing the presence and / or amount from step (c) after treatment with the presence and / or amount from step (a) before treatment, wherein the change in the amount of neurogranin is an indicator of therapeutic efficacy; and e) administering one or more additional doses of the immunogenic composition when the patient demonstrates therapeutic efficacy in step (d).

[0031] In some embodiments, a stable or decreased neurogranin level after treatment is an indicator of effectiveness. In some embodiments, a non-increase in neurogranin level after treatment of approximately 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% is an indicator of effectiveness. In some embodiments, a decrease in neurogranin level after treatment of approximately 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% is an indicator of effectiveness. In some embodiments, an indicator of efficacy is that the amount of neurolanin does not increase by more than approximately 20 pg / mL, 18 pg / mL, 16 pg / mL, 14 pg / mL, 12 pg / mL, 10 pg / mL, 8 pg / mL, 6 pg / mL, 5 pg / mL, 4 pg / mL, 3 pg / mL, or 2 pg / mL after treatment.

[0032] In some embodiments, in step (b), the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of immunogenic peptide. In some embodiments, in step (e), the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of immunogenic peptide.

[0033] In some embodiments, treating a patient involves administering doses at intervals of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, or 40 weeks.

[0034] In some embodiments, the Disclosure relates to a method for treating a patient suffering from Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the patient's Mini-Mental State Examination (MMSE) score; b) comparing the score from step (a) to a threshold score, which is optionally 20-26; c) selecting the patient for treatment if the patient's MMSE score is above the threshold; d) administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2; e) determining the patient's MMSE score after administering one or more doses; f) comparing the MMSE score from step (e) after treatment to the MMSE score from step (a) before treatment, where the change in the MMSE score is an indicator of therapeutic efficacy; and g) administering one or more additional doses of the immunogenic composition when the patient demonstrates therapeutic efficacy in step (f). In some embodiments, the present disclosure relates to a method for treating a patient suffering from Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the patient's AD biomarker signature (e.g., one or more of total tau protein > 400 pg / mL, pT181 tau protein > 60 pg / mL, Aβ42 < 600 pg / mL, and Aβ42:Aβ40 ratio < 0.089); b) administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2; c) determining the patient's AD biomarker signature after administering one or more doses; d) comparing the biomarker signature from the post-treatment step (c) with the biomarker signature from the pre-treatment step (a), wherein the change in the biomarker signature is an indicator of therapeutic efficacy; and e) administering one or more additional doses of the immunogenic composition when the patient demonstrates therapeutic efficacy in step (d).

[0035] In some embodiments, pT181 decreases by at least 8.1 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition. In some embodiments, total tau decreases by at least 71.8 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition. In some embodiments, pT217 decreases by at least 69.2 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition. In some embodiments, Aβ40 decreases by at least 888 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition. In some embodiments, Aβ42 remains stable compared to baseline two years after administration of one or more doses of the immunogenic composition (e.g., a change not exceeding 1%, 5%, 10%, 15%, 20%, or 25% compared to baseline). In some embodiments, Aβ42 remains stable compared to baseline two years after administration of one or more doses of the immunogenic composition (e.g., a change, e.g., a decrease, of about 25 pg / mL, 20 pg / mL, 15 pg / mL, 10 pg / mL, or 5 pg / mL compared to baseline). In some embodiments, after two years after administration of one or more doses of the immunogenic composition, the patient's Aβ42 level is decreased by about 20 pg / mL compared to baseline. In some embodiments, after two years after administration of one or more doses of the immunogenic composition, pT181 is decreased by at least 8.1 pg / mL, pT217 is decreased by at least 69.2 pg / mL, total tau is decreased by at least 71.8 pg / mL, and Aβ40 is decreased by at least 888 pg / mL compared to baseline. In some embodiments, two years after administration of one or more doses of immunogenic compositions, pT181 decreased by at least 8.1 pg / mL, pT217 decreased by at least 69.2 pg / mL, total tau decreased by at least 71.8 pg / mL, Aβ40 decreased by at least 888 pg / mL, and Aβ40 remained stable compared to baseline. In some embodiments, the change in AD biomarker signatures compared to baseline after administration of one or more doses of immunogenic compositions is calculated using an analysis of covariance (ANCOVA) model.

[0036] In some embodiments, pT181 decreases (compared to baseline) two years after administration of one or more doses of the immunogenic composition. For example, pT181 may decrease by at least about 2 to about 15 pg / mL, about 5 to about 15 pg / mL, about 2 to about 10 pg / mL, or about 5 to about 10 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition. In some embodiments, pT181 decreases by at least about 5 to about 10 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition.

[0037] In some embodiments, total tau decreases (compared to baseline) two years after administration of one or more doses of immunogenic compositions. For example, total tau may decrease by at least about 40–100 pg / mL, about 50–90 pg / mL, about 55–85 pg / mL, about 60–80 pg / mL, or about 65–75 pg / mL compared to baseline two years after administration of one or more doses of immunogenic compositions. In some embodiments, total tau decreases by at least about 65–75 pg / mL compared to baseline two years after administration of one or more doses of immunogenic compositions.

[0038] In some embodiments, pT217 decreases (compared to baseline) two years after administration of one or more doses of immunogenic compositions. For example, pT217 may decrease by at least about 40–100 pg / mL, about 50–90 pg / mL, about 55–85 pg / mL, about 60–80 pg / mL, or about 65–75 pg / mL compared to baseline two years after administration of one or more doses of immunogenic compositions. In some embodiments, pT217 decreases by at least about 65–75 pg / mL compared to baseline two years after administration of one or more doses of immunogenic compositions.

[0039] In some embodiments, Aβ40 decreases (compared to baseline) two years after administration of one or more doses of the immunogenic composition. For example, Aβ40 decreases by at least about 700–1100 pg / mL, about 750–1050 pg / mL, about 800–1000 pg / mL, or about 850–950 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition. In some embodiments, Aβ40 decreases by at least about 850–950 pg / mL compared to baseline two years after administration of one or more doses of the immunogenic composition. In some embodiments, Aβ42 remains stable compared to baseline two years after administration of one or more doses of the immunogenic composition (e.g., a change not exceeding 1%, 5%, 10%, 15%, 20%, or 25% compared to baseline). In some embodiments, Aβ42 remains stable compared to baseline two years after administration of one or more doses of the immunogenic composition (e.g., a decrease of about 25 pg / mL, 20 pg / mL, 15 pg / mL, 10 pg / mL, or 5 pg / mL compared to baseline). In some embodiments, compared to baseline two years after administration of one or more doses of the immunogenic composition, pT181 decreases by at least about 5 to about 10 pg / mL, pT217 decreases by at least about 65 to about 75 pg / mL, total tau decreases by at least about 65 to about 75 pg / mL, and Aβ40 decreases by at least about 850 to about 950 pg / mL.

[0040] In some embodiments, two years after administration of one or more doses of immunogenic compositions, pT181 decreases by at least about 5–10 pg / mL, pT217 decreases by at least about 65–75 pg / mL, total tau decreases by at least about 65–75 pg / mL, Aβ40 decreases by at least about 850–950 pg / mL, and Aβ40 remains stable compared to baseline. In some embodiments, the change in AD biomarker signatures compared to baseline after administration of one or more doses of immunogenic compositions is calculated using an analysis of covariance (ANCOVA) model.

[0041] In some embodiments, the present disclosure relates to a method for treating a patient suffering from Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the volume of medial temporal lobe atrophy as assessed by brain MRI of the patient; b) administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2 if the medial temporal lobe atrophy exceeds a threshold (e.g., a Scheltens score of 2 or higher); c) determining the volume of temporal lobe atrophy of the patient after administering one or more doses; d) comparing the temporal lobe atrophy assessed in step (c) after treatment with the temporal lobe atrophy assessed in step (a) before treatment, wherein the change in temporal lobe atrophy is an indicator of therapeutic efficacy; and e) administering one or more additional doses of the immunogenic composition when the patient demonstrates therapeutic efficacy in step (d).

[0042] In some embodiments, the Disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising administering one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 to a patient expressing one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p in a sample. In some embodiments, the amount of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in the patient differs by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more compared to a control sample or threshold. In some embodiments, the amount of hsa-miR191-5p and / or hsa-miR-23a-3p in patient samples is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more than the control sample or threshold. In some embodiments, the amount of hsa-let-7a-5p and / or hsa-miR-15a-5p in patient samples is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or less than the control sample or threshold. In some embodiments, the control sample is from a healthy person or an Alzheimer's disease patient. In some embodiments, the control sample is plasma or CSF.

[0043] In some embodiments, the disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising administering one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 to a patient having NfL in a sample. In some embodiments, the amount of NfL in the patient is less than a threshold of 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 pg / ml. In some embodiments, the amount of NfL in the patient is greater than 20 pg / ml.

[0044] In some embodiments, the disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising administering one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 to a patient with an MMSE score higher than 23. In some embodiments, the patient's MMSE score is 26, 27, 28, 29, or 30.

[0045] In some embodiments, the present disclosure relates to a method for treating Alzheimer's disease (AD) or mild cognitive impairment, comprising administering one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 to a patient having at least one ε4 allele of the ApoE gene.

[0046] In some embodiments, the present disclosure relates to a method for treating a patient suffering from Alzheimer's disease (AD) or mild cognitive impairment, comprising: a) determining the presence and / or amount of one or more metabolites in the patient; b) administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2; c) determining the presence and / or amount of one or more metabolites in the patient after administering one or more doses; d) comparing the presence and / or amount from step (c) after treatment with the presence and / or amount from step (a) before treatment, wherein a change in the amount of neurogranin is an indicator of therapeutic efficacy; and e) administering one or more additional doses of the immunogenic composition when the patient demonstrates therapeutic efficacy in step (d). In some embodiments, a change in the amount of one or more metabolites after treatment is an indicator of efficacy. In some embodiments, an increase in the amount of one or more metabolites after treatment by more than 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% is an indicator of effectiveness. In some embodiments, a decrease in the amount of one or more metabolites after treatment by more than approximately 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% is an indicator of effectiveness. In some embodiments, an indication of efficacy is that the amounts of at least two, at least three, at least four, at least five, at least six, or at least seven metabolites change after treatment. In some embodiments, in step (b), the patient is treated with at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen doses of immunogenic peptide. In some embodiments, in step (e), the patient is treated with at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen additional doses of immunogenic peptide.In some embodiments, treating a patient involves administering doses at intervals of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, or 40 weeks.

[0047] In some embodiments, the Disclosure is a method of selecting to treat a patient suffering from Alzheimer's disease with an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, a) a sample from the patient containing hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-1 The presence and / or quantity of one or more of the following: 91-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p is detected. a) comparing with a control sample or threshold, including hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, The present invention relates to the presence of one or more of hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p and / or a change in the amount in a control sample or a threshold, which is an indicator of Alzheimer's disease in the subject, and a method comprising selecting a patient for treatment based on step (b). In some embodiments, the Disclosure relates to a method for selecting a patient suffering from Alzheimer's disease to be treated with an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, the method comprising: a) detecting the presence and / or amount of 2,4-dihydroxybutanoic acid, phospholipids, phosphatidylcholine, sphingomyelin, and / or sterols in the patient's plasma, serum, or cerebrospinal fluid (CSF); b) comparing with a control sample or threshold, such that the presence and / or change in the amount of one or more metabolites compared to the amount in the control sample or threshold is an indicator of Alzheimer's disease in the subject; and c) selecting the patient for treatment based on step (b).

[0048] In some embodiments, the disclosure relates to a method for treating a patient suffering from Alzheimer's disease or mild cognitive impairment, comprising administering to the patient one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, wherein the immunogenic composition is administered in an amount effective to produce an antibody titer of at least 100 ng / mL against pathological tau. In some embodiments, the disclosure relates to a method for treating a patient suffering from Alzheimer's disease or mild cognitive impairment, comprising administering to the patient one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, wherein the immunogenic composition is administered in an amount effective to produce an antibody titer of at least 1000 ng / mL against the p108 tau peptide. In some embodiments, the disclosure relates to a method for treating a patient suffering from Alzheimer's disease or mild cognitive impairment, comprising administering to the patient one or more doses of an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, wherein the immunogenic composition is administered in an amount effective to produce an area under the curve (AUC) of at least 100,000 of the titer of an antibody (e.g., IgG, IgM antibody) that binds to the p108 tau peptide. In some embodiments, the antibody is an IgG antibody. In some embodiments, the method involves administering an initial dose regimen of six doses of immunogenic peptide or composition, followed by at least five boosters. In some embodiments, the number of boosters administered is five (fix), six, or seven.

[0049] In some embodiments, the immunogenic peptide induces at least one antibody characterized by a Kd against pathogenic tau of about 10 nM or less. In some embodiments, the immunogenic peptide induces at least one antibody characterized by a Kd against pathogenic tau of about 4.2 nM or less (e.g., about 4.2 nM to about 0.01 nM). In some embodiments, the immunogenic peptide induces at least one antibody characterized by a Kd against pathogenic tau of about 1 nM or less (e.g., about 1 nM to about 0.01 nM). In some embodiments, pathogenic tau includes tau 151-391 / 4R.

[0050] In some embodiments, the method includes an initial dosing regimen comprising administering a certain dose of an immunogenic composition once a month, for example, over a period of six months.

[0051] In some embodiments, the method further includes administering one or more boosters following the initial dose regimen. In some embodiments, the method includes administering at least five boosters (e.g., five, six, seven, etc.).

[0052] In some embodiments, if the titer of the antibody against pathological tau is below 100 ng / mL, the method further includes administering one or more boosters in an amount effective to restore the titer of the antibody against pathological tau to at least 100 ng / mL, following the initial dosing regimen, where optionally, following the administration of one or more boosters, the average titer of the antibody against pathological tau is at least 100 ng / mL for at least two years from the initial dosing regimen (e.g., 6 doses of immunogenic peptide). In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters. In some embodiments, the method includes administering at least six boosters. In some embodiments, the method includes administering at least seven boosters. In some embodiments, the patient has Alzheimer's disease.

[0053] In some embodiments, if the titer of the antibody against p108 tau peptide is below 100 ng / mL, the method further comprises administering one or more boosters in an amount effective to restore the titer of the antibody against p108 tau peptide to at least 100 ng / mL, following the initial dosing regimen, wherein optionally, following the administration of one or more boosters, the average titer of the antibody against p108 tau peptide is at least 100 ng / mL for at least two years from the initial dosing regimen (e.g., six doses of immunogenic peptide). In some embodiments, if the titer of the antibody against p108 tau peptide is below 1000 ng / mL, the method further includes administering one or more boosters in an amount effective to restore the titer of the antibody against p108 tau peptide to at least 1000 ng / mL, following the initial dosing regimen, where optionally, following the administration of one or more boosters, the average titer of the antibody against p108 tau peptide is at least 1000 ng / mL for at least two years from the initial dosing regimen (e.g., 6 doses of immunogenic peptide). In some embodiments, one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters. In some embodiments, the method includes administering at least six boosters. In some embodiments, the method includes administering at least seven boosters. In some embodiments, the patient has Alzheimer's disease.

[0054] In some embodiments, if the calculated area under the curve (AUC) of the titer of an antibody (e.g., IgG, IgM antibody) that binds to the p108 tau peptide is below 100,000, the method further includes administering one or more boosters in an amount effective to restore the calculated AUC of the titer of the antibody (e.g., IgG, IgM antibody) that binds to the p108 tau peptide to at least 100,000, following the initial dosing regimen, wherein optionally, following the administration of one or more boosters, the average calculated AUC of the titer of the antibody (e.g., IgG, IgM antibody) that binds to the p108 tau peptide is at least 100,000 for at least two years from the initial dosing regimen (e.g., six doses of immunogenic peptide). In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters. In some embodiments, the method includes administering at least six boosters. In some embodiments, the method includes administering at least seven boosters. In some embodiments, the patient has Alzheimer's disease.

[0055] In some embodiments, the immunogenic composition is administered in an amount effective to stabilize or reduce plasma neurofilament light chain accumulation compared to baseline plasma neurofilament light chain accumulation. In some embodiments, following the initial dosing regimen, the patient exhibits a stable plasma neurofilament light chain concentration compared to baseline accumulation (e.g., an increase not exceeding 1%, 5%, 10%, 15%, 20%, or 25% of neurofilament light chain concentration). In some embodiments, following the initial dosing regimen, the patient exhibits a reduced plasma neurofilament light chain accumulation compared to baseline accumulation. In some embodiments, the method further comprises administering one or more boosters following the initial dosing regimen. In some embodiments, if a patient exhibits increased plasma neurofilament light chain accumulation (e.g., an increase of more than approximately 25%) compared to baseline accumulation following an initial dosing regimen, the method further comprises administering one or more boosters in an amount effective to stabilize or reduce the plasma neurofilament light chain accumulation, where optionally, following the administration of one or more boosters, the patient exhibits stable neurofilament light chain concentrations or a reduction in plasma neurofilament light chain accumulation for at least two years from the initial dosing regimen. In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method comprises administering at least five boosters.

[0056] In some embodiments, following the administration of the immunogenic composition (e.g., following the administration of the initial dose regimen): if the patient is 50–67 years old, the increase in plasma neurofilament light chain concentration does not exceed 2 pg / mL, preferably 1.8 pg / mL, for at least two years; or if the patient is 68–85 years old, the increase in plasma neurofilament light chain concentration does not exceed 2.3 pg / mL for at least two years. In some embodiments, the method further includes administering one or more boosters following the initial dosing regimen if, during the two years following the initial dosing regimen, the mean plasma neurofilament light chain concentration has increased by more than 2 pg / mL (e.g., if the patient is 50–67 years old) or by more than 2.3 pg / mL (e.g., if the patient is 58–85 years old); where the one or more boosters are administered in an amount effective to maintain the mean increase in plasma neurofilament light chains not exceeding 2 pg / mL (e.g., if the patient is 50–67 years old) or 2.3 pg / mL (e.g., if the patient is 58–85 years old). In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters.

[0057] In some embodiments, the immunogenic composition is administered in an amount effective in stabilizing or reducing the total tau (t-tau) level in CSF compared to the CSF t-tau level before administration of the immunogenic composition. In some embodiments, the patient exhibits a stable CSF t-tau level following the initial dosing regimen compared to the CSF t-tau level before administration of the initial dosing regimen. In some embodiments, the patient exhibits a reduced CSF t-tau level following the initial dosing regimen compared to the CSF t-tau level before administration of the initial dosing regimen. In some embodiments, within two years of administration of the immunogenic composition (e.g., within two years of administration of the initial dosing regimen), the CSF t-tau concentration decreases by at least 2 ng / L, optionally at least 2.5 ng / L, and optionally at least 2.7 ng / L.

[0058] In some embodiments, the method further comprises administering one or more boosters following the initial dose regimen. In some embodiments, if the CSF t-tau concentration does not decrease by at least 2 ng / L, optionally at least 2.5 ng / L, or further optionally at least 2.7 ng / mL after the initial dose regimen, for example, within two years after the initial dose regimen, the method further comprises administering one or more boosters following the initial dose regimen in an amount effective to stabilize or reduce the CSF t-tau level, where optionally, following the administration of one or more boosters, the patient shows stabilization or reduction of t-tau levels for at least two years from the initial dose regimen or from the date of booster administration, where optionally, within two years after the initial dose regimen or within two years after booster administration, the CSF t-tau concentration decreases by at least 2 ng / L, optionally at least 2.5 ng / L, and further optionally at least 2.7 ng / L. In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters.

[0059] In some embodiments, the immunogenic composition is administered in a dose effective in suppressing the spread of pathological tau. In some embodiments, the pathological tau comprises tau 151-391 / 4R.

[0060] In some embodiments, the immunogenic composition is effective in suppressing the spread of pathological tau following an initial dose regimen. In some embodiments, the method further comprises administering one or more boosters following an initial dose regimen. In some embodiments, the spread of pathological tau increases, and the method further comprises administering one or more boosters in an amount effective in suppressing the spread of pathological tau following an initial dose regimen, wherein optionally, after the administration of one or more boosters, the spread of pathological tau is suppressed for at least two years from the initial dose regimen. In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method comprises administering at least five boosters.

[0061] In some embodiments, the immunogenic composition is administered in an amount effective to a) reduce the level of threonine 181-phosphorylated tau protein (pT181 tau) in CSF compared to the level of pT181 tau in CSF before administration of the immunogenic composition, and / or b) reduce the level of threonine 217-phosphorylated tau protein (pT217 tau) in CSF compared to the level of pT217 tau in CSF before administration of the immunogenic composition. In some embodiments, the patient shows a reduction in pT181 tau levels and / or pT217 levels in CSF following the initial administration regimen. In some embodiments, within two years of administration of the immunogenic composition, a) the pT181 tau concentration in CSF decreases by at least 5 ng / L, optionally at least 5.3 ng / L, compared to the concentration before administration of the immunogenic composition, and / or b) the pT217 tau concentration in CSF decreases by at least 30 ng / L, optionally at least 34 ng / L, compared to the concentration before administration of the immunogenic composition.

[0062] In some embodiments, the method further comprises administering one or more boosters following the initial dosing regimen. In some embodiments, if the patient shows an increase in pT181 tau levels and / or pT217 levels in the CSF following the initial dosing regimen, the method further comprises administering one or more boosters following the initial dosing regimen in an amount effective in decreasing pT181 tau levels and / or pT217 levels in the CSF, wherein optionally, following the administration of one or more boosters, the patient shows a decrease in pT181 tau levels and / or pT217 levels in the CSF for at least two years from the initial dosing regimen. In some embodiments, if the CSF pT181 tau concentration does not decrease by at least 5 ng / L (optionally at least 5.3 ng / L) and / or the CSF pT217 tau concentration does not decrease by at least 30 ng / L (optionally at least 34 ng / L) within two years from the initial dosing regimen, the method further includes administering one or more boosters in an amount effective in reducing the CSF pT181 tau concentration by at least 5 ng / L (optionally at least 5.3 ng / L) and / or the CSF pT217 tau concentration by at least 30 ng / L (optionally at least 34 ng / L) following the initial dosing regimen. In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters.

[0063] In some embodiments, the immunogenic composition is administered in an amount effective in inhibiting white matter degradation in the patient's fornix and / or genu corpus callosum compared to white matter degradation before administration of the immunogenic composition. In some embodiments, white matter degradation is measured by anisotropy ratio or mean diffusivity.

[0064] In some embodiments, the immunogenic composition is administered in an amount effective to increase the anisotropy ratio of white matter. In some embodiments, the increase in the anisotropy ratio of white matter is maintained or continues to improve (e.g., further increases) for at least two years after administration of the immunogenic composition. In some embodiments, the immunogenic composition is administered in an amount effective to decrease the mean diffusivity of white matter. In some embodiments, the decrease in the mean diffusivity of white matter is maintained or continues to improve (e.g., further decreases) for at least two years after administration of the immunogenic composition. In some embodiments, the increase in anisotropy ratio is detected with respect to the fornix. In some embodiments, the decrease in mean diffusivity is detected with respect to the fornix. Although not limited by theory, the anisotropy ratio (FA) reflects the strength of the directional diffusion of water and tends to decrease over time in AD patients, while mean diffusivity (MD) describes the overall diffusion in each of the major directions and tends to increase over time in AD patients.

[0065] In some embodiments, the immunogenic composition is administered in an amount effective to inhibit axonal degeneration compared to axonal degradation before administration of the immunogenic composition. In some embodiments, axonal degeneration is measured by anisotropy ratio or mean diffusivity. In some embodiments, the immunogenic composition is administered in an amount effective to increase the axonal anisotropy ratio. In some embodiments, the increase in axonal anisotropy ratio is maintained or continues to improve (e.g., further increases) for at least two years after administration of the immunogenic composition. In some embodiments, the immunogenic composition is administered in an amount effective to decrease the axonal mean diffusivity. In some embodiments, the decrease in axonal mean diffusivity is maintained or continues to improve (e.g., further decreases) for at least two years after administration of the immunogenic composition. In some embodiments, white matter degradation is inhibited and / or axonal degradation is inhibited after administration of the initial dose regimen.

[0066] In some embodiments, the method further includes administering one or more boosters following the initial dose regimen. In some embodiments, if the patient shows increased white matter degradation and / or increased axonal degradation following the initial dose regimen, the method further includes administering one or more boosters following the initial dose regimen in an amount effective to inhibit white matter degeneration and / or axonal degeneration, wherein optionally, the administration of one or more boosters inhibits white matter degradation and / or axonal degradation for at least two years from the initial dose regimen. In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters.

[0067] In some embodiments, the immunogenic composition is administered in an amount effective in preventing hippocampal atrophy (for example, effective in preventing a decrease in hippocampal volume compared to the hippocampal volume before administration of the immunogenic composition). In some embodiments, the method includes administering an initial dosing regimen comprising administering the immunogenic composition once a month for six months, followed optionally by the administration of one or more boosters. In some embodiments, if, following the initial dosing regimen comprising administering the immunogenic composition once a month for six months, the patient's hippocampal volume has decreased compared to the patient's hippocampal volume before administration of the initial dosing regimen, the method further includes administering one or more boosters in an amount effective in preventing further hippocampal atrophy, wherein optionally, the one or more boosters are administered in an amount effective in preventing further hippocampal atrophy for at least two years.

[0068] In some embodiments, the patient is 50-67 years old, and within two years of administration of the immunogenic composition, the decrease in the patient's hippocampal volume compared to the patient's hippocampal volume before administration of the immunogenic composition does not exceed 10%, preferably not exceeding 8%.

[0069] In some embodiments, if, following an initial dosing regimen comprising administering an immunogenic composition once a month for six months, the patient's hippocampal volume has decreased by more than 10% compared to the patient's hippocampal volume before administration of the initial dosing regimen, the method further optionally includes administering one or more boosters in an amount effective to prevent further hippocampal atrophy (e.g., to prevent further loss of hippocampal volume of more than 10%) for at least two years. In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters.

[0070] In some embodiments, the immunogenic composition is administered in a dose effective in preventing cortical atrophy (for example, effective in preventing a decrease in cortical volume compared to the cortical volume before administration of the immunogenic composition). In some embodiments, the method includes administering an initial dosing regimen comprising administering the immunogenic composition once a month for six months, followed optionally by one or more booster doses.

[0071] In some embodiments, if, following an initial dosing regimen comprising administering an immunogenic composition once a month for six months, the patient's cortical volume decreases compared to the patient's cortical volume before administration of the initial dosing regimen, the method further comprises administering one or more boosters in an amount effective to prevent further cortical atrophy, wherein optionally, the one or more boosters are administered in an amount effective to prevent further cortical atrophy for at least two years.

[0072] In some embodiments, the patient is 50–67 years old, and within two years of administration of the immunogenic composition, the decrease in the patient's cortical volume compared to the patient's cortical volume before administration of the immunogenic composition does not exceed 5%, preferably 4%. In some embodiments, if, following an initial administration regimen including monthly administration of the immunogenic composition for six months, the patient's cortical volume decreases by more than 5% compared to the patient's cortical volume before administration of the initial administration regimen, the method further optionally includes administering one or more boosters in an amount effective to prevent further cortical atrophy (e.g., preventing further loss of cortical volume exceeding 5%) for at least two years. In some embodiments, the one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters.

[0073] In some embodiments, atrophy (e.g., volume) is measured by MRI volumetrication.

[0074] In some embodiments, the patient is 50–67 years old, and the immunogenic composition is administered in a dose effective in slowing the rate of cognitive decline in the patient. In some embodiments, the method includes administering an initial dosing regimen comprising administering the immunogenic composition once a month for six months, followed optionally by one or more boosters. In some embodiments, the rate of cognitive decline in the patient is measured using the Clinical Dementia Assessment Scale–Total Item (CDR-SB) test, the Alzheimer's Disease Collaborative–Mild Cognitive Impairment and Activities of Daily Living (ADCS MCI ADL) questionnaire, the Mini-Mental State Examination (MMSE), and / or a cognitive battery, the battery comprising the Cogstate International Shopping List Task, the Cogstate One-Card Learning and One-Card Back Tasks, the Letter Fluency Test and the Category Fluency Test, and / or the Number-Symbol Conversion Test.

[0075] In some embodiments, the increase in the patient's CDR-SB test score compared to the patient's CDR-SB test score before administration of the immunogenic composition is not more than 4 points within 2 years from administration of the immunogenic composition (e.g., from administration of the initial dose regimen). In some embodiments, the decrease in the patient's MMSE score compared to the patient's MMSE score before administration of the immunogenic composition is not more than 7 points, preferably not more than 6.5 points, within 2 years from administration of the immunogenic composition (e.g., from administration of the initial dose regimen). In some embodiments, the decrease in the patient's ADCS MCI ADL questionnaire score compared to the patient's ADCS MCI ADL questionnaire score before administration of the immunogenic composition is not more than 14 points, preferably not more than 13.5 points, within 2 years from administration of the immunogenic composition (e.g., from administration of the initial dose regimen).

[0076] In some embodiments, the method further includes administering one or more boosters if: a) the patient's CDR-SB score increases by more than 4 compared to the patient's CDR-SB test score before administration of the immunogenic composition (e.g., initial dose regimen); b) the patient's MMSE score decreases by more than 6.5 or 7 compared to the patient's MMSE score before administration of the immunogenic composition (e.g., initial dose regimen); and / or c) the patient's ADCS MCI ADL questionnaire score decreases by more than 13.5 or 14 compared to the patient's ADCS MCI ADL questionnaire score before administration of the immunogenic composition (e.g., initial dose regimen). In some embodiments, one or more boosters are administered in an amount effective to prevent: a) an increase in the patient's CDR-SB test score of more than 4 compared to the patient's CDR-SB test score before administration of the immunogenic composition (e.g., initial dose regimen); b) a decrease in the patient's MMSE score of more than 6.5 or more than 7 compared to the patient's MMSE score before administration of the immunogenic composition (e.g., initial dose regimen); and / or c) a decrease in the patient's ADCS MCI ADL questionnaire score of more than 13.5 or more than 14 compared to the patient's ADCS MCI ADL questionnaire score before administration of the immunogenic composition (e.g., initial dose regimen). In some embodiments, one or more boosters are administered once every three months. In some embodiments, the method includes administering at least five boosters.

[0077] In any of the above embodiments: In some embodiments, the immunogenic peptide further comprises a carrier protein or peptide. In some embodiments, the carrier comprises at least one of the following: serum albumin, keyhole limpet hemocyanin, immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid, and / or toxoids from other pathogenic bacteria such as diphtheria, Escherichia coli (E. coli), Vibrio cholerae (V. cholera), or Helicobacter pylori (H. pylori), attenuated toxin derivatives, cytokines, e.g., IL-1, IL-1α or IL-1β peptides, IL-2, IFNγ, IL-10, GM-CSF, etc., or chemokines, e.g., MIP1α, MIP1β, or RANTES. In some embodiments, the carrier comprises keyhole limpet hemocyanin (KLH) or a fragment thereof. In some embodiments, KLH or a fragment thereof is coupled to SEQ ID NO: 1 or SEQ ID NO: 2 via a maleimide linker. In some embodiments, the maleimide linker contains GMBS. In some embodiments, the maleimide linker is sulfoGMBS. In some embodiments, the dose contains about 20 to 50 μg, for example, at least about 20 μg, at least about 30 μg, at least about 40 μg, or at least about 50 μg of immunogenic peptide. In some embodiments, each dose contains about 40 μg of immunogenic peptide. In some embodiments, the immunogenic composition further contains an adjuvant, for example, an aluminum compound. In some embodiments, the aluminum compound contains aluminum hydroxide (Al(OH)3). In some embodiments, the adjuvant is about 0.1 mg to about 10 mg of aluminum (Al 3+ ), optionally, approximately 0.5 mg of aluminum (Al 3+ ) contains. In some embodiments, the immunogenic composition optionally further comprises about 0.3 mL of phosphate buffer. In some embodiments, the immunogenic composition comprises an immunogenic peptide containing SEQ ID NO: 2 coupled to KLH via a maleimide linker (e.g., sulfoGMBS) and about 0.5 mg of aluminum (Al 3+) and optionally approximately 0.3 mL of phosphate buffer. In some embodiments, treating a patient involves administering 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 50, or 100 doses of immunogenic peptide. In some embodiments, treating a patient involves administering doses at intervals of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, or 40 weeks. In some embodiments, treating a patient involves administering one or more doses (e.g., six doses) of the immunogenic composition at four-week intervals, followed by one or more doses (e.g., five or six doses) of the immunogenic composition at twenty-week intervals. In some embodiments, the control sample is from a healthy person or a patient with Alzheimer's disease. In some embodiments, the control sample is a CSF sample or a plasma sample. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 1 and one, two, three, four, or five additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those directly adjacent to SEQ ID NO: 1 when aligned to tau 2N4R. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 2 and one, two, three, four, or five additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those directly adjacent to SEQ ID NO: 2 when aligned to tau 2N4R.

[0078] In any of the above embodiments: In some embodiments, one or more boosters comprise an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the immunogenic peptide further comprises a carrier protein or peptide. In some embodiments, the carrier comprises at least one of the following: serum albumin, keyhole limpet hemocyanin, immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid, and / or toxoids from other pathogenic bacteria such as diphtheria, Escherichia coli (E. coli), Vibrio cholerae (V. cholera), or Helicobacter pylori (H. pylori), attenuated toxin derivatives, cytokines, e.g., IL-1, IL-1α or IL-1β peptides, IL-2, IFNγ, IL-10, GM-CSF, etc., or chemokines, e.g., MIP1α, MIP1β, or RANTES. In some embodiments, the carrier comprises keyhole limpet hemocyanin (KLH) or a fragment thereof. In some embodiments, KLH or a fragment thereof is coupled to SEQ ID NO: 1 or SEQ ID NO: 2 via a maleimide linker. In some embodiments, the maleimide linker comprises GMBS. In some embodiments, the maleimide linker is sulfoGMBS. In some embodiments, the booster further comprises an adjuvant, such as an aluminum compound. In some embodiments, the aluminum compound comprises aluminum hydroxide (Al(OH)3). In some embodiments, the adjuvant is about 0.1 mg to about 10 mg of aluminum (Al 3+ ), optionally, approximately 0.5 mg of aluminum (Al 3+ ) contains. In some embodiments, the booster optionally further comprises about 0.3 mL of phosphate buffer. In some embodiments, the booster comprises an immunogenic peptide containing SEQ ID NO: 2 coupled to KLH via a maleimide linker (e.g., sulfoGMBS) and about 0.5 mg of aluminum (Al 3+) and optionally about 0.3 mL of phosphate buffer. In some embodiments, the booster dose contains at least about 20 μg, at least about 30 μg, at least about 40 μg, or at least about 50 μg of immunogenic peptide, optionally about 20-50 μg of immunogenic peptide. In some embodiments, the booster dose contains about 40 μg of immunogenic peptide. In some embodiments, the booster is identical in composition to the immunogenic composition administered as part of the initial dose regimen. In some embodiments, the booster is administered in the same dose as the immunogenic composition administered as part of the initial dose regimen. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 1 and 1, 2, 3, 4, or 5 additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those directly adjacent to SEQ ID NO: 1 when aligned to tau 2N4R. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 2 and one, two, three, four, or five additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those directly adjacent to SEQ ID NO: 2 when aligned with tau 2N4R.

[0079] In any of the above embodiments: In some embodiments, the patient has a diagnosis of near-certainty of Alzheimer's disease according to the revised 2011 NIA-AA diagnostic criteria. In some embodiments, the patient has a diagnosis of near-certainty of Alzheimer's disease according to the revised 2018 NIA-AA diagnostic criteria. In some embodiments, the patient has a Mini-Mental State Examination total score of 20 or higher and 26 or lower. In some embodiments, the patient has brain MRI findings consistent with a diagnosis of Alzheimer's disease. In some embodiments, the patient has medial temporal lobe atrophy as assessed by brain MRI and on a Scheltens score of 2 or higher (rated on a scale of 0 to 4 on the side with more advanced atrophy). In some embodiments, the patient has a positive AD biomarker signature in CSF (e.g., one or more of the following: total tau protein > 400 pg / mL; pT181 tau protein > 60 pg / mL; Aβ42 < 600 pg / mL; and Aβ42:Aβ40 ratio < 0.089). In some embodiments, the patient is 50–85 years old, e.g., 50–67 years, 50–70 years, 68–85 years, or 71–85 years. In some embodiments, the patient is 50–67 years old. In some embodiments, the patient is 50–70 years old. In some embodiments, the patient is 68–85 years old. In some embodiments, the patient has received stabilization therapy with an acetylcholinesterase inhibitor for at least 3 months prior to the initiation of treatment. In some embodiments, the patient has received stabilization dose memantine therapy for at least 3 months prior to the initiation of treatment. In some embodiments, the patient is male. In some embodiments, prior to administration of immunogenic peptides, the patient has a cerebrospinal fluid (CSF) level of less than 600 pg / mL of Aβ. 42The CSF has a phosphorylated tau (p-tau) T181 concentration higher than 60 pg / mL and a total tau (t-tau) concentration higher than 400 pg / mL. In some embodiments, prior to treatment, the patient is under 80 years old, has a plasma neurofilament light chain concentration higher than 10 pg / mL, has detectable tau protein in the CSF, and is free from microbleeds, early or large converging deep hemispheric white matter lesions (Fazekas grade 2 or 3), severe hippocampal atrophy (Scheltens score 4), and hallucinations. In some embodiments, the patient's diagnosis is performed in vitro.

[0080] In some embodiments, the patient has been diagnosed with Alzheimer's disease. In some embodiments, the patient has Alzheimer's disease. In some embodiments, the patient has been diagnosed with mild cognitive impairment. In some embodiments, the patient has mild cognitive impairment.

[0081] This patent or application file includes at least one drawing prepared in color. A copy of this patent or patent application publication with color drawings will be provided by the authorities upon request, upon payment of the necessary fees. In embodiments of the present invention, for example, the following items are provided. (Item 1) An immunogenic composition for use in the treatment of Alzheimer's disease or mild cognitive impairment in a patient who requires it, wherein the immunogenic composition comprises an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2, and prior to treatment, the patient is between 50 and 85 years old. (Item 2) The immunogenic composition for use as described in item 1, wherein the patient is 50 to 70 years old before treatment. (Item 3) The immunogenic composition for use as described in item 1, wherein the patient is 50 to 67 years old before treatment. (Item 4) For use according to any one of items 1 to 3, an immunogenic composition wherein, before treatment, the patient has received stable therapy with an acetylcholinesterase inhibitor for at least 3 months. Immunogenic composition. (Item 5) For use according to any one of items 1 to 4, an immunogenic composition wherein, before treatment, the patient has received stable-dose memantine treatment for at least 3 months. (Item 6) For use according to any one of items 1 to 5, an immunogenic composition wherein the patient has a diagnosis of Alzheimer's disease that is highly probable according to the Revised 2011 NIA-AA Diagnostic Criteria or the 2018 NIA-AA Diagnostic Criteria. (Item 7) For use according to any one of items 1 to 6, an immunogenic composition wherein the patient has brain MRI findings consistent with a diagnosis of Alzheimer's disease. (Item 8) For use according to any one of items 1 to 7, an immunogenic composition wherein the patient has medial temporal lobe atrophy as evaluated by brain MRI and two or more Scheltens scores. (Item 9) For use according to any one of items 1 to 8, an immunogenic composition wherein the patient has one or more of the following: total tau protein in cerebrospinal fluid (CSF) > 400 pg / mL, pT181 tau protein in CSF > 60 pg / mL, Aβ42 in CSF < 600 pg / mL, and / or Aβ42:Aβ40 ratio in CSF < 0.089. (Item 10) For use according to any one of items 1 to 9, an immunogenic composition wherein, before treatment, the patient is less than 80 years old, has a plasma neurofilament light chain concentration higher than 10 pg / mL, has detectable tau protein in CSF, and lacks microbleeds, early or large confluent hemispheric deep white matter lesions (Fazekas grade 2 or 3), severe hippocampal atrophy (Scheltens score of 4), and / or hallucinations. (Item 11) An immunogenic composition for use according to any one of items 1 to 10, wherein the patient has Alzheimer's disease. (Item 12) An immunogenic composition for use according to any one of items 1 to 11, wherein the patient is male. (Item 13) (a) an antibody titer of at least 100 ng / mL against pathological tau, and / or (b) An immunogenic composition for use as described in any one of items 1 to 12, formulated to be administered to a patient in an amount and dosage regime effective in producing an antibody titer of at least 100 ng / mL against the p108 tau peptide. (Item 14) (a) an average antibody titer of at least 100 ng / mL against pathological tau over a period of at least two years, and / or (b) Mean antibody titer of at least 100 ng / mL against p108 tau peptide over a period of at least two years. An immunogenic composition for use according to any one of items 1 to 12, formulated to be administered to the patient in an amount and dosage regime effective in producing the effect. (Item 15) An immunogenic composition for use according to any one of items 1 to 14, wherein the immunogenic peptide induces at least one antibody characterized by a Kd of approximately 10 nM or less, optionally approximately 4.2 nM or less, and optionally approximately 4.2 nM to approximately 0.01 nM for pathogenic tau. (Item 16) The immunogenic peptide is approximately 1 nM or less, and optionally approximately 1 nM to approximately 0.01 nM. An immunogenic composition for use as described in item 15, which induces at least one antibody characterized by Kd against tau. (Item 17) An immunogenic composition for use according to any one of items 13 to 16, comprising pathological tau 151-391 / 4R. (Item 18) An immunogenic composition for use according to any one of items 1 to 17, formulated to be administered to the patient in an amount and dosing regimen effective in stabilizing or reducing plasma neurofilament light chain accumulation compared to baseline plasma neurofilament light chain accumulation. (Item 19) The immunogenic composition for use as described in item 18, wherein, upon administration of the immunogenic composition, the increase in plasma neurofilament light chain concentration compared to baseline in the patient does not exceed 1%, 5%, 10%, 15%, 20%, or 25%. (Item 20) An immunogenic composition for use as described in item 18, formulated to be administered to the patient in an amount and dosage regimen effective in reducing plasma neurofilament light chain accumulation compared to baseline plasma neurofilament light chain accumulation. (Item 21) An immunogenic composition for use as described in item 18, formulated to be administered to the patient in an amount and dosing regimen effective in stabilizing or reducing plasma neurofilament light chain accumulation over a period of at least two years compared to baseline plasma neurofilament light chain accumulation. (Item 22) (a) An increase in plasma neurofilament light chain concentration not exceeding 2 pg / mL (preferably not exceeding 1.8 pg / mL) over at least two years in patients treated between the ages of 50 and 67, or (b) An increase in plasma neurofilament light chain concentration not exceeding 2.3 pg / mL over at least two years in patients treated between the ages of 68 and 85. An immunogenic composition for use according to any one of items 18 to 21, formulated to be administered to the patient in an amount and dosage regime effective in producing the effect. (Item 23) An immunogenic composition for use according to any one of items 1 to 22, formulated to be administered to the patient in an amount and dosage regimen effective in stabilizing the total tau (t-tau) level in CSF compared to the baseline t-tau level in CSF. (Item 24) An immunogenic composition for use according to any one of items 1 to 22, formulated to be administered to the patient in an amount and dosage regimen effective in lowering the t-tau level in CSF compared to the baseline t-tau level in CSF. (Item 25) The immunogenic composition for use as described in item 24, formulated to be administered to the patient in an amount and dosing regimen effective in reducing the CSF t-tau level by at least 2 ng / L (optionally at least 2.5 ng / L, and further optionally at least 2.7 ng / L) compared to the baseline CSF t-tau level, and optionally the reduction lasting for two years. (Item 26) The immunogenic composition for use according to any one of items 11 to 25, wherein the immunogenic composition is formulated to be administered to the patient in an amount and dosage regime effective in suppressing the spread of pathological tau, and optionally the pathological tau comprises tau 151-391 / 4R. (Item 27) An immunogenic composition for use as described in item 26, formulated to be administered to the patient in an amount and dosage regimen effective in suppressing the spread of pathological tau for at least two years. (Item 28) An immunogenic composition for use as described in item 26 or 27, comprising pathological tau 151-391 / 4R. (Item 29) (a) A reduction in threonine-181 phosphorylated tau protein (pT181 tau) levels in CSF compared to baseline CSF pT181 tau levels over an optional period of at least two years, and / or (b) A reduction in threonine-217 phosphorylated tau protein (pT217 tau) levels in CSF compared to baseline CSF pT217 tau levels over an optional period of at least two years. An immunogenic composition for use according to any one of items 1 to 28, formulated to be administered to the patient in an effective amount and dosage regimen. (Item 30) (a) A decrease of at least 5 ng / L, optionally at least 5.3 ng / L, in the CSF pT181 tau concentration compared to the baseline CSF pT181 tau concentration over a period of at least two years, and / or (b) A reduction of at least 30 ng / L, and optionally at least 34 ng / L, in the CSF pT217 tau concentration over at least two years compared to the baseline CSF pT217 tau concentration. An immunogenic composition for use as described in item 29, formulated to be administered to the patient in an effective amount and dosage regimen. (Item 31) An immunogenic composition for use according to any one of items 1 to 30, which is formulated to be administered to the patient in an amount and dosing regimen effective in inhibiting white matter degradation in the patient's fornix and / or genu callosum compared to baseline white matter degradation, for at least two years at the discretion of the patient. (Item 32) An immunogenic composition for use as described in item 31, wherein white matter degradation is measured by anisotropic ratio or mean diffusivity. (Item 33) An immunogenic composition for use according to any one of items 1 to 32, which is formulated to be administered to the patient, optionally, for at least two years, in an amount and dosing regimen effective in inhibiting axonal degeneration compared to baseline axonal degradation. (Item 34) An immunogenic composition for use as described in item 33, wherein axonal degeneration is measured by anisotropy ratio or mean diffusivity. (Item 35) An immunogenic composition for use according to any one of items 1 to 34, formulated to be administered to the patient in an amount and dosing regimen effective in preventing hippocampal atrophy (for example, effective in preventing a decrease in hippocampal volume compared to baseline hippocampal volume) for at least two years, at the patient's discretion. (Item 36) The immunogenic composition for use according to item 35, formulated to be administered to a patient aged 50-67 years in an amount and dosage regimen effective in preventing hippocampal atrophy, wherein the hippocampal atrophy is indicated by a decrease in the patient's hippocampal volume of more than 10% compared to baseline. (Item 37) An immunogenic composition for use as described in item 35 or 36, formulated to be administered to the patient in an amount and dosage regimen effective in preventing hippocampal atrophy for at least two years. (Item 38) An immunogenic composition for use according to any one of items 1 to 37, which is formulated to be administered to the patient in an amount and dosing regimen effective in preventing cortical atrophy (e.g., effective in preventing a decrease in cortical volume compared to baseline cortical volume) for at least two years, at the discretion of the patient. (Item 39) The immunogenic composition for use according to item 38, wherein the immunogenic composition is formulated to be administered to a patient aged 50-67 years in an amount and dosage regimen effective in preventing cortical atrophy, and the cortical atrophy is indicated by a decrease in the patient's cortical volume of more than 5% compared to baseline. (Item 40) An immunogenic composition for use as described in item 38 or 39, formulated to be administered to the patient in an amount and dosage regimen effective in preventing cortical atrophy for at least two years. (Item 41) An immunogenic composition for use according to any one of items 35-40, wherein atrophy (e.g., reduction in volume) is measured by MRI volumetrication. (Item 42) An immunogenic composition for use according to any one of items 1 to 41, formulated to be administered to a patient aged 50 to 67 years in an amount and dosage regimen effective in slowing the rate of cognitive decline in the patient. (Item 43) The immunogenic composition for use as described in item 42, wherein the rate of cognitive decline in the patient is measured using the Clinical Dementia Assessment Scale - Total Item (CDR-SB) Test, the Alzheimer's Disease Collaborative - Mild Cognitive Impairment and Activities of Daily Living (ADCS-MCI-ADL) Questionnaire, the Mini-Mental State Examination (MMSE), and / or a cognitive battery comprising the Cogstate International Shopping List Task, the Cogstate One-Card Learning and One-Card Back Task, the Letter Fluency Test and the Category Fluency Test, and / or the Number-Symbol Conversion Test. (Item 44) An immunogenic composition for use as described in item 43, formulated to be administered to the patient in an amount and dosing regimen effective in preventing an increase of more than 4 in the patient's CDR-SB test score compared to the patient's baseline CDR-SB test score over a period of at least two years, at the patient's discretion. (Item 45) An immunogenic composition for use according to item 43 or 44, which is formulated to be administered to the patient in an amount and dosing regimen effective, preferably effective, in preventing a decrease of more than 7 points in the patient's MMSE score compared to the patient's baseline MMSE score, over an optional period of at least two years, compared to the patient's baseline MMSE score. (Item 46) An immunogenic composition for use according to any one of items 43 to 45, which is formulated to be administered to the patient in an amount and dosing regimen effective, preferably effective, for preventing a decrease of more than 14 points in the patient's ADCS MCI ADL Questionnaire score compared to the patient's baseline ADCS MCI ADL Questionnaire score, compared to the patient's baseline ADCS MCI ADL Questionnaire score, over an optional period of at least two years. (Item 47) The patient has at least one ApoE-ε4 allele, one of items 1-46. An immunogenic composition for use as described in paragraph 1. (Item 48) An immunogenic composition for use according to any one of items 1 to 47, wherein, prior to treatment, the patient has an MMSE score of 20 to 26, or optionally 24 to 26. (Item 49) An immunogenic composition for use as described in any one of items 1 to 48, comprising an optional administration regimen of once-monthly doses over a period of six months. (Item 50) An immunogenic composition for use as described in item 49, further comprising one or more boosters for administration following an initial once-monthly dosing regimen. (Item 51) An immunogenic composition for use as described in item 50, comprising at least five boosters. (Item 52) An immunogenic composition for use according to item 50 or 51, wherein the booster is administered once every three months. (Item 53) An immunogenic composition for use according to any one of items 1 to 52, comprising one or more doses containing at least about 20 μg of the immunogenic peptide (optionally at least about 30 μg, at least about 40 μg, or at least about 50 μg of the immunogenic peptide). (Item 54) An immunogenic composition for use as described in item 53, comprising one or more doses containing approximately 20-50 μg of the immunogenic peptide. (Item 55) An immunogenic composition for use as described in item 54, comprising one or more doses containing approximately 40 μg of the immunogenic peptide. (Item 56) An immunogenic composition for use as described in item 55, comprising the immunogenic peptide in a dose of approximately 40 μg. (Item 57) An immunogenic composition for use as described in any one of items 1 to 56, administered in doses of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 50, or 100. (Item 58) An immunogenic composition for use as described in any one of items 1 to 57, administered as one or more doses (six doses, optionally) at one-month intervals (or four-week intervals, optionally), followed by one or more doses (five, six, or seven doses, optionally) at subsequent 20-week intervals. (Item 59) The immunogenic composition for use according to any one of items 1 to 58, further comprising a carrier, the carrier comprising serum albumin, keyhole limpet hemocyanin (KLH) or a fragment thereof, immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid, toxoid derived from another pathogenic bacterium, attenuated toxin derivatives, cytokines such as IL-1, IL-1α, and IL-1β, IL-2, IFNγ, IL-10, GM-CSF, etc., or chemokines such as MIP1α, MIP1β, and RANTES, etc. (Item 60) The immunogenic composition for use according to item 59, wherein the carrier is KLH or a fragment thereof. (Item 61) The KLH or a fragment thereof is coupled to the immunogenic peptide via a maleimide linker, and optionally the maleimide linker is N-γ-maleimidobutyryl-o An immunogenic composition for use as described in item 60, which is xisulfosuccinimide ester (sulfoGMBS). (Item 62) An immunogenic composition for use according to any one of items 1 to 61, further comprising an adjuvant. (Item 63) An immunogenic composition for use according to item 62, wherein the adjuvant comprises an aluminum compound. (Item 64) An immunogenic composition for use according to item 63, wherein the aluminum compound comprises aluminum hydroxide (Al(OH)3). (Item 65) An immunogenic composition for use as described in any one of items 1 to 64, further comprising, optionally, a volume of approximately 0.3 mL of phosphate buffer. (Item 66) An immunogenic composition for use according to any one of items 1 to 65, wherein the immunogenic peptide comprises SEQ ID NO: 2. (Item 67) An immunogenic peptide containing SEQ ID NO: 2 coupled to KLH via a maleimide linker (optionally sulfoGMBS), and approximately 0.5 mg of aluminum (Al 3+ An immunogenic composition for use according to any one of items 1 to 66, comprising ) and phosphate buffer in a volume of approximately 0.3 mL. (Item 68) An immunogenic composition for use according to any one of items 1 to 65, wherein the immunogenic peptide comprises SEQ ID NO: 1. (Item 69) An immunogenic composition for use according to any one of items 1 to 65 or 68, wherein the immunogenic peptide comprises SEQ ID NO: 1 and up to five additional amino acids located at the C-terminus or N-terminus of the sequence from adjacent amino acids in tau isoform 2N4R. (Item 70) An immunogenic composition for use according to any one of items 1 to 67, wherein the immunogenic peptide comprises SEQ ID NO: 2 and up to five additional amino acids located at the C-terminus or N-terminus of the sequence from adjacent amino acids in tau isoform 2N4R. (Item 71) An immunogenic composition for use according to any one of items 1 to 65, wherein the immunogenic peptide comprises Sequence ID No. 1. (Item 72) An immunogenic composition for use according to any one of items 1 to 65, wherein the immunogenic peptide comprises Sequence ID No. 2. (Item 73) An immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 for use in the treatment of Alzheimer's disease (AD) or mild cognitive impairment in patients who require it, wherein the use in said treatment is (a) Determine the amount of neurofilament light chains (NfL) in the patient. (b) Administering one dose or more of the immunogenic composition, (c) After administering one or more doses as described above, determine the amount of NfL in the patient. (d) Comparing the amount from step (c) after treatment with the amount from step (a) before treatment, the change in the amount of NfL is an indicator of treatment effectiveness, and (e) When the patient demonstrates therapeutic efficacy in step (d), administer an additional dose of the immunogenic composition one or more times. An immunogenic composition containing [the specified substance]. (Item 74) The immunogenic composition for use as described in item 73, wherein the amount of NfL two years after administration of one or more doses of the immunogenic composition has not increased by more than approximately 3.2 pg / mL compared to baseline. (Item 75) An immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 for use in the treatment of Alzheimer's disease (AD) or mild cognitive impairment in patients who require it, wherein the use in said treatment is (a) Determine the presence and / or amount of neurogranin in the patient (b) Administering one dose or more of the immunogenic composition, (c) After administering one or more doses as described above, determine the amount of neurolanin in the patient. (d) Comparing the amount from step (c) after treatment with the amount from step (a) before treatment, wherein the change in neurogranin levels is an indicator of therapeutic effectiveness, and (e) When the patient demonstrates therapeutic efficacy in step (d), administer an additional dose of the immunogenic composition one or more times. An immunogenic composition containing [the specified substance]. (Item 76) An immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 for use in the treatment of Alzheimer's disease (AD) or mild cognitive impairment in patients who require it, wherein the use in said treatment is (a) Determine the Mini-Mental State Examination (MMSE) score of the patient, (b) Compare the score from step (a) with a threshold score, wherein the threshold score is optionally 20 to 26. (c) Selecting the patient for treatment if the patient's MMSE score exceeds the threshold, (d) Administering one dose or more of the immunogenic composition, (e) After administering one or more doses, determine the MMSE score of the patient. (f) Comparing the MMSE score from step (e) after treatment with the MMSE score from step (a) before treatment, wherein the change in the MMSE score is an indicator of treatment effectiveness, and (g) When the patient demonstrates therapeutic efficacy in step (f), administer an additional dose of the immunogenic composition one or more times. An immunogenic composition containing [the specified substance]. (Item 77) An immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 for use in the treatment of Alzheimer's disease (AD) or mild cognitive impairment in patients who require it, wherein the use in said treatment is (a) Determine the AD biomarker signature of the patient (optionally, one or more of the following: total tau protein > 400 pg / mL, pT181 tau protein > 60 pg / mL, Aβ42 < 600 pg / mL, and Aβ42:Aβ40 ratio < 0.089), (b) Administering one dose or more of the immunogenic composition, (c) After administering one or more doses, determine the AD biomarker signature of the patient. (d) Comparing the biomarker signature from the post-treatment step (c) with the biomarker signature from the pre-treatment step (a), wherein the change in the biomarker signature is an indicator of treatment effectiveness, and (e) When the patient demonstrates therapeutic efficacy in step (d), administer an additional dose of the immunogenic composition one or more times. An immunogenic composition containing [the specified substance]. (Item 78) Two years after administration of the immunogenic composition, pT181 decreased by at least 8.1 pg / mL compared to baseline, and / or pT217 decreased by at least 69.2 pg / mL compared to baseline, and / or total tau decreased by at least 71.8 pg / mL compared to baseline, and / or Aβ40 decreased by at least 888 pg / mL compared to baseline, the immunogenic composition for use according to item 77. (Item 79) An immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 for use in the treatment of Alzheimer's disease (AD) or mild cognitive impairment in patients who require it, wherein the use in said treatment is (a) Determine the medial temporal lobe atrophy volume as assessed by the patient's brain MRI, (b) If medial temporal lobe atrophy exceeds the threshold (optionally, a Scheltens score of 2 or higher), administer one dose or more of the immunogenic composition. (c) After administering one or more doses as described above, determine the volume of temporal lobe atrophy in the patient. (d) Comparing temporal lobe atrophy assessed in step (c) after treatment with temporal lobe atrophy assessed in step (a) before treatment, wherein the change in temporal lobe atrophy is an indicator of treatment effectiveness, and (e) When the patient demonstrates therapeutic efficacy in step (d), administer an additional dose of the immunogenic composition one or more times. An immunogenic composition containing [the specified substance]. (Item 80) (a) an antibody titer of at least 100 ng / mL against pathological tau, and / or (b) Antibody titer of at least 100 ng / mL against p108 tau peptide An immunogenic composition for use according to any one of items 73 to 79, which is formulated to be administered to the patient in an amount and dosage regime effective in producing the effect. (Item 81) (a) an average antibody titer of at least 100 ng / mL against pathological tau over a period of at least two years, and / or (b) Mean antibody titer of at least 100 ng / mL against p108 tau peptide over a period of at least two years. An immunogenic composition for use according to any one of items 73 to 79, which is formulated to be administered to the patient in an amount and dosage regime effective in producing the effect. (Item 82) An immunogenic composition for use according to any one of items 73 to 81, wherein the immunogenic peptide induces at least one antibody characterized by a Kd of approximately 10 nM or less, optionally approximately 4.2 nM or less, and optionally approximately 4.2 nM to approximately 0.01 nM against pathological tau. (Item 83) An immunogenic composition for use as described in item 82, wherein the immunogenic peptide induces at least one antibody characterized by a Kd of approximately 1 nM or less, and optionally between approximately 1 nM and approximately 0.01 nM, against pathological tau. (Item 84) An immunogenic composition for use according to any one of items 80 to 83, comprising pathological tau 151-391 / 4R. (Item 85) An immunogenic composition for use according to any one of items 73 to 84, wherein, prior to treatment, the patient is between 50 and 85 years of age. (Item 86) An immunogenic composition for use according to any one of items 73 to 85, comprising one or more doses containing at least about 20 μg of the immunogenic peptide (optionally, at least about 30 μg, at least about 40 μg, or at least about 50 μg of the immunogenic peptide). (Item 87) An immunogenic composition for use as described in item 86, comprising one or more doses containing approximately 20-50 μg of the immunogenic peptide. (Item 88) An immunogenic composition for use as described in item 87, comprising one or more doses containing approximately 40 μg of the immunogenic peptide. (Item 89) An immunogenic composition for use as described in item 88, comprising approximately 40 μg of the immunogenic peptide in each dose. (Item 90) The immunogenic composition for use according to any one of items 73 to 89, further comprising a carrier, the carrier comprising serum albumin, keyhole limpet hemocyanin (KLH) or a fragment thereof, immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid, toxoid derived from another pathogenic bacterium, attenuated toxin derivatives, cytokines such as IL-1, IL-1α, and IL-1β, IL-2, IFNγ, IL-10, GM-CSF, etc., or chemokines such as MIP1α, MIP1β, and RANTES, etc. (Item 91) The immunogenic composition for use according to item 90, wherein the carrier is KLH or a fragment thereof. (Item 92) An immunogenic composition for use according to item 91, wherein the KLH or a fragment thereof is coupled to the immunogenic peptide via a maleimide linker, wherein the maleimide linker is optionally N-γ-maleimidobutyryl-oxysulfosuccinimide ester (sulfoGMBS). (Item 93) An immunogenic composition for use according to any one of items 73 to 92, further comprising an adjuvant. (Item 94) An immunogenic composition for use according to item 93, wherein the adjuvant comprises an aluminum compound. (Item 95) An immunogenic composition for use as described in item 94, wherein the aluminum compound comprises aluminum hydroxide (Al(OH)3). (Item 96) The immunogenic composition for use according to any one of items 73 to 95, wherein the immunogenic composition further comprises, optionally, about 0.3 mL in volume of phosphate buffer. (Item 97) An immunogenic composition for use according to any one of items 73 to 96, wherein the immunogenic peptide comprises SEQ ID NO: 2. (Item 98) The immunogenic composition comprises an immunogenic peptide comprising SEQ ID NO: 2 coupled to KLH via a maleimide linker (optionally sulfo-GMBS), about 0.5 mg of aluminum (Al 3+ ), and about 0.3 mL volume of phosphate buffer, and is an immunogenic composition for use according to any one of items 73 to 97. (Item 99) An immunogenic composition for use according to any one of items 73 to 96, wherein the immunogenic peptide comprises SEQ ID NO: 1. (Item 100) An immunogenic composition for use according to any one of items 73 to 96 and 99, wherein the immunogenic peptide consists of SEQ ID NO: 1 and up to 5 additional amino acids at the C-terminus or N-terminus of a sequence from adjacent amino acids in tau isoform 2N4R. (Item 101) An immunogenic composition for use according to any one of items 73 to 98, wherein the immunogenic peptide consists of SEQ ID NO: 2 and up to 5 additional amino acids at the C-terminus or N-terminus of a sequence from adjacent amino acids in tau isoform 2N4R. (Item 102) An immunogenic composition for use according to any one of items 73 to 96, wherein the immunogenic peptide consists of SEQ ID NO: 1. (Item 103) An immunogenic composition for use according to any one of items 73 to 96, wherein the immunogenic peptide consists of SEQ ID NO: 2. (Item 104) An immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 for use in the treatment of Alzheimer's disease (AD) or mild cognitive impairment in a patient who needs it, wherein the use in the treatment (a) determining the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p in the patient; (b) administering one or more doses of the immunogenic composition; (c) After administering one or more doses, determine the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p in the patient. (d) Comparing the presence and / or amount from step (c) after treatment to the presence and / or amount from step (a) before treatment, wherein a change in the amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p is an indicator of treatment effectiveness, and (e) When the patient demonstrates therapeutic efficacy in step (d), administer an additional dose of the immunogenic composition one or more times. An immunogenic composition containing [the specified substance]. (Item 105) An immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2 for use in the treatment of Alzheimer's disease (AD) or mild cognitive impairment in patients who require it, wherein the use in said treatment is (a) Determine the presence and / or amount of one or more metabolites in the patient, (b) Administering one dose or more of the immunogenic composition, (c) After administering one or more doses, determine the presence and / or amount of one or more metabolites in the patient. (d) Comparing the presence and / or amount from step (c) after treatment to the presence and / or amount from step (a) before treatment, wherein the change in the amount of neurogranin is an indicator of therapeutic effectiveness, and (e) When the patient demonstrates therapeutic efficacy in step (d), administer an additional dose of the immunogenic composition one or more times. An immunogenic composition containing [the specified substance]. (Item 106) A method for diagnosing a patient suffering from Alzheimer's disease, wherein the patient or a sample from the patient contains hsa-let-7a-5p, hsa-miR-10a-5p, hs The method involves detecting the presence and / or quantity of one or more of the following: a-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p, specifically hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-m A method comprising determining that the presence of one or more of iR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p and / or a change in the amount compared to the amount in a control sample or a threshold is an indicator of Alzheimer's disease in the subject, and diagnosing the presence or absence of Alzheimer's disease in the patient. (Item 107) A method for diagnosing a patient suffering from Alzheimer's disease, comprising detecting the presence and / or amount of 2,4-dihydroxybutanoic acid, phospholipids, phosphatidylcholine, sphingomyelin, and / or sterols in the patient's plasma, serum, or cerebrospinal fluid (CSF), wherein the presence and / or change in the amount of one or more metabolites compared to the amount in a control sample or a threshold is an indicator of Alzheimer's disease in the subject, and diagnosing the presence or absence of Alzheimer's disease in the patient. (Item 108) The method according to item 106 or 107, further comprising administering to a patient diagnosed with Alzheimer's disease an immunogenic composition comprising an immunogenic peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2. (Item 109) A method for selecting to treat a patient suffering from Alzheimer's disease with an immunogenic composition comprising an immunogenic peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, (a) To detect the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p in the patient or a sample from the patient. (b) By comparing with a control sample or a threshold, the presence of one or more of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p and / or a change in the amount compared to the amount in the control sample or the threshold is an indicator of Alzheimer's disease in the subject, and (c) Select the patient for treatment based on step (b) A method that includes this. (Item 110) A method for selecting to treat a patient suffering from Alzheimer's disease with an immunogenic composition comprising an immunogenic peptide containing SEQ ID NO: 1 or SEQ ID NO: 2, (a) 2,4-dihydroxybutanoic acid, phospholipids, phosphatidylcholine, sphingomyelin, and / or sterols in the plasma, serum, or cerebrospinal fluid (CSF) of the said patient To detect presence and / or quantity, (b) Comparison with a control sample or threshold, wherein the presence of one or more metabolites and / or a change in the amount compared to the control sample or threshold is an indicator of Alzheimer's disease in the subject, and (c) Select the patient for treatment based on step (b) A method that includes this. (Item 111) The method according to item 109 or 110, further comprising administering the immunogenic composition to the selected patient. [Brief explanation of the drawing]

[0082] [Figure 1] Distribution of total MMSE scores in the patient population at the time of screening visit. [Figure 2] Comparison of each patient's total MMSE scores at V01 and V05. [Figure 3] Mean change in CDR-SB compared to baseline during the study (ages 50-70 and 71-85). [Figure 4] Mean change in CDR-SB compared to baseline during the study (ages 50-67 and 68-85). [Figure 5] Mean change in MMSE compared to baseline during the study (ages 50-70 and 71-85). [Figure 6] Mean change in MMSE compared to baseline during the study (ages 50-67 and 68-85). [Figure 7] Mean change in ADCS-MCI-ADL24 compared to baseline during the study (ages 50-70 and 71-85). [Figure 8] Mean change in ADCS-MCI-ADL24 compared to baseline during the study (ages 50-67 and 68-85). [Figure 9] IgG and IgM titer levels compared to AADvac1 peptide. [Figure 10] Anti-KLH antibody titer level. [Figure 11] Antibody response to AADvac1 [Figure 12]Distribution of antibodies against tau 151-391 / 4R and AADvac1 after treatment. [Figure 13] Comparison of IgG titers and area under the curve at V08 between young (50-70 years old) and elderly (71-85 years old) subgroups. [Figure 14] Correlation between the area under the IgG curve at V16 and the patient's age. [Figure 15] Comparison of IgG titers and area under the curve at V08 between young (50-67 years old) and elderly (68-85 years old) subgroups. [Figure 16] pT217 and pT181 tau levels in patients with different neurological conditions. [Figure 17] Changes in pT217 tau level from V02 to V16. [Figure 18] Changes in pT181 tau level from V02 to V16. [Figure 19] Changes in total tau, pT217 tau, and pT181 tau levels from V02 to V16 in patients who were positive for pT181 tau. [Figure 20] Distribution of NfL in the patient population at baseline. [Figure 21] Changes in NfL levels from V02 to V16. [Figure 22] Changes in NfL levels from V02 to V16 in patient age groups (51-70 years and 71-85 years). [Figure 23] Changes in NfL levels from V02 to V16 in patient age groups (51-67 years and 68-85 years). [Figure 24] Changes in tau level from V02 to V16. [Figure 25] Changes in neurograin levels from V02 to V16. [Figure 26] Changes in the Aβ1-42:Aβ1-40 ratio and Aβ1-42 and Aβ1-40 levels from V02 to V16. [Figure 27] Scheltens atrophy score and left hippocampal volume distribution of patients at screening visits. [Figure 28] Comparison of left and right hippocampal volumes at screening visits. [Figure 29] Distribution of left and right hippocampal volume in a patient population. [Figure 30] Distribution of Fazekas white matter lesion scores in a patient population at screening visits. [Figure 31] Distribution of microbleeds at screening visits. [Figure 32] Changes in brain volume of the region of interest in the younger subgroup (under 71 years old) at V16. [Figure 33] Changes in brain volume in areas of interest (longitudinal cortical volume (CVL), longitudinal temporal lobe volume (TLVL), and longitudinal lateral ventricle (LVVL)) in the young subgroup (under 68 years of age) at V16. [Figure 34] Changes in brain volume in regions of interest (longitudinal section of left hippocampal volume (LHVL), longitudinal section of right hippocampal volume (RHVL), and whole brain volume (WBV)) in the young subgroup (under 68 years of age) at V16. [Figure 35] Changes in anisotropy ratios in various brain regions. Figure 35: MicroRNA levels in AD patients compared to controls. [Figure 36] Changes in patient microRNA levels compared to V02, measured at V11 or V16 after treatment with AADvac1 or placebo. [Figure 37] MicroRNA levels compared to baseline measured at V11 or V16. [Figure 38] Metabolite (acylcarnitine) levels in AD and control patients. [Figure 39] Metabolite (glycerophospholipid) levels in AD and control patients. [Figure 40] Metabolite (glycerophospholipid) levels in AD and control patients. [Figure 41] Metabolite levels (glycerophospholipids, sphingolipids, and sugars) in AD and control patients. [Figure 42] Metabolite (amino acid and biogenic amine) levels in AD and control patients. [Figure 43] Peptide levels in AD and control patients. [Figure 44A]Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44B] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44C] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44D] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44E] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44F] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44G] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44H] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 44I] Safety endpoint data for the AADvac1 group and the placebo group. [Figure 45A] CSF biomarker (tau) levels in the AADvac1 group and the placebo group. [Figure 45B] CSF biomarker (tau) levels in the AADvac1 group and the placebo group. [Figure 45C] CSF biomarker (tau) levels in the AADvac1 group and the placebo group. [Figure 46A] Diffusion tensor imaging (DTI) MRI results for the AADvac1 group and the placebo group. [Figure 46B] Diffusion tensor imaging (DTI) MRI results for the AADvac1 group and the placebo group. [Figure 46C] Diffusion tensor imaging (DTI) MRI results for the AADvac1 group and the placebo group. [Figure 46D] Diffusion tensor imaging (DTI) MRI results for the AADvac1 group and the placebo group. [Figure 46E] Diffusion tensor imaging (DTI) MRI results for the AADvac1 group and the placebo group. [Figure 47A] CDR-SB score and cortical atrophy in relation to AADvac1 therapy. [Figure 47B] CDR-SB score and cortical atrophy in relation to AADvac1 therapy. [Figure 47C] CDR-SB score and cortical atrophy in relation to AADvac1 therapy. [Figure 47D] CDR-SB score and cortical atrophy in relation to AADvac1 therapy. [Figure 48A] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48B] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48C] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48D] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48E] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48F] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48G] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48H] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48I] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48J] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48K] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48L] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48M] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 48N] CDR-SB score, MMSE score, ADCS-MCI-ADS score, MRI volume, and plasma NfL level for AADvac1 therapy. [Figure 49A] Antibody response to tau peptides and pathogenic tau. [Figure 49B] Antibody response to tau peptides and pathogenic tau. [Figure 49C] Antibody response to tau peptides and pathogenic tau. [Figure 49D] Antibody response to tau peptides and pathogenic tau. [Figure 50] Antibody response in elderly populations. [Figure 51A] Serum antibody affinity for pathological tau, and comparison with competing tau monoclonal antibodies. [Figure 51B] Serum antibody affinity for pathological tau, and comparison with competing tau monoclonal antibodies. [Figure 52] Diagnostic criteria and demographic characteristics of a subgroup of patients positive for the AD biomarker (CSF). [Figure 53A] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53B] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53C] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53D] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53E] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53F] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53G] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53H] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53I] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53J] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53K] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53L] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53M] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53N] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53O]Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 53P] Plots of immune response and treatment efficacy in a subgroup of patients positive for the AD biomarker (CSF). [Figure 54] Demographic characteristics of a subgroup of AD patients with nearly confirmed cases. [Figure 55A] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55B] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55C] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55D] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55E] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55F] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55G] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55H] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55I] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Figure 55J] Correlation between immune response and treatment efficacy in a subgroup of AD patients with near-certain cases. [Modes for carrying out the invention]

[0083] To better understand this disclosure, certain exemplary embodiments are considered herein. In addition, certain terms are considered to aid understanding.

[0084] Unless otherwise defined, all scientific and technical terms used herein have the same meanings as those generally understood by those skilled in the art in the field to which this disclosure pertains. All references cited herein are incorporated by reference as a whole. In the event of any conflict between the terms or discussions in the references and this disclosure, this disclosure shall prevail.

[0085] When used herein, the singular form of a word also encompasses its plural form unless the context specifically indicates otherwise; for example, the terms “a,” “an,” and “the” are understood to be singular or plural. For example, “an element” means one or more elements. The term “or” means “and / or” unless the specific context specifically indicates otherwise.

[0086] The terms “comprising” or “comprises” and their variations shall be understood to imply the inclusion of the specified element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps. Throughout this specification, the words “consisting of” or “consists of” and their variations shall be understood to imply the inclusion of the specified element, integer, or step, or group of elements, integers, or steps, and the exclusion of any other element, integer, or step, or group of elements, integers, or steps. Throughout this specification, variations of the word "consisting essentially of" or "consists essentially of" will be understood to imply the inclusion of any other elements, integers, or steps, or groups of elements, integers, or steps, that do not substantially affect the fundamental novel features of the disclosure and / or claims.

[0087] "Approximately" can be understood to mean within ±10% of the stated value, for example, within ±10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%. When used in relation to percentage values, "approximately" can be understood to mean within ±1% (for example, "approximately 5%" can be understood to mean within the range of 4% to 6%), or within ±0.5% (for example, "approximately 5%" can be understood to mean within the range of 4.5% to 5.5%). Unless otherwise clearly indicated by the context, all numerical values ​​provided herein are modified by the term "approximately." All ranges used herein include endpoints.

[0088] As used herein, the terms “treatment,” “to treat,” etc., mean achieving a desired pharmacological and / or physiological effect. The effect may be prophylactic in that it completely or partially prevents the onset of the disease or its symptoms, and / or therapeutic in that it at least partially repairs, delays, slows, reduces, or improves one or more symptoms of the disease and / or adverse effects resulting from the disease. For example, as used herein, the terms “treatment,” etc., encompass any treatment of Alzheimer’s disease (AD) or related tauopathies in mammals, in particular humans, which include (a) preventing the onset of the disease in a subject, e.g., a subject identified as having a predisposition to or at risk of developing the disease, but who has not yet been diagnosed with it; (b) delaying the onset or progression of the disease, e.g., compared to the expected onset or progression of the disease in the absence of treatment; (c) suppressing the disease, e.g., stopping its progression; and / or (d) reducing the disease, i.e., causing disease regression. In some embodiments, “to treat” means administering, for example subcutaneously, a certain effective dose or a combination of effective doses of a composition, such as a composition comprising an immunogenic peptide as disclosed herein, to an animal (including a human) suspected of having or already having AD or another tauopathy. This may also mean reducing, eliminating, or at least partially cessating one or more symptoms and / or complications of the disease and / or disease, and having any beneficial effect thereon.

[0089] "Prevention" refers to administration to patients who are susceptible to a particular disease or who have other risks. It can be said that anyone in the general population is at risk of tauopathy, such as Alzheimer's disease (AD). In some embodiments, subjects are identified by one or more markers, such as one or more genetic markers, indicating a higher risk or susceptibility to tauopathy, such as AD, compared to the general population. "Tauopathy" refers to a disease associated with the formation of pathological tau. Some individuals have a high genetic risk of AD. In some embodiments, prevention, as used herein, includes eliminating or reducing the risk in a patient, such as a patient at high risk of tauopathy, or delaying the onset of the disease. Delay in onset or progression can be measured, for example, against the standard disease progression time in a similar population or individual.

[0090] "Physiological tau" refers to any one of the six isoforms of normal human tau: 2N4R (SEQ ID NO: 3), 1N4R (SEQ ID NO: 4), 2N3R (SEQ ID NO: 5), 0N4R (SEQ ID NO: 6), 1N3R (SEQ ID NO: 7), and 0N3R (SEQ ID NO: 8). This definition excludes any tau with any of the phosphorylation modifications associated with Alzheimer's disease and other tauopathies.

[0091] [Table 1]

[0092] [Table 2]

[0093] "Pathological tau" includes various pathological tau conformations and structures, encompassing all of the following: tau types IA, IB, IIA, and IIB; misordered, misdisordered tau (monomers, dimers, trimers, oligomers); misdisordered soluble tau; sarcosyl-insoluble tau; extracellular tau deposition; tau aggregates; paired helical fibrils; pathological conditions of neurofibrillaries including neurofibrillary lesions, tangles, lint, fibrils, axonal spheroids; highly phosphorylated truncated tau and full-length tau; or any other forms of tau associated with AD or another tauopathy.

[0094] "Linked" means that a portion is attached to an immunogenic peptide, antibody, or compound. The portion may be coupled, complexed, or covalently or noncovalently attached. The portion may be chemically crosslinked, or expressed or synthesized as a fusion with a peptide or antibody. "Part" refers to any compound (e.g., any organic molecule, peptide, protein, nucleic acid, carrier, adjuvant, etc.) that can be attached to an immunogenic peptide, antibody, or binding protein. "Carrier" refers to a drug that can be linked to an immunogenic peptide to increase its size and help induce an immune response. While not theoretically constrained, in some cases, small peptides may be less effective immunogens because they lack essential Th cell epitopes and / or act as haptens with low capture efficiency by antigen-presenting cells (APCs). Therefore, in some embodiments, peptide immunogens can be linked to suitable carriers to help induce an immune response. In certain embodiments, preferred carriers include serum albumin, keyhole limpet hemocyanin, immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid, and / or toxoids or attenuated toxin derivatives from other pathogenic bacteria such as diphtheria, Escherichia coli (E. coli), Vibrio cholerae (V. cholera), or Helicobacter pylori (H. pylori). Other carriers for stimulating or enhancing the immune response include cytokines such as IL-1, IL-1α, or IL-1β peptides, IL-2, IFNγ, IL-10, and GM-CSF, and chemokines such as MIP1α, MIP1β, or RANTES. Immunogenic peptides can also be linked to agents that enhance inter-tissue transport, as described in O'Mahony, International Publication No. 97 / 17613 and International Publication No. 97 / 17614. In some embodiments, the immunogenic peptide further comprises a carrier peptide or protein. In some embodiments, the carrier is keyhole limpet hemocyanin (KLH) or a fragment thereof, for example, a fragment that enhances the immune response.In some embodiments, the immunogenic peptide includes or consists of a peptide having the amino acid sequence KDNIKHVPGGGS (SEQ ID NO: 1) coupled to KLH. In some embodiments, the immunogenic peptide includes or consists of a peptide having the sequence CKDNIKHVPGGGS (SEQ ID NO: 2) coupled to KLH.

[0095] "Immunogenicity" refers to anything that can induce an immune response. This immune response can be antibody-mediated, cell-mediated, or both.

[0096] An "adjuvant" refers to a substance that has the ability to increase, amplify, or modulate the immune response to an associated peptide.

[0097] The term “isolated” as used herein means that it is taken out from one or more components of the natural environment. For example, a polynucleotide of genomic, cDNA, synthetic, or any combination thereof may be isolated if (1) the “isolated polynucleotide” is not bound to all or part of any polynucleotide found in nature, (2) it is operably linked to a polynucleotide that is not linked in nature, (3) it does not exist in nature as part of a larger sequence, and / or (4) it is otherwise isolated from other components of the natural environment.

[0098] When used herein, "mild cognitive impairment" (MCI) refers to a stage between the cognitive impairment expected of normal aging and the cognitive impairment associated with dementia, such as Alzheimer's disease. In the context of this application, the underlying cause of MCI is understood to be Alzheimer's disease (AD) pathology. MCI may be identified in patients through assessments of mental capacity, including but not limited to the Wechsler Memory Scale-revised, Short Test of Mental Status, Montreal Cognitive Assessment (MoCA), or Mini-Mental State Examination (MMSE). Kokmen et al. A short test of mental status: description and preliminary results. Mayo Clinic Proceedings. 1987;62;281-88;Ziad et al. al.The Montreal Cognitive Assessment,MoCA:A Brief Screening Tool for Mild Cognitive Impairment.Journal of the American Geriatrics Society.2005;53(4):695-99;Hua See et al., Tensor-based morphometry as a neuroimaging biomarker for Alzheimer’s disease: an MRI study of 676 AD, MCI, and normal subjects. NeuroImage. 2008;43(3):458-69; Wechsler, D., 1987. WMS-R Wechsler Memory Scale-Revised Manual. The Psychological Corporation. Harcourt Brace Jovanovich, Inc., New York. In some embodiments, MCI is evaluated using the Alzheimer's Disease Cooperative Study-Mild Cognitive Impairment Activities of Daily Living (ADCS MCI ADL) inventory.

[0099] As used herein, both “Alzheimer's disease” (AD) (used synonymously herein with “Alzheimer's dementia” or “dementia of the AD type”) and “mild cognitive impairment” (MCI) can be caused by AD lesions. AD can be distinguished from MCI using the NIA-AA diagnostic criteria (see, e.g., the ATN diagnostic criteria of the NIA-AA research framework, Jack et al., Alzheimer’s & Dementia, (2018)) and one or more neuropsychological tests used for the identification of MCI (e.g., Wechsler Memory Scale-Revised, Mini-Mental State Examination, MoCA, and / or MMSE).

[0100] Immunogenic peptide This specification discloses tau fragments used to induce an immune response to pathological tau. In one embodiment, this specification discloses an immunogenic peptide comprising one or more regions of the tau protein. The immunogenic peptide may be derived from a region of the tau protein involved in the formation of the core of paired helical fibrils (PHFs) and which promotes PHF assembly in vitro. In some embodiments, the immunogenic peptide comprises or consists of a fragment from the tau protein encompassing four therapeutic epitopes, numbered based on the longest human tau isoform tau 2N4R, including tau 267-273 (SEQ ID NO: 9), tau 298-304 (SEQ ID NO: 11), tau 329-335 (SEQ ID NO: 13), or tau 361-367 (SEQ ID NO: 15). In some embodiments, the immunogenic peptide comprises or consists of fragments from tau protein, numbered based on the longest human tau isoform tau 2N4R, including tau 268-273 (SEQ ID NO: 10), tau 299-304 (SEQ ID NO: 12), tau 330-335 (SEQ ID NO: 14), or tau 362-367 (SEQ ID NO: 16). In some embodiments, the immunogenic peptide comprises or consists of fragments from tau protein, including tau 314-342 (SEQ ID NO: 17), tau 352-380 (SEQ ID NO: 18), or tau 357-368 (SEQ ID NO: 19). In some embodiments, the immunogenic peptide comprises the peptide sequence CKDNIKHVPGGGS (SEQ ID NO: 2). In some embodiments, the immunogenic peptide is a fragment of pathogenic tau protein comprising or consisting of CKDNIKHVPGGGS (SEQ ID NO: 2) or KDNIKHVPGGGS (SEQ ID NO: 1). In some embodiments, the immunogenic peptide is a fragment of pathogenic tau protein containing or consisting of CKDNIKHVPGGGS(SEQ ID NO: 2) or KDNIKHVPGGGS(SEQ ID NO: 1) having up to 5, up to 4, up to 3, up to 2, or up to 1 mutation.In some embodiments, the immunogenic peptide comprises or consists of CKDNIKHVPGGGS (SEQ ID NO: 2) or KDNIKHVPGGGS (SEQ ID NO: 1), and further is a fragment of a pathogenic tau protein comprising 1, 2, 3, 4, or 5 additional amino acids inserted, for example, at the ends and / or within the sequence. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 1 and 1, 2, 3, 4, or 5 additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those immediately adjacent to SEQ ID NO: 1 when aligned against tau 2N4R. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 2 and 1, 2, 3, 4, or 5 additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those immediately adjacent to SEQ ID NO: 2 when aligned against tau 2N4R. In some embodiments, the immunogenic peptide is a fragment of a pathogenic tau protein having at least 99%, 95%, 92%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% sequence identity to CKDNIKHVPGGGS (SEQ ID NO: 2) or KDNIKHVPGGGS (SEQ ID NO: 1).

[0101]

Table 3

[0102] In some embodiments, an immunogenic peptide comprising or consisting of a fragment of tau as discussed above may be further modified such that one or more mutations are inserted into the sequence while retaining at least one function of the original structure and / or non-mutated protein, such as the ability to fold and present an epitope in the non-mutated protein and / or the ability to form the core of a PHF.

[0103] In some embodiments, the immunogenic peptides containing or comprising the tau fragments discussed above may be partially attached (e.g., covalently or non-covalently) to a carrier that enhances the immune response (e.g., compared to immunogenic peptides without a carrier). Exemplary carriers include serum albumin, keyhole limpet hemocyanin (KLH), immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid, or toxoids from other pathogenic bacteria such as diphtheria, Escherichia coli (E. coli), Vibrio cholerae (V. cholera), or Helicobacter pylori (H. pylori), or attenuated toxin derivatives, cytokines such as IL-1, IL-1α, or IL-1β peptides, IL-2, IFNγ, IL-10, GM-CSF, etc., and chemokines such as MIP1α, MIP1β, or RANTES. In some embodiments, the carrier contains KLH.

[0104] While not constrained by theory, small peptides may be less effective immunogens because they lack essential Th cell epitopes and / or act as haptens with low capture efficiency by antigen-presenting cells (APCs). Therefore, peptide immunogens can be coupled to suitable carriers to aid in inducing an immune response. In some embodiments, larger peptides, e.g., portions of tau with at least 10, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 amino acids in length, may result in an improved immune response by acting as better immunogens. In some embodiments, the immunogenic peptide further comprises a carrier peptide or protein. In some embodiments, the immunogenic peptide is a fragment of pathogenic tau protein containing or consisting of CKDNIKHVPGGGS(SEQ ID NO: 2) or KDNIKHVPGGGS(SEQ ID NO: 1) coupled to a carrier, e.g., KLH or a fragment thereof. In some embodiments, the carrier is keyhole limpet hemocyanin (KLH) or a fragment thereof, for example, a fragment that enhances the immune response. In some embodiments, the immunogenic peptide comprises or consists of a peptide having the sequence CKDNIKHVPGGGS(SEQ ID NO: 2) or KDNIKHVPGGGS(SEQ ID NO: 1) coupled to KLH. In some embodiments, the immunogenic peptide is a fragment of pathogenic tau protein comprising or consisting of CKDNIKHVPGGGS(SEQ ID NO: 2) or KDNIKHVPGGGS(SEQ ID NO: 1) coupled to a carrier, for example, KLH or a fragment thereof, having up to 5, up to 4, up to 3, up to 2, or up to 1 mutation. In some embodiments, the immunogenic peptide comprises or consists of CKDNIKHVPGGGS(SEQ ID NO: 2) or KDNIKHVPGGGS(SEQ ID NO: 1), further comprising 1, 2, 3, 4, or 5 additional amino acids, for example, inserted at the terminal and / or internal of the sequence, and is a fragment of pathogenic tau protein coupled to a carrier, such as KLH or a fragment thereof.In some embodiments, the immunogenic peptide consists of SEQ ID NO: 1 and 1, 2, 3, 4, or 5 additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those directly adjacent to SEQ ID NO: 1 when aligned with tau 2N4R, and the immunogenic peptide is coupled to a carrier, such as KLH or a fragment thereof. In some embodiments, the immunogenic peptide consists of SEQ ID NO: 2 and 1, 2, 3, 4, or 5 additional residues at the N-terminus and / or C-terminus, where the additional residues are identical to those directly adjacent to SEQ ID NO: 2 when aligned with tau 2N4R, and the immunogenic peptide is coupled to a carrier, such as KLH or a fragment thereof.

[0105] In some embodiments, the immunogenic peptide is a fragment of pathogenic tau protein coupled to a carrier, such as KLH or a fragment thereof, having at least 99%, 95%, 92%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% sequence identity with CKDNIKHVPGGGS(SEQ ID NO: 2) or KDNIKHVPGGGS(SEQ ID NO: 1). In some embodiments, the immunogenic peptide is AADvac1.

[0106] In some embodiments, the carrier is covalently linked to the immunogenic peptide. In some embodiments, the carrier is noncovalently linked to the immunogenic peptide. In some embodiments, the immunogenic peptide may be linked to the carrier at its amino terminus, carboxyl terminus, or at any site within the peptide (internally). In some embodiments, the immunogenic peptide is linked to the carrier at its N terminus, or at 1, 2, 3, 4, or 5 amino acids from this terminus. In some embodiments, the immunogenic peptide is linked to the carrier at its C terminus, or at 1, 2, 3, 4, or 5 amino acids from this terminus. In some embodiments, the immunogenic peptide is linked to the carrier at internal amino acids.

[0107] Immunogenic agents may be linked to a carrier by chemical crosslinking. Techniques for linking immunogens to carriers include the formation of disulfide bonds using 3-(2-pyridylthio)propionic acid N-succinimidyl (SPDP) and 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid succinimidyl (SMCC) (for example, if the peptide lacks a sulfhydryl group, this may be provided by the addition of a cysteine ​​residue). In some embodiments, these reagents create a disulfide bond between themselves and a peptide cysteine ​​residue on a protein, and then create an amide bond via an ε-amino on lysine or another free amino group on another amino acid. Various such disulfide / amide forming agents are described in Immun. Rev. 62, 185 (1982). Other bifunctional coupling agents that may be used include, for example, those that form thioethers rather than disulfide bonds. Many thioether-forming agents are commercially available, including reactive esters of 6-maleimidocaproic acid, 2-bromoacetic acid, and 2-iodoacetic acid, and 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid. In some embodiments, the carboxyl group can be activated by combining it with succinimide or 1-hydroxyl-2-nitro-4-sulfonic acid, sodium salt. In some embodiments, the immunogenic peptide or fragment thereof is linked to the carrier by chemical crosslinking. In some embodiments, the carrier is conjugated to the peptide via 3-(2-pyridylthio)propionic acid N-succinimidyl (SPDP) or 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid succinimidyl (SMCC). In some embodiments, an immunogenic peptide comprising or consisting of the peptide sequence KDNIKHVPGGGS (SEQ ID NO: 1) or CKDNIKHVPGGGS (SEQ ID NO: 2) is linked to a carrier or fragment thereof by N-succinimidyl 3-(2-pyridylthio)propionic acid (SPDP) or 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid succinimidyl (SMCC).In some embodiments, an immunogenic peptide comprising or consisting of the peptide sequence KDNIKHVPGGGS (SEQ ID NO: 1) or CKDNIKHVPGGGS (SEQ ID NO: 2) is linked to KLH or a fragment thereof by N-succinimidyl 3-(2-pyridylthio)propionic acid (SPDP) or succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid (SMCC).

[0108] In some embodiments, the carrier is conjugated to the immunogenic peptide by a crosslinking agent containing N-[γ-maleimidobutyryloxy]succinimide (GMBS). In some embodiments, the crosslinking agent contains GMBS or is GMBS. In some embodiments, the carrier is conjugated to the immunogenic peptide by a crosslinking agent containing a derivative of GMBS. In some embodiments, the crosslinking agent is N-γ-maleimidobutyryl-oxysulfosuccinimide (sulfoGMBS).

[0109] In some embodiments, an immunogenic peptide comprising or consisting of the peptide sequence KDNIKHVPGGGS(SEQ ID NO: 1) or CKDNIKHVPGGGS(SEQ ID NO: 2) is linked to a carrier or fragment thereof by a crosslinking agent, for example, GMBS or a derivative thereof (e.g., sulfoGMBS). In some embodiments, an immunogenic peptide comprising or consisting of the peptide sequence KDNIKHVPGGGS(SEQ ID NO: 1) or CKDNIKHVPGGGS(SEQ ID NO: 2) is linked to KLH or a fragment thereof by a crosslinking agent, for example, GMBS or a derivative thereof (e.g., sulfoGMBS).

[0110] The immunogenic peptide may be directly linked to the carrier, or indirectly linked to a mobile linker, such as a spacer amino acid sequence, e.g., (EAAAK) n They may be connected via fixed linkers such as (GGGS) and (GGGG)3, or via movable linkers such as (GGGG)3.

[0111] In some embodiments, immunogenic peptides can be expressed as fusion proteins with a carrier. The immunogenic peptide can be expressed directly or via a spacer amino acid sequence, e.g., (EAAAK), at the amino terminus, at the carboxyl terminus, or at any site within the peptide (internally). n It may be connected to the carrier via a fixed linker such as GGGS and (GGGG)3, or via a movable linker such as GGGS and (GGGG)3.

[0112] In some embodiments, the fusion protein may contain multiple repeats of the immunogenic peptide. In some embodiments, the immunogenic peptide is linked to the carrier protein at its N-terminus. In some embodiments, the immunogenic peptide is linked to the carrier protein at its C-terminus. In some embodiments, the immunogenic peptide is linked to the carrier protein by internal amino acid residues. In some embodiments, an immunogenic peptide containing or consisting of the peptide sequence KDNIKHVPGGGS(SEQ ID NO: 1) or CKDNIKHVPGGGS(SEQ ID NO: 2) is linked to KLH at its N-terminus. In some embodiments, an immunogenic peptide containing the peptide sequence KDNIKHVPGGGS(SEQ ID NO: 1) or CKDNIKHVPGGGS(SEQ ID NO: 2) is linked to KLH at its C-terminus. In some embodiments, an immunogenic peptide containing the peptide sequence KDNIKHVPGGGS(SEQ ID NO: 1) or CKDNIKHVPGGGS(SEQ ID NO: 2) is linked to KLH by internal amino acids. For further examples of immunogenic peptides, carriers, and methods for preparing them, refer to PCT / IB2012 / 002246, which is incorporated herein by reference in its entirety.

[0113] Pharmaceutical composition The immunogenic peptides disclosed herein can be prepared and / or formulated as pharmaceutical compositions suitable for administration to a subject, e.g., a human patient, suffering from, at risk of, or otherwise requiring treatment for AD or another tauopathy. The pharmaceutical composition can include a therapeutic agent (e.g., an immunogenic peptide as described above), one or more of other pharmaceutically acceptable components such as excipients (solvents, adjuvants, etc.) and / or additional therapeutic agents (e.g., other agents that target pathological tau or other proteins associated with AD and / or other tauopathies). A variety of pharmaceutically acceptable excipients are known in the art. For example, A. Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7.sup.th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3 ed. Amer. Pharmaceutical Assoc.

[0114] In some embodiments, the pharmaceutical compositions disclosed herein include pharmaceutically acceptable excipients and / or diluents. For example, any medium used for formulating pharmaceutical compositions for administration to animals or humans may be used. Diluents may be selected so as not to affect the biological activity of the combination. Examples of such diluents include distilled water, phosphate-buffered saline, Ringer's solution, dextrose solution, and Hanks' solution. The pharmaceutical compositions and formulations disclosed herein may also include other excipients, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers. Examples of suitable pharmaceutical excipients, known in the art, include phosphate-buffered saline, water, emulsions such as oil / water emulsions, various wetting agents, and sterile solutions. Compositions containing such excipients can be formulated by known conventional methods.

[0115] In some embodiments, the immunogenic peptides disclosed herein may be provided as pharmaceutical compositions suitable for subcutaneous administration. In some embodiments, the immunogenic peptides disclosed herein may be provided as pharmaceutical compositions suitable for intramuscular administration.

[0116] In various embodiments, the pharmaceutical composition may be provided as a formulation comprising one or more inactive components and / or one or more additional active components in addition to the immunogenic peptide. In some embodiments, the compositions of the Disclosure may be formulated using components and techniques known in the Art as formulations suitable for administration to mammalian subjects, such as humans.

[0117] In some embodiments, the pharmaceutical compositions disclosed herein comprise an immunogenic peptide and an adjuvant. In some embodiments, the adjuvant comprises an aluminum compound. In some embodiments, the adjuvant comprises aluminum hydroxide. In some embodiments, the adjuvant comprises about 0.1 to 1.0 mg of aluminum (Al) in amounts of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1.0 mg. 3+) is included. In some embodiments, the pharmaceutical composition contains a keyhole limpet hemocyanin and an immunogenic peptide of the sequence CKDNIKHVPGGGS (SEQ ID NO: 2) coupled to aluminum hydroxide. In some embodiments, the pharmaceutical composition is formulated in phosphate buffer. In some embodiments, the pharmaceutical composition contains about 10 to 190 μg of the immunogenic peptide of the sequence CKDNIKHVPGGGS (SEQ ID NO: 2) coupled to keyhole limpet hemocyanin, for example, about 10 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 110 μg, about 120 μg, about 130 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg, about 180 μg, or about 190 μg. In some embodiments, the pharmaceutical composition contains approximately 40 μg of immunogenic peptide of the sequence CKDNIKHVPGGGS (SEQ ID NO: 2) coupled to keyhole limpet hemocyanin, and 0.5 mg Al 3+ The phosphate buffer contains the following. In some embodiments, the pharmaceutical composition contains approximately 160 μg of immunogenic peptide of the sequence CKDNIKHVPGGGS (SEQ ID NO: 2) coupled to keyhole limpet hemocyanin, and 0.5 mg Al 3+ The phosphate buffer contains the phosphate buffer. For an exemplary peptide vaccine structure and a description of further formulations and methods for their preparation, refer to PCT / IB2012 / 002246 (which is incorporated herein by reference in whole).

[0118] The adjuvant may be administered as a single composition together with the immunogen, or before, simultaneously with, or after the administration of the immunogen. The immunogen and adjuvant may be packaged and supplied in the same vial, or packaged in separate vials and mixed before use. In some embodiments, the immunogen and adjuvant are packaged with markings indicating the intended therapeutic application. If the immunogen and adjuvant are packaged separately, the packaging may include instructions to mix them before use.

[0119] Use of an immunogenic composition comprising an immunogenic peptide In various embodiments, the present disclosure provides a method of treating a patient who needs it, the method comprising administering an immunogenic peptide or a pharmaceutical composition comprising an immunogenic peptide. The immunogenic peptides disclosed herein can be administered by parenteral, topical, intradermal, intravenous, oral, subcutaneous, intraperitoneal, intranasal or intramuscular means for prophylactic and / or therapeutic treatment. In some embodiments, the delivery is by subcutaneous delivery. In some embodiments, the delivery is by intramuscular delivery.

[0120] In some embodiments, the immunogenic peptide is delivered by subcutaneous delivery to the upper arm. In some embodiments, the immunogenic peptide is delivered by subcutaneous delivery to the abdomen. In some embodiments, the immunogenic peptide is delivered by subcutaneous delivery to the thigh. In some embodiments, the immunogenic peptide is delivered by subcutaneous delivery to the upper back. In some embodiments, the immunogenic peptide is delivered by subcutaneous delivery to the buttocks.

[0121] In some embodiments, the immunogenic peptide is delivered by intramuscular delivery to the deltoid muscle of the arm. In some embodiments, the immunogenic peptide is delivered by intramuscular delivery to the vastus lateralis muscle of the thigh. In some embodiments, the immunogenic peptide is delivered by intramuscular delivery to the ventral gluteal muscle of the buttocks. In some embodiments, the immunogenic peptide is delivered by intramuscular delivery to the dorsal gluteal muscle of the buttocks.

[0122] In various embodiments, the immunogenic peptide is administered one or more times, for example, using the same dose for each administration, with one or more time intervals between vaccinations. In some embodiments, the immunogenic peptide is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times or more, for example, using the same dose for each administration. In some embodiments, the immunogenic peptide is administered at intervals of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, or 4 years. In some embodiments, the immunogenic peptide is administered at intervals, then at other intervals, for example, five doses at 4-week intervals, then five doses at 6-month intervals, or six doses at 3-week intervals, then four doses at 2-month intervals. In some embodiments, the immunogenic peptide is administered at 6-week intervals, then five doses at 3-month intervals, for example, doses are administered at weeks 0, 6, 12, 18, 24, 30, 42, 54, 66, 78, and 90. In some embodiments, the immunogenic peptide is administered at 4-week intervals, then five doses at 3-month intervals, for example, doses are administered at weeks 0, 4, 8, 12, 16, 20, 32, 44, 56, 68, and 80. In some embodiments, the immunogenic peptide is administered over six doses at four-week intervals, followed by five doses at fourteen-week intervals, for example, at weeks 0, 4, 8, 12, 16, 20, 34, 48, 62, 76, and 90.

[0123] In various embodiments, the methods and materials disclosed herein are adapted for and can be used for the treatment of Alzheimer's disease or related tauopathy in patients exhibiting symptoms of the disease, for example, by subcutaneous or intramuscular administration. In various embodiments, the methods and materials disclosed herein are used, for example, by subcutaneous or intramuscular administration, for patients diagnosed with Alzheimer's disease using one of the biomarkers disclosed herein and / or by brain imaging, but who have not yet shown clinical symptoms of the disease. In some embodiments, the diagnosis of the patient is performed in vitro.

[0124] In various embodiments, one or more immunogenic peptides, for example, peptides comprising the sequence of SEQ ID NO: 1 or SEQ ID NO: 2 disclosed herein, can be administered subcutaneously or intramuscularly for the treatment of Alzheimer's disease. In some embodiments, a method for treating AD or another tauopathy is provided, comprising administering one or more doses comprising an effective amount of a composition comprising the peptide as disclosed herein to a patient in need thereof. In some embodiments, the effective dose is a dose that partially or completely relieves (i.e., eliminates or reduces) at least one symptom associated with the disorder / disease state under treatment, a dose that slows, delays or prevents the onset or progression of the disorder / disease state, a dose that slows, delays or prevents the progression of the disorder / disease state, a dose that weakens the severity of the disease, a dose that improves one or more symptoms, a dose that results in remission (partial or complete) of the disease, and / or a dose that prolongs survival. In some embodiments, the effective dose is a dose that reduces or improves the effects of AD, as indicated, for example, by a detectable change in one or more biomarkers. In some embodiments, the effective dose is the dose that reduces the amount of tau lesions in the patient's brain. Examples of disease conditions targeted for treatment are described in detail herein. In some embodiments, the patient has AD or is at risk of developing AD.

[0125] Examples of immunogenic compositions that may be used in the methods disclosed herein include immunogenic peptides and compositions disclosed in PCT / IB2012 / 002246 (which is incorporated herein by reference in whole). In some embodiments, the immunogenic composition comprises AADvac1, which comprises the immunogenic peptide CKDNIKHVPGGGS (SEQ ID NO: 2) (e.g., about 40 μg of the peptide) coupled to keyhole limpet hemocyanin (KLH) via a maleimide linker with an aluminum hydroxide adjuvant (e.g., 0.5 mg Al 3+ It is contained in a phosphate buffer solution (for example, in a volume of about 0.3 mL) along with the other ingredients.

[0126] In some embodiments, the immunogenic peptide or pharmaceutical composition disclosed herein, such as AADvac1, is administered, for example, subcutaneously to a patient in need of treatment for Alzheimer's disease. In some embodiments, the patient is 40–95 years old. In some embodiments, the patient is 45–90 years old. In some embodiments, the patient is 50–85 years old. In some embodiments, the patient is 50–67 years old. In some embodiments, the patient is 68–85 years old. In some embodiments, the patient is 50–70 years old. In some embodiments, the patient is 71–85 years old. In some embodiments, the subject is identified as having a probable case of AD according to the revised National Institute on Aging-Alzheimer's Disease Association (NIA-AA) diagnostic criteria.

[0127] For example, pre-screening of patients suitable for treatment using the AD identification method disclosed herein, as well as administration of treatment to patients identified by the diagnostic criteria disclosed herein, are also intended.

[0128] Diagnostic methods - diagnostic criteria The diagnosis of AD in a patient for treatment with immunogenic peptides or pharmaceutical compositions disclosed herein, and the assessment of the severity of AD in a patient, may include one or more neurological or clinical tests of reflexes, coordination, eye movements, speech, memory, problem-solving, attention, calculation, and / or language. Thresholds and / or diagnostic criteria for determining the diagnosis of AD based on these tests are well known in the art. Examples of diagnostic criteria for AD include, but are not limited to, the 2011 revised NIA-AA diagnostic criteria, the 2018 revised NIAA-AA diagnostic criteria, the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) diagnostic criteria, the International Working Group (IWG) diagnostic criteria, and the revised IWG-2 diagnostic criteria. Dubois et al., Lancet Neurology,(2014)13(6):p614-629;McKhann et al.,Neurol.,(1984)34(7):939-944;Jack et al.,Alzheimer's & Dementia,(2018)14:535-562.

[0129] In some embodiments, subjects are identified as having AD according to the revised NINCDS-ADRDA diagnostic criteria. In some embodiments, subjects are identified as having AD according to the IWG diagnostic criteria. In some embodiments, subjects are identified as having AD according to the revised IWG-2 diagnostic criteria.

[0130] In some embodiments, patient diagnosis is performed in vitro.

[0131] For example, one diagnostic criterion for the neuropathological diagnosis of AD is the revised National Institute on Aging / Reagan Institute of the Alzheimer Association (NIA-AA) diagnostic criteria. McKhann et al., Alzheimer's & Dementia, (2011) 7:263-269; Hyman et al., Alzheimer's & Dementia, (2012) 8:1-13. The NIA-AA provides criteria for diagnosing patients with dementia as having (1) near-certain AD-type dementia, (2) suspected AD-type dementia, and (3) near-certain or suspected AD with evidence of the pathophysiological processes of AD. In detail, dementia is diagnosed when a patient has the following symptoms: 1) Symptoms that impair the ability to function in work or daily activities; 2) Symptoms corresponding to a decline from previous levels of function and performance; 3) Symptoms that cannot be explained by delirium or a major mental disorder; 4) Cognitive impairment is detected and diagnosed through the following combinations. a. Interviews with the patient and well-known informants and b. Objective cognitive function assessment, either a "bedside" mental state assessment or a neuropsychological examination; 5) At least two of the following domains are involved in the cognitive or behavioral disorder: a. Impairment in the ability to acquire and remember new information—symptoms include: repeating questions or conversations, misplacing personal belongings, forgetting events or appointments, and getting lost on familiar routes; b. Impairment in reasoning and processing complex tasks, and impaired judgment—symptoms include: poor understanding of safety risks, poor financial management skills, poor decision-making skills, and inability to plan complex or sequential activities; c. Impairment of visuospatial ability—Symptoms include inability to recognize faces or everyday objects or to locate objects being seen directly despite having sufficient visual acuity, inability to operate simple tools, or inability to properly dress oneself; d. Impairment of language function, speaking, reading, and writing - symptoms include: difficulty finding common words while speaking, stammering; mispronunciation, misspelling, and writing errors. e. Changes in personality, behavior, or attitude—Symptoms include: unusual mood swings, such as agitation; decreased motivation, autonomy, apathy, loss of desire, withdrawal, decreased interest in former activities, loss of empathy, compulsive or obsessive behavior, and socially unacceptable behavior.

[0132] In some embodiments, individuals with a near-certain diagnosis of AD-type dementia meet the above diagnostic criteria and also possess the following characteristics: A. Insidious onset. Symptoms do not suddenly appear within hours or days, but rather develop gradually over months or even years. B. The progression of cognitive deterioration is clear from reports or observations; and C. The first and most prominent cognitive deficit is evident in the records and tests of one of the following categories. a. Amnesia: This is the most common symptomatic manifestation in AD type dementia. This deficit must include impairment in learning and recalling recently acquired information. There must also be evidence of cognitive impairment in at least one other cognitive domain as defined above in the text. b. Occurrence of non-amnesic symptoms: -Language symptom manifestation: The most prominent deficit is in word picking, but deficits must also be found in other cognitive domains. -Visuospatial symptom manifestation: The most prominent deficits are in spatial cognition, including object agnosia, facial recognition impairment, simultaneous agnosia, and alexia. Deficiencies should also be found in other cognitive domains. - Executive dysfunction: The most prominent deficits are impairments in reasoning, judgment, and problem-solving. Deficiencies should also be found in other cognitive domains. D. A diagnosis of near-certain AD dementia should not be applied if the following evidence exists: (a) substantially associated cerebrovascular disease defined by a stroke history time-related to the onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe high-intensity white matter load; or (b) the central features of Lewy body dementia excluding dementia itself; or (c) prominent features of behavioral frontotemporal dementia; or (d) prominent features of semantic primary progressive aphasia or non-fluent / agrammatic primary progressive aphasia; or (e) evidence of another co-occurring active neurological disorder or non-neurological medical comorbidity or use of pharmacotherapy that may substantially affect cognition.

[0133] In some embodiments, a person suspected of having AD may be (1) a patient who meets the central clinical diagnostic criteria in that he or she has cognitive impairment characteristics, but either presents with a sudden onset of cognitive impairment or there is insufficient evidence of a detailed course of progressive decline or objective cognitive records, or (2) a patient who, pathologically, presents with mixed symptoms that meet all the central clinical diagnostic criteria for dementia type AD, but has evidence of associated cerebrovascular disease, features of Lewy body dementia excluding dementia itself, or evidence of another neurological disorder or non-neurological medical comorbidity, or is using a drug therapy that may substantially affect cognition.

[0134] In some embodiments, individuals with near-certain or suspected cases of AD, accompanied by evidence of the pathophysiological processes of AD, also have positive biomarker-based test results. These biomarkers include low AB levels in cerebrospinal fluid (CSF). 42Diagnoses include positive positron emission tomography (PET) amyloid and tau imaging, elevated CSF tau (both total tau and phosphorylated tau), decreased fluorodeoxyglucose (FDG) uptake on PET in the temporoparietal cortex, and / or disproportionate atrophy on structural magnetic resonance imaging in the medial, basal, and lateral temporal lobes, as well as the medial parietal cortex. In some embodiments, patient biomarker testing is performed in vitro. In some embodiments, total tau is measured using an ELISA assay. In some embodiments, the ELISA assay is Innotest hTAU Ag and phosphotau (181P) ELISA assay. In some embodiments, pT181 tau is measured using an ELISA assay. In some embodiments, the ELISA assay is Innotest hTAU Ag and phosphotau (181P) ELISA assay. In some embodiments, pT217 tau is measured using an ELISA assay. In some embodiments, the ELISA assay is a digital ELISA assay. In some embodiments, Aβ40 is measured using an ELISA assay. In some embodiments, Aβ42 is measured using an ELISA assay. In some embodiments, one or more biomarkers are measured by another suitable immunoassay, such as, but not limited to, the Elecsys® assay. Lifke et al., Elecsys® Total-Tau and Phospho-Tau(181P)CSF Assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid. Clinical Biochemistry, (2019) 72:30-38. In some embodiments, one or more biomarkers are measured using mass spectrometry. For example, Pottiez et al., A mass spectrometry-based method to quantify in parallel Tau and amyloid β 1-42 in CSF for the diagnostic of Alzheimer’s Disease.J.Proteome Res.,(2017)16(3):1228-1238;Russell et al.,Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by Mass Spectrometry Provides New Biomarker Candidates.Journal of Alzheimer’s Disease,(2017)55(1):303-313。

[0135] In some embodiments, the patient has a diagnosis of near-certain Alzheimer's disease, as determined, for example, by the National Institute on Aging-Alzheimer's Disease Association (NIA-AA) diagnostic criteria revised 2011. In some embodiments, the patient has a diagnosis of suspected Alzheimer's disease, as determined, for example, by the National Institute on Aging-Alzheimer's Disease Association (NIA-AA) diagnostic criteria revised 2011. In some embodiments, the patient has a diagnosis of near-certain or suspected AD, accompanied by evidence of the pathophysiological processes of AD, as determined, for example, by the National Institute on Aging-Alzheimer's Disease Association (NIA-AA) diagnostic criteria revised 2011. In some embodiments, the diagnosis is based on a clinical evaluation of symptoms. In some embodiments, the diagnosis is based on the 2011 revised National Institute on Aging / Reagan Institute of Alzheimer's Disease. The diagnosis is made based on the Alzheimer Association (NIA-AA) diagnostic criteria. In some embodiments, the diagnosis is made based on a probable case of AD determined according to the 2011 revised NIA-AA diagnostic criteria. In some embodiments, one or more alternative diagnostic methods are used. In some embodiments, the diagnosis is confirmed by at least one additional method.

[0136] Another set of diagnostic criteria for the neuropathological diagnosis of AD that may be used in the methods disclosed herein is the updated National Institute on Aging / Reagan Institute of the Alzheimer Association (NIA-AA) research framework. Jack et al., Alzheimer's & Dementia, (2018) 14:535-562. The updated NIA-AA research framework places diagnostic criteria on the diagnosis of AD using biomarkers from living individuals, rather than on the clinical outcomes of the disease. Patients are placed on the Alzheimer's disease continuum based on three biomarker groups: (a) cortical amyloid PET ligand binding or low CSF Aβ 42 (b) Biomarkers for Aβ plaques such as (a) (labeled "A"), (b) biomarkers for fibrillary tau such as elevated CSF phosphorylated tau (P-tau) and cortical tau PET ligand binding (labeled "T"), and (c) biomarkers for neurodegeneration or neuronal injury such as CSF T-tau, decreased FDG PET metabolism, and atrophy on MRI (labeled "N"). This sets up the AT(N) system of biomarker features, where only "A" and "T" are considered potential biomarker definitions for AD. For example, if a person has biomarker evidence for Aβ deposition alone, and the pathological tau biomarkers are normal (i.e., A+ and T-), they will be labeled "Alzheimer's disease." On the other hand, if a patient has biomarker evidence for both Aβ and pathological tau, they will be labeled "Alzheimer's disease." Examples of biomarker profiles and categories are shown in Table 3.

[0137] [Table 4]

[0138] In some embodiments, patients are diagnosed with Alzheimer's disease without any detectable clinical symptoms. In some embodiments, patients have a diagnosis of Alzheimer's disease based solely on biomarkers. In some embodiments, patients have a diagnosis of Alzheimer's disease or the Alzheimer's disease continuum, as determined, for example, by the 2018 Revised NIA-AA Research Framework. In some embodiments, patients have a diagnosis of Alzheimer's type pathological changes or the Alzheimer's disease continuum, as determined, for example, by the 2018 Revised NIA-AA Research Framework. In some embodiments, patients have a diagnosis of Alzheimer's disease and associated suspected non-Alzheimer's type pathological changes, or the Alzheimer's disease continuum, as determined, for example, by the 2018 Revised NIA-AA Research Framework. In some embodiments, the 2018 Revised Research Framework described herein may be used in combination with one or more of the assays or methods described herein.

[0139] In some embodiments, one or more cognitive impairment tests are used to diagnose or assess a patient. An exemplary cognitive impairment test that may be used with the methods disclosed herein is the Mini-Mental State Examination (MMSE), a questionnaire commonly used for dementia screening. Folstein et al., J.Psychiatr.Res., (1975) 12:189-198. The MMSE has a maximum score of 30 points and can usually be administered in 5 to 10 minutes. The questions are typically divided into seven categories, each corresponding to a different cognitive domain or function: (a) Orientation to time (5 points) For example, "What year is it? What season is it? What day is it today? What day of the week is it today? What month is it now?" (b) Orientation to place (5 points), for example, "Where am I: What state am I in? What county am I in? What town / city am I in? What hospital am I in? What floor am I on?" (c) 3-word memorization (3 points): For example, the examiner clearly and slowly lists the names of three unrelated objects, and then asks the patient to name all three. Points are awarded based on the patient's answers. The examiner repeats the three words, if possible, until the patient can name all three. (d) Notes and calculations (5 points), for example, "Tell me the numbers obtained by subtracting 7 from 100 in order" (93, 86, 79, 72, 65, ...). Stop after 5 answers. Alternative method: "Spell WORLD backwards" (DLROW); (e) Recall three words (3 points), for example, "What were the three things I mentioned earlier?" (f) Language (8 points), for example, the examiner shows the patient two simple objects and asks them to name them, "Please repeat the following sentence: 'No ifs, ands, or buts'", or "Please make and write any sentence you like"; and (g) Visual composition (1 point) "Please copy this figure exactly" (the examiner gives the patient a blank sheet of paper, shows them a symbol, and asks them to draw it.)

[0140] A patient's MMSE score may be adjusted to match their educational background. For example, a patient with an educational level of Grade 7 or lower may have cognitive impairment with a score of 22 or less, while a patient with a college degree or higher may have cognitive impairment with a score of 26 or less. In some embodiments, a patient's total MMSE score is 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or less than 30. In some embodiments, a patient's total MMSE score is at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, or at least 29. In some embodiments, a patient's total MMSE score is at most 29, at most 28, at most 27, at most 26, at most 25, at most 24, at most 23, or at most 22. In some embodiments, a patient's total MMSE score is higher than 19 and lower than 27. In some embodiments, the patient's total MMSE score is higher than 20 and lower than 26.

[0141] In some embodiments, patient diagnosis is performed in vitro.

[0142] Diagnostic methods - Biomarkers In some embodiments, the presence of AD in a subject can be identified and / or confirmed using biomarkers. These biomarkers may be drugs whose concentration, presence, and / or activity are associated with the disease and may also be used to provide a diagnosis of AD. Biomarkers may be present in any part of the body, e.g., plasma, urine, or cerebrospinal fluid (CSF). In some embodiments, CSF provides a source of AD biomarkers. In some embodiments, plasma provides a source of AD biomarkers. Protein biomarkers for AD diagnosis include, but are not limited to, tau species identified in serum, plasma, or CSF, including Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau (p-tau). Biomarkers of inflammation and oxidative stress, as well as urine-based biomarkers, may also provide important information regarding the onset and progression of AD. (Blennow et al., Lancet Neurology, (2003) 2(10):605-613; Formichi) et al., Journal of Cellular Physiology, (2006) 208 (1): 39-46; al., American Journal of Pathology, (2002) 160(4):1269-1278; Hampel et al. al., Archives of General Psychiatry, (2004) 61(1): 95-102; Koopman et al., Neurochemistry International, (2009) 55(4): 214-218.

[0143] In some embodiments, the determination that a patient is suitable for the diagnosis of AD and / or treatment as disclosed herein is made, at least in part, based on the measurement of a protein biomarker. In some embodiments, the biomarker is tau protein in plasma. In some embodiments, the biomarker is tau protein in cerebrospinal fluid (CSF). In some embodiments, the biomarker is total tau (t-tau) protein in CSF. In some embodiments, a patient suffering from and / or suitable for treatment of Alzheimer's disease has total tau protein in CSF greater than 400 pg / mL, for example, greater than 500 pg / mL, greater than 600 pg / mL, greater than 700 pg / mL, greater than 800 pg / mL, greater than 900 pg / mL, or greater than 1000 pg / mL. In some embodiments, the biomarker is threonine 181 phosphorylated tau protein (pT181 tau) in CSF. In some embodiments, patients with and / or suitable for treatment of Alzheimer's disease have pT181 tau in CSF at levels greater than 60 pg / mL, e.g., greater than 70 pg / mL, greater than 80 pg / mL, greater than 90 pg / mL, greater than 100 pg / mL, greater than 120 pg / mL, or greater than 150 pg / mL. In some embodiments, the biomarker is the Aβ40 peptide in CSF. In some embodiments, the biomarker is Aβ42 in CSF. In some embodiments, patients with and / or suitable for treatment of Alzheimer's disease have Aβ42 levels in CSF less than 600 pg / mL, e.g., less than 550 pg / mL, less than 500 pg / mL, less than 450 pg / mL, less than 400 pg / mL, less than 350 pg / mL, or less than 300 pg / mL. In some embodiments, the biomarker is the Aβ42:Aβ40 ratio in CSF. In some embodiments, patients suffering from and / or suitable for treatment of Alzheimer's disease have a CSF Aβ42:Aβ40 ratio of less than 0.089, for example, less than 0.08, less than 0.075, less than 0.07, less than 0.065, less than 0.06, less than 0.055, less than 0.05, less than 0.045, less than 0.04, less than 0.035, or less than 0.03.In some embodiments, the biomarker includes one or more combinations of total tau protein, pathological tau protein, Aβ42 peptide, Aβ40 peptide, and the Aβ42:Aβ40 ratio in CSF. In some embodiments, the patient has total tau protein greater than 400 pg / mL, pT181 tau protein greater than 60 pg / mL, Aβ42 less than 600 pg / mL, and / or an Aβ42:Aβ40 ratio less than 0.089.

[0144] Non-coding RNAs, such as microRNAs or lncRNAs, can also be used as biomarkers for AD. In some embodiments, AD diagnosis is based, at least in part, on the measurement of microRNAs. Wu et al., Journal of Alzheimer's Disease, (2016) 49(3):755-766. MicroRNAs (also abbreviated as miRNAs) are small non-coding RNA molecules (containing about 22 nucleotides) found in plants, animals, and some viruses. Without being constrained by any theory, miRNAs function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs function by base pairing with complementary sequences within mRNA molecules. Since miRNA levels can be dysregulated in disease states, they can therefore be used as biomarkers. Exemplary microRNAs that can function as biomarkers for AD are shown in Table 4. In some embodiments, AD diagnosis is based, at least in part, on the measurement of microRNA biomarkers. In some embodiments, the biomarker is hsa-let-7a-5p. In some embodiments, the biomarker is hsa-miR-10a-5p. In some embodiments, the biomarker is hsa-miR-145-5p. In some embodiments, the biomarker is hsa-miR-103a-3p. In some embodiments, the biomarker is hsa-miR-191-5p. In some embodiments, the biomarker is hsa-miR-374a-5p. In some embodiments, the biomarker is hsa-miR-26a-5p. In some embodiments, the biomarker is hsa-miR-107. In some embodiments, the biomarker is hsa-miR-15a-5p. In some embodiments, the biomarker is hsa-miR-126-3p. In some embodiments, the biomarker is hsa-miR-224-5p. In some embodiments, the biomarker is hsa-miR-18a-5p. In some embodiments, the biomarker is hsa-miR-23a-3p. In some embodiments, the biomarker is hsa-miR-26b-5p.In some embodiments, the biomarker is hsa-miR-21-5p. In some embodiments, a combination of two or more microRNA biomarkers is used.

[0145] [Table 5]

[0146] Methods for measuring microRNA levels are known in the art and are not limited to, but include, reverse transcriptase quantitative PCR (RT-qPCR), PCR, or high-throughput sequencing.

[0147] In some embodiments, the amount of microRNA in a patient's plasma or CSF is compared to the amount or threshold from a control sample. The control sample may be a negative or positive control sample and may be derived from a healthy individual or an AD patient. The comparison may also be made against disease progression or disease state at different points in time or during treatment. In some embodiments, the control sample is a plasma or CSF sample obtained from an individual not diagnosed with Alzheimer's disease. In some embodiments, the control sample is a plasma or CSF sample obtained from an individual with Alzheimer's disease. In some embodiments, the threshold is determined relative to an individual not diagnosed with Alzheimer's disease. In some embodiments, the threshold is determined relative to an individual with Alzheimer's disease.

[0148] In some embodiments, a method for diagnosing a patient suffering from AD is to (a) detect the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p in or from the patient; (b) where hsa-let-7a- The presence of one or more of 5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p and / or a change in the amount in a control sample or a threshold is an indicator of Alzheimer's disease in the subject; and (c) the presence or absence of Alzheimer's disease in the patient based on step (b). In some embodiments, the amounts of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p in patients differ from those in control samples by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more.

[0149] In some embodiments, the amount of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p in the patient is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more than in the control sample. In some embodiments, the patient's HSA-LET-7A-5P, HSA-MIR-10A-5P, HSA-MIR-145-5P, HSA-MIR-103A-3P, HSA-MIR-191-5P, HSA-MIR-374A-5P, HSA-MIR-26A-5P, HSA-MIR-107, HSA-MIR-15A-5P, HSA-MIR-26A-5P, HSA-MIR-107, HSA-MIR-15A-5P, HSA-MIR-107 The amounts of a-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p are 1 / 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 of the control sample, or less. In some embodiments, the patient has HSA-LET-7A-5P, HSA-MIR-10A-5P, HSA-MIR-145-5P, HSA-MIR-103A-3P, HSA-MIR-191-5P, HSA-MIR-374A-5P, HSA-MIR-26A-5P, HSA-MIR-107, HSA-MIR-15A-5P, HSA-MIR- The amounts of R-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p are approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 500% higher than in the control sample.In some embodiments, the amount of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p in the patient is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than in the control sample. In some embodiments, compared to a control sample or threshold, hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126- The presence and / or changes in the quantity of at least two, at least three, at least four, at least five, at least six, or at least seven or more of the following: 3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and hsa-miR-21-5p, are indicators of Alzheimer's disease in the subject.

[0150] In some embodiments, a method for diagnosing a patient with AD includes obtaining a CSF or plasma sample from the patient. In some embodiments, the method further includes extracting one or more of the following from the patient's CSF or plasma: hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p. In some embodiments, the method further includes performing cDNA synthesis from miRNA. In some embodiments, the presence or amount of one or more of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p is detected by qPCR.

[0151] In some embodiments, patients with Alzheimer's disease are given at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times, or more, of the control sample of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p It has the following levels: hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p. In some embodiments, patients with Alzheimer's disease have at least 1 / 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 1 / 100 of the control sample of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5 It has levels p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p. In some embodiments, patients with Alzheimer's disease had 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 500% higher levels of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, and hsa-miR-191 compared to the control sample. It has levels of -5p, hsa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p.In some embodiments, patients with Alzheimer's disease had 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower levels of hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-145-5p, hsa-miR-103a-3p, hsa-miR-191-5p, h It has levels of sa-miR-374a-5p, hsa-miR-26a-5p, hsa-miR-107, hsa-miR-15a-5p, hsa-miR-126-3p, hsa-miR-224-5p, hsa-miR-18a-5p, hsa-miR-23a-3p, hsa-miR-26b-5p, and / or hsa-miR-21-5p.

[0152] Metabolites, such as amino acids or phospholipids, can also be used as biomarkers for diagnosing AD. Metabolites are intermediate end products of metabolism. Examples of metabolites include, but are not limited to, alcohols, amino acids, nucleotides, antioxidants, organic acids, polyols, and vitamins. In some embodiments, the diagnosis of AD is based, in part, on the measurement of one or more metabolites. Oresic et al., Translational Psychiatry, (2016) Translational Psychiatry, (2011) 1:e57. Exemplary metabolites that can act as biomarkers for AD include, but are not limited to, 2,4-dihydroxybutanoic acid, phospholipids, phosphatidylcholines, sphingomyelins, sterols, arginine, serotonin, spermidine, sphingomyelin, and propionylcarnitine. In some embodiments, the diagnosis of AD is based, in part, on the measurement of one or more metabolites. In some embodiments, the metabolites may include one or more of the metabolites shown in Figures 38 to 42.

[0153] Methods for measuring metabolite levels are known in the art and are not limited to mass spectrometry and enzyme-linked immunosorbent assays. In some embodiments, the amount of a patient's metabolites is measured by combining liquid chromatography with mass spectrometry. In some embodiments, the amount of a patient's metabolites is measured by time-of-flight mass spectrometry. In some embodiments, the amount of a patient's metabolites is measured by tandem mass spectrometry. In some embodiments, the amount of metabolites in the patient's plasma or CSF is compared to the amount or threshold from a control sample.

[0154] In some embodiments, the amount of metabolites in a patient's plasma or CSF is compared to the amount or threshold from a control sample. The control sample may be a negative or positive control sample and may come from a healthy individual or a patient known to have Alzheimer's disease. The comparison may also be made against disease progression or disease state at different points in time or in the course of treatment. In some embodiments, the control sample is a sample of plasma or CSF obtained from an individual not diagnosed with Alzheimer's disease. In some embodiments, the control sample is a sample of plasma or CSF obtained from an individual with Alzheimer's disease. In some embodiments, the threshold is determined relative to an individual not diagnosed with Alzheimer's disease. In some embodiments, the threshold is determined relative to an individual with Alzheimer's disease.

[0155] In some embodiments, a method for diagnosing a patient with AD includes (a) detecting the presence and / or amount of one or more metabolites in or from the patient; (b) where the presence and / or change in the amount of one or more metabolites compared to the amount in a control sample or a threshold is an indicator of Alzheimer's disease in the subject; and (c) diagnosing the presence or absence of Alzheimer's disease in the patient based on step (b). In some embodiments, the amount of the patient's metabolites differs from that of a control sample by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more. In some embodiments, the amount of metabolites in the patient is 1 / 2 / 3 / 4 / 5 / 6 / 7 / 8 / 9 / 10 / 100 of that in the control sample, or less. In some embodiments, the presence and / or change in the amount of at least two, at least three, at least four, at least five, at least six, or at least seven or more metabolites compared to the control sample or a threshold is an indicator of Alzheimer's disease in the subject.

[0156] In some embodiments, a method for diagnosing a patient with Alzheimer's disease (AD) includes obtaining a CSF, serum, or plasma sample from the patient. In some embodiments, the method further includes extracting one or more metabolites from the patient's CSF, serum, or plasma. In some embodiments, the detection of the presence or amount of one or more metabolites is carried out by mass spectrometry.

[0157] In some embodiments, the amount of the patient's metabolite differs from that of the control sample by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more. In some embodiments, the amount of the patient's metabolite is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 500%, or 1000% more than that of the control sample. In some embodiments, the amount of the patient's metabolite is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than that of the control sample. In some embodiments, the presence and / or changes in the amount of at least two, at least three, at least four, at least five, at least six, or at least seven or more metabolites compared to a control sample or threshold are indicators of the Alzheimer's disease in question.

[0158] In some embodiments, patients with Alzheimer's disease have metabolite levels at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times, or more, of the control sample. In some embodiments, patients with Alzheimer's disease have metabolite levels at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times, or less, of the control sample.

[0159] In some embodiments, patient diagnosis is performed in vitro.

[0160] Patient selection methods - biomarkers This specification discloses biomarkers that can be used to select patients suitable for the treatment disclosed herein, as well as methods for treating selected patients. In some embodiments, biomarkers can be used to distinguish between subgroups of patients who would benefit from the treatment disclosed herein. In some embodiments, biomarkers can be used to select patients who would benefit from the treatment composition discussed herein, such as one containing an immunogenic peptide, such as SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1. In some embodiments, biomarkers can be used to select patients who would not benefit from the treatment with an immunogenic composition such as AADvac1. In some embodiments, the presence of one or more biomarkers in a patient or a sample from a patient, or a change in their level compared to a control or threshold, is an indicator that the patient is likely to benefit from the treatment with AADvac1. In some embodiments, the presence of one or more biomarkers, or a change in their level compared to a control or threshold, is an indicator that the patient is unlikely to benefit from the treatment with AADvac1.

[0161] In some embodiments, the biomarker used for patient selection for treatment with AADvac1, for example, a therapeutic composition as discussed herein, for example, one comprising an immunogenic peptide, for example, one comprising SEQ ID NO: 1 or SEQ ID NO: 2, for example, one comprising one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p. In some embodiments, hsa-let-7a-5p is used for patient selection for treatment with AADvac1. In some embodiments, hsa-miR-15a-5p is used for patient selection for treatment with AADvac1. In some embodiments, hsa-miR191-5p is used for patient selection for treatment with AADvac1. In some embodiments, hsa-miR-23a-3p is used for patient selection for treatment with AADvac1. In some embodiments, the presence or alteration in the levels of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p is an indicator that a patient is likely to benefit from treatment. In some embodiments, one or more miRNA biomarkers are used alone or in combination with one or more additional biomarkers, such as one or more of the other biomarkers considered herein.

[0162] In some embodiments, a method for selecting and / or treating a patient with respect to Alzheimer's disease involves (a) detecting the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p in a sample from or of the patient (e.g., CSF, plasma, or serum sample); and (b) adding hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR (c) Selecting a patient for treatment when one or more of 191-5p and hsa-miR-23a-3p are present, or when there is a change in the level of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p compared to a control sample or threshold; and (c) treating a patient by administering one or more doses of an immunogenic composition containing an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0163] In some embodiments, amounts of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p are detected and / or compared to a control sample or a threshold. In some embodiments, amounts of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in patients that differ from a control sample by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more are indicators of the likelihood that a patient will benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, the amounts of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in a patient that are 1 / 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or less than 1 / 100 of the control sample are indicators that the patient is likely to benefit from treatment with therapeutic compositions as discussed herein, such as those containing immunogenic peptides, such as those containing SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1. In some embodiments, amounts of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in a patient that are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times, or more, compared to a control sample, are indicators that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1.In some embodiments, amounts of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in patients that are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 500% higher than in a control sample are indicators that patients are likely to benefit from treatment with therapeutic compositions as discussed herein, such as those containing immunogenic peptides, such as those containing SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1. In some embodiments, amounts of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in patients compared to a control sample are indicators that the patient is likely to benefit from treatment with therapeutic compositions as discussed herein, such as those containing immunogenic peptides, such as those containing SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1. In some embodiments, the presence and / or changes in the amounts of at least two, at least three, or at least four of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and / or hsa-miR-23a-3p in a patient is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one comprising an immunogenic peptide, e.g., one comprising SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1.

[0164] In some embodiments, a method for selecting and / or treating a patient with respect to Alzheimer's disease includes (a) detecting the presence and / or amount of one or more metabolites in a sample from or of the patient (e.g., plasma or serum sample); (b) selecting the patient for treatment when one or more metabolites are present in the patient or a sample from the patient, or when there is a change in the level of one or more metabolites compared to a control sample or threshold; and (c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the metabolites may include one or more of the metabolites listed in Figures 38 to 42.

[0165] In some embodiments, the amount of one or more metabolites is detected and / or compared to a control sample or threshold. In some embodiments, the amount of a patient's metabolites that differs by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more from the control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing immunogenic peptides, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, the amount of a patient's metabolites that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or less from the control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing immunogenic peptides, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, an amount of a patient's metabolites that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more than that of a control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, an amount of a patient's metabolites that is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 500% more than that of a control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, a patient's metabolite levels that are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than those of a control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, such as one containing an immunogenic peptide, such as one containing SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1.In some embodiments, the presence and / or changes in the amount of at least two, at least three, at least four, at least five, at least six, at least seven, or more metabolites in a patient is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, such as one comprising an immunogenic peptide, such as one comprising SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1.

[0166] Neurofilament light chains (NfLs) are biomarkers of nerve axonal injury and, although not theoretically constrained, may show elevated levels in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Mattsson et al., JAMA Neurol., (2017) 74(5):557-566; Bergman et al., Neurol. Neuroimmunol. Neuroinflamm., (2016) 3(5):e271. The presence of NfLs may also correlate with other markers of AD progression, such as future atrophy, metabolic decline, and cognitive impairment. Mattsson et al., JAMA Neurol., (2019) 76(7):791-799. Although not theoretically constrained, NfLs may serve as a biomarker for selecting patients for the treatments discussed herein, or for monitoring or evaluating the effectiveness of treatments.

[0167] In some embodiments, NfL is used as a biomarker for selecting patients for treatment with therapeutic compositions as discussed herein, such as those comprising immunogenic peptides, such as those comprising SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1. In some embodiments, the presence or alteration of NfL levels (alone or in combination with one or more additional biomarkers) is an indicator that a patient is likely to benefit from the treatment.

[0168] Methods for measuring neurofilament light chain levels are known in the art and are not limited to, but include, the Bradford assay, Western blotting, immunoassays such as ELISA and Simoa NF-light® assay, and mass spectrometry. In some embodiments, neurofilament light chain levels are measured by the Simoa NF-light® assay.

[0169] In some embodiments, a method for selecting a patient for the treatment of Alzheimer's disease includes (a) detecting the presence and / or amount of NfL in the patient or a sample from the patient; (b) selecting the patient for treatment when NfL is present in the patient or a sample from the patient, or when there is a change in the level of NfL compared to a control sample or threshold; and (c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0170] In some embodiments, the amount of NfL is detected and / or compared to a control sample or a threshold. In some embodiments, a patient's neurofilament light chain amount that differs by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more from a control sample is an indicator of the likelihood that the patient will benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, a patient's NfL level exceeding a threshold of approximately 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 pg / ml, or 100 pg / mL is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, the method further includes confirming the patient's AD by one or more of the methods disclosed herein before selecting the patient for treatment in step (b).

[0171] In some embodiments, homocysteine ​​is used to select a patient for treatment with a therapeutic composition as discussed herein, for example, one comprising an immunogenic peptide, for example, one comprising SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, the presence or alteration of homocysteine ​​levels (alone or in combination with one or more additional biomarkers) is an indicator that the patient is likely to benefit from the treatment.

[0172] Methods for measuring homocysteine ​​levels are known in the art and are not limited to immunoassays and ELISAs.

[0173] In some embodiments, a method for selecting a patient for treatment of Alzheimer's disease includes (a) detecting the presence and / or amount of homocysteine ​​in the patient or a sample from the patient; (b) selecting the patient for treatment when homocysteine ​​is present in the patient or a sample from the patient, or when there is a change in the level of homocysteine ​​compared to a control sample or threshold; and (c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0174] In some embodiments, the amount of homocysteine ​​is detected and / or compared to a control sample or a threshold. In some embodiments, a patient's homocysteine ​​level that differs by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more from a control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, a patient's homocysteine ​​level that is higher than a threshold of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 100 μM is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, a patient's homocysteine ​​level greater than a 15 μM threshold is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, such as one containing an immunogenic peptide, such as one containing SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1.

[0175] Neurogranin is a calmodulin-binding protein primarily expressed in the brain, particularly in dendritic spines, and is involved in the protein kinase C signaling pathway. Neurogranin is the major postsynaptic protein that regulates calmodulin utilization and binds to it in the absence of calcium. Neurogranin concentrations in CSF have been suggested as a marker of synaptic dysfunction in age-related neurodegeneration and Alzheimer's disease (AD). Casaletto et al., (2017) Neurology, 89(17):1782-1788; De Vos et al., (2015) Alzheimer's & Dementia, 11(12):1461-1469; Willemse et al., (2018) Clinical Chemistry, 64(6):927-937. While not theoretically constrained, neurogranin may serve as a biomarker for selecting patients for or monitoring treatment as discussed herein.

[0176] In some embodiments, a method for selecting a patient for treatment of Alzheimer's disease includes (a) detecting the presence and / or amount of neurogranin in the patient or a sample from the patient; (b) selecting the patient for treatment when neurogranin is present in the patient or a sample from the patient, or when there is a change in neurogranin levels compared to a control sample or threshold; and (c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0177] In some embodiments, the amount of neurogranin is detected and / or compared to a control sample or a threshold. In some embodiments, a patient's neurogranin level that differs by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more from a control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, a patient's neurogranin level that is higher than a threshold of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 100 pg / ml is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, e.g., one containing an immunogenic peptide, e.g., one containing SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1. In some embodiments, a patient's neurogranin level 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 500% higher than that of a control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, such as one containing an immunogenic peptide, such as one containing SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1. In some embodiments, a patient's neurogranin level 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than that of a control sample is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, such as one containing an immunogenic peptide, such as one containing SEQ ID NO: 1 or SEQ ID NO: 2, such as AADvac1.

[0178] In some embodiments, the selected patient has AD. In some embodiments, the selected patient is diagnosed with AD using the method disclosed herein.

[0179] In some embodiments, the selected patient has MCI. In some embodiments, the selected patient is diagnosed with MCI using the method disclosed herein.

[0180] Patient selection methods - genotype A patient's genotype may provide an additional factor in determining treatment options. In some embodiments, a patient's genotype is used in selecting a patient for treatment with a therapeutic composition as discussed herein, e.g., one comprising an immunogenic peptide, e.g., one comprising SEQ ID NO: 1 or SEQ ID NO: 2, e.g., AADvac1, and being homocysteine. In some embodiments, the presence of at least one ε4 allele is an indicator that the patient is likely to benefit from the treatment.

[0181] In some embodiments, a method for selecting a patient for the treatment of Alzheimer's disease includes (a) determining the genotype for each of the two alleles of the ApoE gene present in the patient; (b) selecting the patient for treatment if the patient has at least one ApoE-ε4 allele; and (c) treating the patient by administering one or more doses of an immunogenic composition comprising an immunogenic peptide including SEQ ID NO: 1 or SEQ ID NO: 2.

[0182] Methods for determining genotype or allele are known in the art and are not limited to, but include, reverse transcriptase quantitative PCR (RT-qPCR), PCR, high-throughput sequencing, Sanger sequencing, or fluorescence in situ hybridization (FISH). In some embodiments, the genotype is determined by Sanger sequencing. In some embodiments, the genotype is determined by whole-genome sequencing. In some embodiments, the genotype is determined by PCR. In some embodiments, the presence of one ApoE-ε4 allele is an indicator that a patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, the presence of two ApoE-ε4 alleles is an indicator that a patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1.

[0183] In some embodiments, the selected patient has AD. In some embodiments, the selected patient is diagnosed with AD using the method disclosed herein.

[0184] In some embodiments, the selected patient has MCI. In some embodiments, the selected patient is diagnosed with MCI using the method disclosed herein.

[0185] Patient selection methods - patient characteristics The selection of patients who are suitable for, or likely to benefit from, treatment with the compositions disclosed herein may also be determined by patient characteristics. Such characteristics may include, but are not limited to, age, sex, disease severity, or age of disease onset. In some embodiments, disease severity is used to select patients for treatment with the therapeutic compositions discussed herein, such as those comprising immunogenic peptides, such as those comprising SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, the patient's MMSE score is used to select patients for treatment with the therapeutic compositions discussed herein, such as those comprising immunogenic peptides, such as those comprising SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1.

[0186] In some embodiments, a method for selecting a patient for treatment of Alzheimer's disease includes (a) determining the patient's Mini-Mental State Examination (MMSE) score; (b) comparing the score from step a to a threshold score; (c) selecting the patient for treatment if the patient's MMSE score is above the threshold; and (d) treating the patient by administering one or more doses of an immunogenic composition comprising a peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2.

[0187] In some embodiments, an MMSE score is determined and compared to a control patient or a threshold. In some embodiments, an MMSE score 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points lower than the control or threshold is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, an MMSE score 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points higher than the control or threshold is an indicator that the patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, MMSE scores of at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 are indicators that a patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, MMSE scores of at most 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 are indicators that a patient is likely to benefit from treatment with a therapeutic composition as discussed herein, for example, one containing an immunogenic peptide, for example, one containing SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1. In some embodiments, MMSE scores 24–26 are indicators of the likelihood that a patient will benefit from treatment with a therapeutic composition as discussed herein, for example, one comprising an immunogenic peptide, for example, one comprising SEQ ID NO: 1 or SEQ ID NO: 2, for example, AADvac1.

[0188] The patient's age may also be used in selecting patients who are suitable for, or likely to benefit from, treatment with the compositions disclosed herein, e.g., AADvac1. While not theoretically bound, treatment with the compositions disclosed herein that target pathological tau, e.g., AADvac1, may be more beneficial to patients with early-onset Alzheimer's disease, for example, in younger patients where tau may play a larger role in the pathology of the disease. In some embodiments, patients selected for treatment have early-onset Alzheimer's disease. In some embodiments, patients selected for treatment are 80, 78, 76, 74, 72, 70, 68, 66, 64, 62, 60, 58, 56, 54, 54, or under 50 years old. In some embodiments, patients selected for treatment are 50–68 years old. In some embodiments, patients selected for treatment are 50–70 years old. In some embodiments, patients selected for treatment are not older than approximately 60, 62, 64, 66, 68, 70, 72, 74, or 76 years of age.

[0189] In some embodiments, the selected patient has AD. In some embodiments, the selected patient is diagnosed with AD using the method disclosed herein.

[0190] In some embodiments, the selected patient has MCI. In some embodiments, the selected patient is diagnosed with MCI using the method disclosed herein.

[0191] Diagnostic Methods - Brain Imaging In some embodiments, the determination that a patient is suitable for AD diagnosis and / or treatment as disclosed herein is made, at least in part, based on brain imaging techniques. Brain imaging techniques can provide direct structural and functional details of the brain. Techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) may make it possible to visualize the presence of brain volume loss, neuronal loss, atrophy of the medial temporal lobe region, and / or neurofibrillary tangles in the brain of an AD patient. Frisoni GB, J.Neurol.Neurosurgery and Psychiatry,(2001)70(6):711-718;Scheltens et al.,Lancet Neurology,(2002)1(1):13-21;Barnes et al.,Archives of Neurology,(2006)63(10):1434-1439;Barnes et al. al.,Neurobiology of Aging,(2007)28(1):20-28;Whitwell et al.,Topics in Magnetic Resonance Imaging,(2005)16(6):409-425;Becker et al.,Neurology,(1996)46(3):692-700;Grady et al. al.,Brain,(2001)124(4):739-756;Woodard et al. al., Neuropsychology, (1998) 12(4):491-504.

[0192] In some embodiments, the diagnosis of AD and / or the determination that the patient is suitable for treatment is based on brain imaging. In some embodiments, the diagnosis and / or determination is based on a magnetic resonance imaging (MRI) scan of the brain. In some embodiments, the diagnosis and / or determination is based on a computed tomography (CT) scan of the brain. In some embodiments, the diagnosis and / or determination is based on a positron emission tomography (PET) scan of the brain. In some embodiments, the patient has brain MRI findings consistent with a diagnosis of AD at the time of screening. In some embodiments, the patient has evidence of the pathophysiological processes of AD.

[0193] In some embodiments, brain imaging is assessed using radiological classification scales. For example, one imaging-based radiological classification scale that may be used in the methods disclosed herein is the Medial Temporal Lobe Atrophy Scale (MTA scale) or the Scheltens scale. Scheltens et al., J. Neurol., (1995) 242:557-560; Scheltens et al., J. Neurol. Neurosurg. Psychiatry, (1992) 55:967-972; Dubois et al., Lancet Neurol., (2007) 6:734-746. The analysis is performed on coronal T1-weighted images, e.g., slices of the hippocampal body (forepontine level). This scale may be based on visual scores of choroid fissure width, inferior horn width, and hippocampal body height. A score of 0 indicates no atrophy; 1 indicates only choroid fissure enlargement; 2 indicates enlargement of the inferior horn of the lateral ventricle; 3 indicates moderate hippocampal volume loss (reduced height); and a score of 4 indicates severe hippocampal volume loss. In some embodiments, patients have a Scheltens score of 2 or higher, e.g., a Scheltens score of 2, 3, or 4, based on brain MRI.

[0194] In some embodiments, the diagnosis of AD and / or the determination that a patient is suitable for treatment is based on clinical scale scores. For example, the Hachinski Ischemia Score (HIS) scale is a clinical tool currently used to distinguish between types of dementia (primary degenerative, vascular or polyinfarctial, mixed). Hachinski et al., Arch. Neurol., (1975) 32:632-637. This is a 13-item test in which patients with higher scores are more likely to have vascular dementia, and patients with lower scores are more likely to have Alzheimer's-type senile dementia. These 13 items assess, for example, sudden onset, gradual deterioration, fluctuating course, nocturnal confusion, relatively preserved personality, depression, somatic symptoms, emotional lability, history of hypertension, history of stroke, evidence of associated atherosclerosis, focal neurological symptoms, and focal neurological signs. In some embodiments, patients treated by the methods herein have an HIS score of 4 or less, for example, a score of 4, 3, 2, or 1.

[0195] Brain imaging techniques can also be useful for predicting, diagnosing, and / or monitoring the progression of Alzheimer's disease (AD). In some embodiments, brain imaging is used to monitor the progression of AD. In some embodiments, brain imaging is used to monitor the severity of AD throughout treatment. In some embodiments, AD progression is monitored by magnetic resonance imaging (MRI) scans of the brain. In some embodiments, AD progression is monitored by computed tomography (CT) scans of the brain. In some embodiments, AD progression is monitored by positron emission tomography (PET) scans of the brain. In some embodiments, AD progression throughout treatment is monitored by magnetic resonance imaging (MRI) scans of the brain. In some embodiments, AD progression throughout treatment is monitored by computed tomography (CT) scans of the brain. In some embodiments, AD progression throughout treatment is monitored by positron emission tomography (PET) scans of the brain. Other diagnostic techniques, such as biomarkers, may also be used to monitor disease progression.

[0196] Methods for monitoring disease progression and treatment effectiveness - Biomarkers In some embodiments, biomarkers may be used to monitor the progression of Alzheimer's disease and evaluate the effectiveness of treatment as disclosed herein. Biomarkers specific to AD lesions can provide a method for assessing the severity of the disease and / or distinguishing AD from other neurological disorders with similar symptoms.

[0197] In some embodiments, the progression of AD is monitored by measuring the levels of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p, for example, in plasma and / or CSF. In some embodiments, the effectiveness of treatment is evaluated by determining the presence and / or levels of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p, for example, in plasma, serum, and / or CSF.

[0198] In some embodiments, the effectiveness of the treatment may be monitored using the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p. In some embodiments, a method for treating a patient suffering from Alzheimer's disease or mild cognitive impairment involves (a) determining the presence and / or amount of one or more of the following in the patient (e.g., by measuring one or more levels in CSF, serum, or plasma samples); (b) administering one or more doses of an immunogenic composition containing a peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2; (c) after administering one or more doses, determining the presence and / or amount of the following in the patient: (d) Determining the presence and / or amount of one or more of the 3p (for example, by measuring one or more levels in a CSF, serum, or plasma sample); (c) Comparing the presence and / or amount from step (c) after treatment with the presence and / or amount from step (a) before treatment, wherein a change in the amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p is an indicator of therapeutic efficacy; and (e) When the patient demonstrates therapeutic efficacy in step (d), administering one or more additional doses of an immunogenic composition containing the peptide comprising SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a decrease in the amount of hsa-let-7a-5p and / or hsa-miR-15a-5p after treatment is an indicator of efficacy. In some embodiments, a decrease in hsa-let-7a-5p and / or hsa-miR-15a-5p levels by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or less after treatment is an indicator of efficacy.In some embodiments, an increase of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100 times or more in hsa-miR191-5p and / or hsa-miR-23a-3p after treatment is an indicator of efficacy.

[0199] In some embodiments, the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of AADvac1 before the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p is determined. In some embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of AADvac1 are administered after the presence and / or amount of one or more of hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p has been determined.

[0200] In some embodiments, the progression of AD is monitored, for example, by measuring the levels of one or more metabolites in plasma, serum, and / or CSF. In some embodiments, the effectiveness of treatment is evaluated, for example, by determining the presence and / or levels of one or more metabolites in plasma, serum, and / or CSF. In some embodiments, the metabolites may include one or more of the metabolites listed in Figures 38 to 42.

[0201] In some embodiments, the effectiveness of treatment can be monitored using the presence and / or amount of one or more metabolites. In some embodiments, a method for treating a patient suffering from Alzheimer's disease or mild cognitive impairment includes: (a) determining the presence and / or amount of one or more metabolites in the patient (e.g., by measuring one or more levels in CSF, serum, or plasma samples); (b) administering one or more doses of an immunogenic composition containing a peptide including SEQ ID NO: 1 or SEQ ID NO: 2; (c) determining the presence and / or amount of one or more metabolites in the patient after administering one or more doses (e.g., by measuring one or more levels in CSF, serum, or plasma samples); (d) comparing the presence and / or amount from step (c) after treatment with the presence and / or amount from step (a) before treatment, wherein the change in the amount of one or more metabolites is an indicator of therapeutic effectiveness; and (e) administering one or more additional doses of the immunogenic composition containing the peptide including SEQ ID NO: 1 or SEQ ID NO: 2 when the patient demonstrates therapeutic effectiveness in step (d). In some embodiments, a decrease in the amount of one or more metabolites after treatment is an indicator of effectiveness. In some embodiments, a decrease of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 100 times, or more, in metabolites after treatment is an indicator of effectiveness. In some embodiments, an increase of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 100 times, or more, in one or more metabolites after treatment is an indicator of effectiveness.

[0202] In some embodiments, the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of AADvac1 before the presence and / or amount of one or more metabolites is determined. In some embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of AADvac1 are administered after the presence and / or amount of one or more metabolites has been determined.

[0203] A longitudinal increase in NfL correlates with high pT181 and total tau (tTau) levels in CSF, as well as low Aβ levels, small hippocampal volume, low FDG-PET, and poor cognitive performance. A faster increase in NfL correlates with a faster rate of atrophy, metabolic decline, and cognitive deterioration. In some embodiments, the progression of AD is monitored by measuring NfL levels in plasma and / or CSF. In some embodiments, the effectiveness of treatment is evaluated by measuring NfL levels in plasma and / or CSF.

[0204] In some embodiments, a method for treating a patient suffering from Alzheimer's disease or mild cognitive impairment includes: (a) determining the presence and / or amount of NfL chains in the patient (e.g., in serum, plasma, or CSF samples); (b) administering one or more doses of an immunogenic peptide containing SEQ ID NO: 1 or SEQ ID NO: 2; (c) determining the presence and / or amount of NfL in the patient (e.g., in serum, plasma, or CSF samples) after administering one or more doses; (d) comparing the presence and / or amount from step (c) after treatment with the presence and / or amount from step (a) before treatment, wherein the change in the amount of NfL is an indicator of therapeutic efficacy; and (e) when the patient demonstrates therapeutic efficacy in step (d), administering one or more additional doses of an immunogenic composition containing the peptide containing SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a stable or decreased amount of NfL after treatment is an indicator of efficacy. In some embodiments, an indicator of effectiveness is a decrease in NfL accumulation after treatment compared to pre-treatment accumulation (e.g., accumulation rate) (e.g., a lower annual or semi-annual accumulation rate). In some embodiments, an indicator of effectiveness is a decrease in NfL accumulation after treatment compared to accumulation (e.g., accumulation rate) in the average Alzheimer's disease patient population (e.g., a lower annual or semi-annual accumulation rate). In some embodiments, an indicator of effectiveness is that the amount of NfL after treatment does not increase by more than approximately 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. In some embodiments, an indicator of effectiveness is that the amount of NfL does not increase by more than approximately 6 pg / mL, 5 pg / mL, 4 pg / mL, 3 pg / mL, or 2 pg / mL after treatment. In some embodiments, an indicator of effectiveness is that the amount of NfL decreases by more than approximately 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after treatment.

[0205] In some embodiments, before the presence and / or amount of NfL is determined, the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of AADvac1. In some embodiments, after the presence and / or amount of NfL is determined, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of AADvac1 are administered.

[0206] In some embodiments, a method for treating a patient suffering from Alzheimer's disease or mild cognitive impairment includes: (a) determining the presence and / or amount of neurogranin in the patient (e.g., in serum, plasma, or CSF samples); (b) administering one or more doses of an immunogenic peptide containing SEQ ID NO: 1 or SEQ ID NO: 2; (c) determining the presence and / or amount of neurogranin in the patient (e.g., in serum, plasma, or CSF samples) after administering one or more doses; (d) comparing the presence and / or amount from step (c) after treatment with the presence and / or amount from step (a) before treatment, wherein the change in the amount of neurogranin is an indicator of therapeutic efficacy; and (e) when the patient demonstrates therapeutic efficacy in step (d), administering one or more additional doses of an immunogenic composition containing the peptide containing SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, a stable or decreased amount of neurogranin after treatment is an indicator of efficacy. In some embodiments, an indicator of effectiveness is that the amount of neurolanin does not increase by more than approximately 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after treatment. In some embodiments, an indicator of effectiveness is that the amount of neurolanin does not increase by more than approximately 20 pg / mL, 18 pg / mL, 16 pg / mL, 14 pg / mL, 12 pg / mL, 10 pg / mL, 8 pg / mL, 6 pg / mL, 5 pg / mL, 4 pg / mL, 3 pg / mL, or 2 pg / mL after treatment. In some embodiments, an indication of effectiveness is a decrease in neurolanin levels by more than approximately 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after treatment.

[0207] In some embodiments, before the presence and / or amount of neurolanin is determined, the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of AADvac1. In some embodiments, after the presence and / or amount of neurolanin is determined, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of AADvac1 are administered.

[0208] In some embodiments, behavioral measures, such as MMSE, are used, either alone or in combination with one or more biomarkers discussed herein, before, during, and / or after treatment to confirm efficacy. In some embodiments, a method for treating a patient with Alzheimer's disease or mild cognitive impairment includes: (a) determining the patient's total MMSE score; (b) administering one or more doses of an immunogenic peptide containing SEQ ID NO: 1 or SEQ ID NO: 2; (c) determining the patient's total MMSE score after administering one or more doses; (d) comparing the total MMSE score from step (c) after treatment with the MMSE score from step (a) before treatment, wherein the change in neurogranin levels is an indicator of therapeutic efficacy; and (e) administering one or more additional doses of the immunogenic composition containing the peptide containing SEQ ID NO: 1 or SEQ ID NO: 2 when the patient demonstrates therapeutic efficacy in step (d). In some embodiments, a stable total MMSE score is an indicator of efficacy. In some embodiments, an indicator of effectiveness is that the total MMSE score does not decrease by more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 point.

[0209] In some embodiments, the patient is treated with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 doses of AADvac1 before the presence and / or amount of neurogranin is determined. In some embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional doses of AADvac1 are administered after the total MMSE score is determined in step (c).

[0210] In some embodiments, patients are diagnosed with AD using a combination of brain imaging (e.g., MRI imaging of brain atrophy) and biomarker assessment. In some embodiments, the biomarker assessment includes measuring the presence and / or amount of amyloid in a biological sample from the patient. In some embodiments, the biomarker assessment includes measuring the presence and / or amount of tau, e.g., pathological tau, in a biological sample from the patient. In some embodiments, the biomarker assessment includes measuring the presence and / or amount of amyloid and tau (e.g., pathological tau) in a biological sample from the patient in combination with brain imaging. In some embodiments, the biomarker assessment further includes measuring NfL and / or neurogranin in a biological sample from the patient. In some embodiments, the biomarker assessment includes measuring amyloid and / or tau (e.g., pathological tau), and further includes measuring hsa-let-7a-5p, hsa-miR-15a-5p, hsa-miR191-5p, and hsa-miR-23a-3p in a biological sample from the patient.

[0211] Evaluation of treatment effectiveness In some embodiments, the treatment is effective in preventing, reducing, alleviating, slowing, and / or partially or completely improving one or more symptoms of AD. In some embodiments, the treatment is monitored or determined before, during, and / or after administration of immunogenic peptides or pharmaceutical compositions disclosed herein. In some embodiments, the treatment is monitored or determined using one or more tests disclosed herein. In some embodiments, the treatment is monitored and / or confirmed by taking baseline test measurements before treatment and comparing them with post-treatment test measurements. In some embodiments, baseline tests and / or examinations performed during and / or after treatment include any of the tests discussed above (e.g., behavioral, biomarker, neuroimaging, cognitive, functional, etc.) for diagnosing that a patient has AD and / or is suitable for treatment.

[0212] One example of a usable test for determining therapeutic effectiveness is the University of Washington Clinical Dementia Rating (CDR), which yields both an overall score and a sum of scores (sum of box (SB) scores). Hughes et al., Br.J.Psychiatry, (1982) 140:566-572; Berg et al., Ann Neurol., (1988) 23(5):477-484; Lynch et al., Dement.Geriatr.Cogn.Disord., (2006) 21(1):40-43. In some embodiments, the CDR is obtained through semi-structured interviews with the patient and informant, and scores are assigned for cognitive function in six functional domains: memory, orientation, judgment and problem-solving, community matters, home and hobbies, and personal care. Each domain is scored on a 5-point functional scale as follows: 0, no impairment; 0.5, suspected impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care scores are on a 4-point scale, and scores of 0.5 are not available). The CDR-SB score is obtained by summing each of the domain column scores, where the score ranges from 0 to 18. Berg et al., Arch. Neurol., (1993) 50(4):349-358; Morris et al., Neurology, (1991) 41(4):469-478; Morris et al., Neurology, (1996) 46(3):707-719. In some embodiments, the efficacy of the treatment is evaluated by the CDR-SB after administering one or more rounds of the immunogenic peptide or pharmaceutical composition disclosed herein. In some embodiments, the total score is obtained by summing the patient's domain scores in a standard 6-domain CDR assessment. In some embodiments, the patient's CDR-SB scores before and after treatment are compared to determine treatment effectiveness.In some embodiments, treatment efficacy is assessed by the mean change in CDR-SB score from baseline to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, or 104 weeks after the start of treatment. In some embodiments, treatment is effective if the patient's CDR-SB score does not increase after treatment compared to the baseline before treatment. In some embodiments, treatment is effective if the increase in the patient's CDR-SB score after treatment does not exceed 1, 2, 3, 4, 5, 6, 7, or 8 compared to the baseline before treatment. In some embodiments, treatment is effective if the increase in the patient's CDR-SB score in each of the six domains after treatment does not exceed 1 compared to the baseline before treatment. In some embodiments, therapeutic efficacy is assessed by the change in CDR-SB score from baseline to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, or 104 weeks after the start of treatment, compared to a reference placebo score. In some embodiments, the difference in CDR-SB score between patients treated with AADvac1 as described herein and patients treated with placebo is approximately -0.60 at 104 weeks post-treatment. In some embodiments, the difference in CDR-SB score between patients treated with AADvac1 as described herein and patients treated with placebo is approximately 0.05 at 104 weeks post-treatment. In some embodiments, the difference in CDR-SB score between patients treated with AADvac1 as described herein and patients treated with placebo is approximately -0.97 at 104 weeks post-treatment. In some embodiments, the difference in CDR-SB scores between patients treated with AADvac1 as described herein and patients treated with placebo is approximately -0.15 at 104 weeks post-treatment. In some embodiments, the difference in CDR-SB scores between patients treated with AADvac1 as described herein and patients treated with placebo is approximately -0.70 at 104 weeks post-treatment.In some embodiments, the difference in CDR-SB scores between patients treated with AADvac1 as described herein and those treated with placebo is approximately 0.80 at 104 weeks post-treatment. In some embodiments, the difference in CDR-SB scores between patients treated with AADvac1 as described herein and those treated with placebo is approximately -0.12 at 104 weeks post-treatment. In some embodiments, the difference in CDR-SB scores between patients treated with AADvac1 as described herein and those treated with placebo is approximately -0.97 to approximately 0.80 at 104 weeks post-treatment. In some embodiments, the treatment is effective if the patient's CDR-SB score does not increase after treatment compared to the baseline before treatment. In some embodiments, the treatment is effective if the increase in the patient's CDR-SB score after treatment does not exceed 1, 2, 3, 4, 5, 6, 7, or 8 compared to the baseline before treatment. In some embodiments, treatment is considered effective if the post-treatment increase in the patient's CDR-SB score does not exceed 1 compared to the pre-treatment baseline in each of the six domains.

[0213] Other cognitive tests that can similarly be used to assess treatment effectiveness include, but are not limited to, tests of memory, language, and executive function. One such test is the Cogstate International Shopping List Task (ISLT), which is a computer-administered and scored auditory / speech list learning test. Lim et al., Behav. Res. Methods, (2009) 41(4):1190-1200; Lim et al., Arch. Clin. Neuropsychol., (2012) 27(2):136-147; Ames et al., J. Clin. Exp. Neuropsych., (2012) 34(8):853-863. In this test, patients are asked to remember 12 common food items that are read aloud in no particular order, and their ability to recall these words either immediately (immediate free recall) or 20 minutes later (delayed free recall) is assessed. The test is administered three times, and the total recall ISLT score and delayed recall ISLT score are calculated by summing the number of items recalled. In some embodiments, the effectiveness of the treatment is assessed by the Cogstate ISLT. In some embodiments, the patient's Cogstate ISLT scores before and after treatment are compared to determine the effectiveness of the treatment. In some embodiments, if the ISLT score is higher after treatment compared to baseline before treatment, or remains unchanged, the treatment is considered effective. In some embodiments, treatment is effective if the post-treatment deterioration of the total recall ISLT score does not exceed 1, 2, 3, 4, 5, 6, 7, 8, or 9 points compared to the baseline before treatment. In some embodiments, treatment is effective if the post-treatment deterioration of the delayed recall ISLT score does not exceed 1, 2, 3, or 4 points compared to the baseline before treatment. In some embodiments, the patient's post-treatment Cogstate ISLT score relative to baseline is compared to a reference score obtained from a placebo group, e.g., a group that received a treatment expected to have no therapeutic value. In some embodiments, treatment is effective if the post-treatment ISLT score relative to baseline is higher, improved further, or not worsened significantly compared to a reference score obtained from a placebo group, e.g., a group that received a treatment expected to have no therapeutic value.

[0214] Another cognitive test that can be used is the Cogstate One-Card Learning Task, which is a sequential visual recognition learning task that assesses visual recognition memory and attention. In this test, playing cards are presented face down in the center of a computer screen with a green background. After randomly changing intervals of 2.5 to 3.5 seconds, the cards are turned over and face up, and the patient must answer "yes" if the card has appeared before during the test, and "no" if it has not. Fredrickson et al., Met. Neuroepidemiology, (2010), 34:66-75. In some embodiments, task accuracy is defined as the number of correct answers expressed as a ratio to the total number of trials. In some embodiments, task accuracy is expressed as the arcsine transform of the square root of the ratio of correct answers. In some embodiments, the effectiveness of treatment is assessed by the Cogstate One-Card Learning Task. In some embodiments, the Cogstate One-Card Learning Task scores of patients before and after treatment are compared to determine the effectiveness of treatment. In some embodiments, treatment is effective if the Cogstate One Card Learning task score is higher after treatment compared to a baseline score before treatment, or remains unchanged. In some embodiments, the patient's post-treatment Cogstate One Card Learning task score compared to baseline is compared to a reference score obtained from a placebo group, e.g., a group that received a treatment expected to have no therapeutic value. In some embodiments, treatment is effective if the post-treatment One Card Learning score compared to baseline is higher, further improved, or not significantly worse compared to a reference score obtained from a placebo group, e.g., a group that received a treatment expected to have no therapeutic value.

[0215] Another cognitive test that can be used is the Cogstate One Back task. This test assesses working memory and attention and uses a similar setup to the One Card Learning task. Instead of determining whether a card has appeared before during the test, patients must answer "yes" if the card is exactly the same as the previous card, or "no" if it is not the same as the previous card. Fredrickson et al., Met. Neuroepidemiology, (2010), 34:66-75. Working speed can be measured as the mean of the log10 transformed values ​​of reaction times when correct. In some embodiments, the effectiveness of the treatment is assessed by the Cogstate One Back task. In some embodiments, the Cogstate One Back task scores of patients before and after treatment are compared to determine the effectiveness of the treatment. In some embodiments, if the Cogstate One Back task score is lower after treatment compared to the baseline before treatment, or remains unchanged, the treatment is effective. In some embodiments, the patient's Cogstate One Back task score after treatment compared to baseline is compared to a reference score obtained from a placebo group, e.g., a group that was given a treatment expected to have no therapeutic value. In some embodiments, a treatment is considered effective if the post-treatment One-Bach task score relative to baseline is lower, significantly improved, or not significantly worsened compared to a reference score obtained from a placebo group, for example, a group given a treatment expected to have no therapeutic value.

[0216] Other cognitive tests that may be used are categorical fluency tests and alphabetical fluency tests. These are assessments of executive function and language. Lezak et al., Neuropsychological Assessment. (2012) New York, NY: Oxford University Press. In categorical fluency tests, patients are asked to list as many words as possible from a given category, such as animals or fruits, within a given time. In alphabetical fluency tests, patients are asked to list as many words as possible that begin with a given letter of the alphabet, within a given time. In some embodiments, categorical fluency test scores are defined by the number of acceptable words listed. In some embodiments, alphabetical fluency test scores are defined by the total number of acceptable words listed over three trials. In some embodiments, the effectiveness of treatment is assessed by categorical fluency tests. In some embodiments, the categorical fluency test scores of patients before and after treatment are compared to determine the effectiveness of treatment. In some embodiments, the effectiveness of treatment is assessed by alphabetical fluency tests. In some embodiments, the patient's letter fluency test scores are compared before and after treatment to determine the effectiveness of the treatment. In some embodiments, the treatment is effective if the categorical fluency test and letter fluency test scores are higher after treatment or remain unchanged compared to the baseline before treatment. In some embodiments, the patient's post-treatment categorical fluency test score relative to baseline is compared to a reference score obtained from a placebo group, e.g., a group that received a treatment expected to have no therapeutic value. In some embodiments, the treatment is effective if the post-treatment categorical fluency test score relative to baseline is higher, improved further, or not worsened compared to a reference score obtained from a placebo group, e.g., a group that received a treatment expected to have no therapeutic value. In some embodiments, the patient's post-treatment letter fluency test score relative to baseline is compared to a reference score obtained from a placebo group, e.g., a group that received a treatment expected to have no therapeutic value.In some embodiments, a treatment is considered effective if the post-treatment letter fluency test score relative to baseline is higher, significantly improved, or not significantly worse compared to a reference score obtained from a placebo group, for example, a group given a treatment expected to have no therapeutic value.

[0217] Another cognitive test that can be used is the digit-symbol conversion test. This measures executive function, working memory, and processing speed. Boake et al., J. Clin. Exp. Neuropsychol., (2002) 24:383-405; Lezak et al., Neuropsychological Assessment. (2012) New York, NY: Oxford University Press. Patients are instructed to write symbols corresponding to numbers according to the legend at the top of the sheet. The number of symbols correctly answered within an allowable time, usually 120 seconds, becomes the score. In some embodiments, the effectiveness of treatment is evaluated by the digit-symbol conversion test. In some embodiments, the patient's digit-symbol conversion test scores before and after treatment are compared to determine the effectiveness of treatment. In some embodiments, if the digit-symbol conversion test score is higher after treatment compared to the baseline before treatment, or remains unchanged, the treatment is effective. In some embodiments, the patient's digit-symbol conversion test score after treatment compared to baseline is compared to a reference score obtained from the placebo group. In some embodiments, a treatment is considered effective if the post-treatment digit-symbol conversion test score relative to baseline is higher, significantly improved, or not significantly worse compared to a reference score obtained from a placebo group, for example, a group given a treatment expected to have no therapeutic value.

[0218] In some embodiments, treatment effectiveness is assessed by a combination of cognitive tests. In some embodiments, the custom cognitive battery includes the Cogstate International Shopping List task, the Cogstate One-Card Learning task, the Cogstate One-Card Back task, a categorical fluency test, a letter fluency test, and a digit-symbol conversion test. In some embodiments, a z-score is calculated for each test in the custom cognitive battery. In some embodiments, an overall z-score is calculated from the test results of the custom cognitive battery. In some embodiments, the z-score is calculated from the patient's actual overall score on the custom cognitive battery at each visit and normalized by the mean baseline score and standard deviation in the full analysis set. In some embodiments, treatment effectiveness is assessed by the mean change in the overall z-score of the custom cognitive battery from baseline to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, or 104 weeks after the start of treatment.

[0219] In some embodiments, therapeutic efficacy may also be measured by improvements in the patient's daily life. For example, the Alzheimer's Disease Collaborative Study – Mild Cognitive Impairment and Activities of Daily Living (ADCS) The MCI ADL (Mild Cognitive Inventory of Daily Living) questionnaire may be used. This is an interview-based, informant-reported scale that assesses the abilities of AD patients in basic and instrumental activities of daily living, such as eating, handling money, shopping, getting around, and remembering appointments. et al., Alzheimer Dis.Assoc.Disord., (1997)11 Suppl 2:S33-39; Pedrosa et al., J.Nutr.HealthAging, (2010)14:703-709. This questionnaire assigns patients a score based on the degree of assistance they need for specific tasks, ranging from 0, where the patient is fully independent in performing an activity, to 4, where they are completely unable to perform the activity independently. The 18-item version of this test (ADCS-MCI-ADL-18) includes questions about shopping, hobbies, and household appliances, while the 24-item version (ADCS-MCI-ADL-24) has six additional items, including driving and medication management. In some embodiments, the effectiveness of treatment is assessed using the ADCS-MCI-ADL-18. In some embodiments, the ADCS-MCI-ADL-18 score of patients before and after treatment is compared to determine treatment effectiveness. In some embodiments, treatment effectiveness is evaluated by ADCS-MCI-ADL-24. In some embodiments, the ADCS-MCI-ADL-24 score of patients before and after treatment is compared to determine treatment effectiveness. In some embodiments, treatment effectiveness is evaluated by both ADCS-MCI-ADL-18 and ADCS-MCI-ADL-24. In some embodiments, both the ADCS-MCI-ADL-18 and ADCS-MCI-ADL-24 scores of patients before and after treatment are compared to determine treatment effectiveness. In some embodiments, treatment effectiveness is evaluated by the mean change in the ADCS-MCI-ADL-18 score from baseline to 104 weeks after the start of treatment. In some embodiments, treatment effectiveness is evaluated by the mean change in the ADCS-MCI-ADL-24 score from baseline to 104 weeks after the start of treatment. In some embodiments, treatment efficacy is assessed by the mean change in both ADCS-MCI-ADL-18 and ADCS-MCI-ADL-24 scores from baseline to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, or 104 weeks after the start of treatment.

[0220] In some embodiments, therapeutic efficacy may be measured by the patient's antibody titer and / or immunogenicity (alone or in combination with one or more alternative tests, e.g., the tests discussed herein). Administration of an immunogenic peptide may induce an antibody response in the patient. In some embodiments, efficacy is evaluated by whether an IgG antibody response to the immunogenic peptide disclosed herein occurs in the patient. In some embodiments, efficacy is evaluated by whether an IgM antibody response to the immunogenic peptide disclosed herein occurs in the patient. In some embodiments, efficacy is evaluated by the geometric mean titer of the immunogenic peptide-inducible IgG antibody. In some embodiments, efficacy is evaluated by the geometric mean titer of the immunogenic peptide-inducible IgM antibody. In some embodiments, the IgG or IgM antibody response is measured by enzyme-linked immunosorbent assay (ELISA). In some embodiments, the mean titer of the IgG or IgM antibody is measured by ELISA.

[0221] In some embodiments, therapeutic efficacy may be measured by changes in brain function, such as brain metabolism. In some embodiments, fluorodeoxyglucose-positron emission tomography (FDG-PET). FDG-PET has been useful in detecting changes in brain function in AD, identifying changes in early AD, and assisting in differentiating AD from other causes of dementia. Using FDG as a tracer, the quiescent brain metabolic rate of glucose, an indicator of neuronal activity, can be measured. Mosconi, Clin. Transl. Imaging, (2013) 1(4):217-233; Kantarci, Am. J. Neuroradiol., (2014) 35(6 Suppl):S12-177. In some embodiments, therapeutic efficacy is evaluated by FDG-PET. In some embodiments, therapeutic efficacy is evaluated by measuring brain metabolism using FDG-PET. In some embodiments, FDG-PET evaluates brain metabolism by changes in brain glucose metabolic rate. In some embodiments, changes in cerebral glucose metabolic rate are expressed as changes in the standardized uptake ratio (SUVR) in multiple regions of interest. In some embodiments, therapeutic efficacy is evaluated by changes in cerebral metabolism as measured by FDG-PET from baseline to 4, 8, 12, 16, 20, 24 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months after the start of treatment.

[0222] In some embodiments, therapeutic efficacy may be measured by hippocampal atrophy, a feature of AD that may correlate with AD neurological lesions. Atrophy can be detected using MRI, and therefore anatomical volumetric analysis using MRI can be used as a biomarker for AD progression. Fleisher et al., Neurology, (2008) 70(3):191-199. In some embodiments, therapeutic efficacy is evaluated by MRI volumetric analysis. In some embodiments, therapeutic efficacy is evaluated by changes in MRI volumetric analysis from baseline to 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months after the start of treatment.

[0223] In some embodiments, therapeutic efficacy is assessed by measurements of one or more biomarkers. In some embodiments, therapeutic efficacy is assessed by plasma tau protein levels after initiation of treatment compared to baseline before treatment. In some embodiments, therapeutic efficacy is assessed by cerebrospinal fluid (CSF) tau protein levels after initiation of treatment compared to baseline before treatment. In some embodiments, therapeutic efficacy is assessed by total tau protein levels in CSF after initiation of treatment compared to baseline before treatment. In some embodiments, treatment is continued or discontinued based on one or more efficacy measurements. In some embodiments, total tau is measured using an ELISA assay. In some embodiments, the ELISA assay is Innotest hTAU Ag and phosphotau (181P) ELISA assay. In some embodiments, pT181 tau is measured using an ELISA assay. In some embodiments, the ELISA assay is Innotest hTAU Ag and phosphotau (181P) ELISA assay. In some embodiments, pT217 tau is measured using an ELISA assay. In some embodiments, the ELISA assay is a digital ELISA assay.

[0224] In some embodiments, treatment is effective if the total tau protein concentration in CSF decreases or remains unchanged after the initiation of treatment compared to baseline before treatment. In some embodiments, treatment is effective if the increase in total tau protein concentration in CSF does not exceed 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% after the initiation of treatment compared to baseline before treatment. In some embodiments, treatment is effective if the total tau (t-tau) protein concentration in CSF decreases by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% after the initiation of treatment compared to baseline before treatment. In some embodiments, treatment efficacy is assessed by the level of threonine 181-phosphorylated tau protein (pT181 tau) in CSF after the initiation of treatment compared to baseline before treatment. In some embodiments, treatment is effective if the CSF pT181 tau concentration decreases or remains unchanged after initiation of treatment compared to baseline before treatment. In some embodiments, treatment is effective if the increase in CSF pT181 tau concentration does not exceed 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% after initiation of treatment compared to baseline before treatment. In some embodiments, treatment is effective if the CSF pT181 tau concentration decreases by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% after initiation of treatment compared to baseline before treatment. In some embodiments, treatment efficacy is assessed by the level of threonine-217 phosphorylated tau protein (pT217 tau) in CSF after initiation of treatment compared to baseline before treatment. In some embodiments, treatment is effective if the CSF pT217 tau concentration decreases or remains unchanged after the initiation of treatment compared to baseline before treatment. In some embodiments, treatment is effective if the increase in CSF pT217 tau concentration does not exceed 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% after the initiation of treatment compared to baseline before treatment.In some embodiments, treatment is effective if the pT217 tau concentration in CSF decreases by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% after the start of treatment compared to baseline before treatment. In some embodiments, the concentration of pT217 tau is measured as described in International Publication No. 2019 / 186276 A2 (this content is incorporated by reference in whole).

[0225] In some embodiments, therapeutic efficacy is assessed by the Aβ42 peptide level in CSF after initiation of treatment compared to baseline before treatment. In some embodiments, the treatment is effective if the Aβ42 concentration in CSF remains unchanged after initiation of treatment compared to baseline before treatment. In some embodiments, the treatment is effective if the change in Aβ42 concentration in CSF does not exceed 10%, 20%, 30%, 40%, or 50% after initiation of treatment compared to baseline before treatment. In some embodiments, therapeutic efficacy is assessed by the Aβ42:Aβ40 ratio in CSF after initiation of treatment compared to baseline before treatment. In some embodiments, the treatment is effective if the Aβ42:Aβ40 ratio in CSF remains unchanged after initiation of treatment compared to baseline before treatment. In some embodiments, the treatment is effective if the change in the Aβ42:Aβ40 ratio in CSF does not exceed 10%, 20%, 30%, 40%, or 50% after initiation of treatment compared to baseline before treatment. In some embodiments, therapeutic efficacy is evaluated by the levels of one or more of the following in CSF: total tau protein, pathological tau protein, Aβ42 peptide, Aβ40 peptide, and / or Aβ42:Aβ40 ratio at 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months post-treatment compared to baseline before treatment. In some embodiments, treatment is continued if it is deemed effective according to the methods and diagnostic criteria described herein, for example, by administering at least one, two, or more additional doses of the composition containing the immunogenic peptide to the patient. In some embodiments, treatment is continued indefinitely if it is deemed effective according to the methods and diagnostic criteria described herein. In some embodiments, Aβ40 is measured using an ELISA assay. In some embodiments, Aβ42 is measured using an ELISA assay.

[0226] Patient selection criteria In various embodiments, patients treated with one or more of the methods disclosed herein may have received, or have received in the past, treatment with one or more other drugs given before, during, and / or after treatment with the pharmaceutical compositions disclosed herein. Treatments targeting cognitive symptoms (e.g., forgetfulness, confusion, and problems with thinking and reasoning) include, but are not limited to, cholinesterase inhibitors (Aricept, Exelon, Razadyne) and memantine (Namenda). In some embodiments, patients have received stabilization therapy with acetylcholinesterase inhibitors (e.g., Aricept, Exelon, Razadyne) for at least 1, 2, 3, 4, 5, or 6 months prior to administration of the immunogenic peptides disclosed herein, for example, at least 3 months. In some embodiments, the patient has received stabilization therapy with memantine (e.g., Namenda) for at least 1, 2, 3, 4, 5, or 6 months prior to administration of the immunogenic peptides disclosed herein. In some embodiments, the patient has received a stabilization dose regimen of memantine (e.g., Namenda) for at least 3 months prior to administration of the immunogenic peptides disclosed herein.

[0227] Methods for selecting patients who would benefit from the treatments disclosed herein are also considered. In some embodiments, the patient is not contraindicated for MRI imaging, for example, the patient does not have MRI-incompatible metal implants or MRI-incompatible stent implants. In some embodiments, the patient does not have infarcts in one or more major vascular regions of the brain as detected by brain MRI. In some embodiments, the patient does not have two or more lacunar infarcts as detected by brain MRI, defined as localized CSF signal intensity lesions with any size less than 1.5 cm in diameter. In some embodiments, the patient does not have any lacunar infarcts as detected by brain MRI in the thalamus, the hippocampus of either hemisphere, or the head of the left caudate nucleus. The amount of white matter lesions in the brain may be quantified using the Fazekas scale, where brain regions are graded from 0 (no lesion) to 3 (irregular or large fused lesions) in relation to the size and fusion of the lesions. In some embodiments, the patient does not have fusion hemispheric deep white matter lesions (Fazekas grade 3) as detected by brain MRI, for example, Fazekas grade 0, 1, or 2. In some embodiments, the patient does not have focal lesions affecting cognitive status caused by a central nervous system disorder other than AD, such as current or acute infectious disease, space-occupying lesions, normal pressure hydrocephalus, or any other abnormalities associated with a severe central nervous system disorder other than Alzheimer's disease, as detected by brain MRI. In some embodiments, the patient has not undergone surgery (under general anesthesia) within three months prior to the treatment disclosed herein.

[0228] In some embodiments, the patient does not currently or previously have an allergy to one or more components of the vaccine disclosed herein. In some embodiments, the female patient is not pregnant or lactating. In some embodiments, the patient has no history of and / or does not currently have a systemic autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis (RA), or Sjögren's syndrome, or any disease requiring immunosuppressive or immunomodulatory therapy. In some embodiments, the patient is not receiving or is not expected to receive immunosuppressive or immunomodulatory therapy at the time of treatment or in the future. In some embodiments, the patient has no recent history of cancer. In some embodiments, the patient has not received any specific cancer treatment (excluding basal cell carcinoma or cervical neoplasm in situ) in the 1 month to 10 years prior to the treatment disclosed herein, for example, within the past 5 years. In some embodiments, the patient has not had a myocardial infarction in the 0 to 5 years prior to the treatment disclosed herein, for example, within the past 2 years. In some embodiments, the patient has not had hepatitis B, C, HIV, or syphilis as confirmed by serological testing. In some embodiments, the patient does not have an active infectious disease at the time of treatment disclosed herein. In some embodiments, the patient does not have a history of immunodeficiency. In some embodiments, the patient does not have an existing immunodeficiency at the time of treatment disclosed herein.

[0229] In some embodiments, patients suffering from other systemic diseases besides Alzheimer's disease (AD) may be excluded from treatment because they may receive less therapeutic benefit from the treatments disclosed herein. For example, patients with congestive heart failure, a high body mass index, diabetes mellitus, renal failure, or hepatic disease. In some embodiments, patients do not suffer from other clinically significant systemic diseases that may worsen their condition. For example, using the New York Heart Association Functional Classification (NYHA), a patient's heart failure is classified according to the severity of their symptoms from 1 (no limitation of physical activity), 2 (some limitation of physical activity), 3 (significant limitation of physical activity), to 4 (painful to perform any physical activity). In some embodiments, patients do not have poorly controlled congestive heart failure as defined by the NYHA as 2, 3, or 4. In some embodiments, patients do not have poorly controlled congestive heart failure as defined by the NYHA as 3 or higher, i.e., 3 or 4. In some embodiments, the patient does not have a body mass index (BMI) higher than 48, 46, 44, 42, 40, 38, 36, 34, or 32. In some embodiments, the patient does not have a body mass index (BMI) higher than 40. In some embodiments, the patient does not have poorly controlled diabetes as defined by a blood glycated hemoglobin (HbA1c) level higher than 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, or 14.0%. In some embodiments, the patient does not have poorly controlled diabetes as defined by a blood glycated hemoglobin (HbA1c) level higher than 7.5%. In some embodiments, the patient does not have severe renal failure as defined by estimated glomerular filtration rate (eGFR) levels of 60 mL / min, 50 mL / min, 40 mL / min, 30 mL / min, 20 mL / min, or less than 10 mL / min. In some embodiments, the patient does not have severe renal failure as defined by eGFR levels of less than 30 mL / min.In some embodiments, patients do not have chronic liver disease as defined by alanine aminotransferase (ALT) levels higher than 50 U / L, 55 U / L, 60 U / L, 65 U / L, 70 U / L, 75 U / L, or 80 U / L in women, or 60 U / L, 65 U / L, 70 U / L, 75 U / L, 80 U / L, 85 U / L, 90 U / L, 95 U / L, or 100 U / L in men, and aspartate aminotransferase (AST) levels higher than 60 U / L, 65 U / L, 70 U / L, 75 U / L, 80 U / L, 85 U / L, 90 U / L, 95 U / L, or 100 U / L in men. In some embodiments, patients do not have chronic liver disease as defined by ALT levels higher than 66 U / L in women, or 80 U / L in men. In some embodiments, the patient does not have chronic liver disease as defined by an AST level higher than 82 U / L.

[0230] In some embodiments, the patient does not suffer from hypothyroidism as defined by thyroid-stimulating hormone (TSH) levels greater than 4.0 mIU / L, 4.5 mIU / L, 5.0 mIU / mL, 5.5 mIU / L, 6.0 mIU / L, 7.0 mIU / L, 8.0 mIU / L, 9.0 mIU / L, or 10.0 mIU / L, and / or thyroxine (FT4) levels less than 1.5 ng / dL, 1.4 ng / dL, 1.3 ng / dL, 1.2 ng / dL, 1.1 ng / dL, 1.0 ng / dL, 0.9 ng / dL, 0.8 ng / dL, 0.7 ng / dL, 0.6 ng / dL, 0.5 ng / dL, or 0.4 ng / dL. In some embodiments, the patient does not suffer from hypothyroidism as defined by a TSH level greater than 5.0 mIU / mL and / or an FT4 level less than 0.7 ng / dL.

[0231] In some embodiments, the patient does not have a diagnosis of a major psychosis such as schizophrenia, any type of psychotic disorder, or bipolar affective disorder. In some embodiments, the patient does not have a current depressive episode as defined by a Geriatric Depression Scale (GDS) of 6 or more. In some embodiments, the patient has not had a major depressive episode within one year prior to the treatment disclosed herein. In some embodiments, the patient does not have dementia resulting from metabolic or toxic encephalopathy or systemic medical disease. In some embodiments, the patient does not have a history of alcohol or drug abuse or dependence within two years prior to the treatment disclosed herein. In some embodiments, the patient does not have Wernicke encephalopathy. In some embodiments, the patient has no history or evidence of any CNS disorder other than AD that could cause dementia (e.g., infectious or inflammatory / demyelinating CNS conditions, Creutzfeldt-Jakob disease, Parkinson's disease, Huntington's disease, brain tumor, subdural hematoma). In some embodiments, the patient has no history of cerebrovascular disease (ischemic or hemorrhagic stroke) or a diagnosis of suspected, probable, or definite vascular dementia. In some embodiments, the patient has no history of or current diagnosis of epilepsy. In some embodiments, the patient has not received treatment with experimental immunotherapy agents, including intravenous immunoglobulin (IVIg). In some embodiments, the patient has not received treatment with experimental immunotherapy agents, including IVIg, within the 6, 5, 4, 3, 2, or 1 month prior to the treatment disclosed herein. In some embodiments, the patient has not received treatment with experimental immunotherapy agents, including IVIg, within the 3 months prior to the treatment disclosed herein. In some embodiments, the patient has not received treatment with experimental therapies for disease modification for AD. In some embodiments, the patient has not received treatment with experimental therapies for disease modification for AD within the 3 months prior to the treatment disclosed herein. In some embodiments, the patient has not received treatment with any active vaccine for AD.In some embodiments, the patient has not received any active vaccine treatment for AD. In some embodiments, the patient has not received immunosuppressant treatment. In some embodiments, the patient does not have vitamin B12 deficiency as defined by serum vitamin B12 levels of less than 250 pg / mL, 240 pg / mL, 230 pg / mL, 220 pg / mL, 210 pg / mL, 200 pg / mL, 190 pg / mL, 180 pg / mL, 170 pg / mL, 160 pg / mL, or 150 pg / mL. In some embodiments, the patient does not have vitamin B12 deficiency as defined by serum vitamin B12 levels of less than 191 pg / mL. In some embodiments, the patient has not changed the dosage of previous or current drug therapy due to a comorbidity within 90, 60, 30, 15, or 10 days prior to the treatment disclosed herein. In some embodiments, the patient has not had their previous or current drug therapy dose changed due to a comorbidity within 30 days prior to the treatment disclosed herein.

[0232] In some embodiments, the patient does not have (a) MRI findings inconsistent with a diagnosis of AD, (b) any neurological condition other than AD that could cause or significantly contribute to symptoms of dementia, and (c) any systemic autoimmune disorder, such as systemic lupus erythematosus.

[0233] Evaluation of treatment tolerability In some embodiments, the tolerability of the treatments disclosed herein is measured, for example, to determine whether to continue treatment and / or to select a suitable dosage. Tolerability may refer to the extent to which a patient can tolerate the apparent adverse effects of a drug. The patient's tolerability of a treatment method may be determined using various cognitive skills tests, such as MRI brain scans, physical examinations, and neurological examinations, before and after treatment. In some embodiments, the tolerability of a treatment is assessed by the patient's vital signs measured before and after treatment. A treatment method may be determined to be tolerable if the absolute or relative changes in post-treatment test parameters compared to the baseline before treatment do not exceed a predetermined range.

[0234] In some embodiments, the tolerability of the treatment is assessed by the patient's electrocardiogram (ECG), measured before and after treatment. In some embodiments, the treatment is determined to be tolerable if the patient's ECG, e.g., heart rate, rhythm, interval, or waveform, does not change after treatment compared to the baseline before treatment. In some embodiments, the treatment is determined to be tolerable if the patient's ECG does not show signs of ischemia or infarction after treatment compared to the baseline before treatment. In some embodiments, the tolerability of the treatment is assessed by the patient's laboratory measurements, measured before and after treatment. In some embodiments, the tolerability of the treatment is assessed by MRI scans of the patient's brain, measured before and after treatment. In some embodiments, the treatment is determined to be tolerable if the patient's MRI does not change after treatment compared to the baseline before treatment. In some embodiments, the tolerability of the treatment is indicated by the absence of change in brain region atrophy after treatment compared to the baseline before treatment. In some embodiments, treatment tolerability is indicated by the absence of microbleeds, lacunars, superficial hemosiderin deposition, or white matter lesions or high signal intensity after treatment compared to baseline before treatment.

[0235] In some embodiments, treatment tolerability is assessed by physical and / or neurological examinations of the patient, measured before and after treatment. The Columbia Suicide Severity Rating Scale (C-SSR) is a commonly used suicidal ideation and behavioral assessment, consisting of six questions that determine how many times a patient has had suicidal ideation or suicidal thoughts in the past month, as well as lifetime and past three-month behaviors, such as the number of suicidal ideations and intentions to act on them. The number of affirmative responses may correlate with the risk of suicide. In some embodiments, treatment tolerability is assessed by the C-SSRS, measured before and after treatment. In some embodiments, treatment is determined to be tolerable if the number of affirmative responses on the C-SSRS does not change with treatment compared to baseline. In some embodiments, treatment is determined to be tolerable if the increase in the number of affirmative responses on the C-SSRS after treatment compared to baseline is not more than one, two, three, or four. In some embodiments, treatment is determined to be tolerable if the number of positive responses on the C-SSRS after treatment is less than 5, less than 4, less than 3, less than 2, or less than 1. In some embodiments, treatment tolerability is assessed by reviewing the patient's diary compared to before and after treatment. In some embodiments, if treatment is deemed to be tolerable according to the methods and diagnostic criteria described herein, treatment is continued. In some embodiments, if treatment is deemed to be untolerable according to the methods and diagnostic criteria described herein, treatment is continued, but the dosage administered is reduced.

[0236] The present disclosure is further illustrated by the following examples, which should not be construed as limiting. The entire application, and all references, patents, and published patent applications cited through the figures, are incorporated herein by reference for all purposes. [Examples]

[0237] Example 1: Clinical Trial A 24-month randomized, placebo-controlled, double-blind, multicenter phase 2 study was conducted to evaluate the safety and efficacy of a 40 μg synthetic peptide (AADvac1) derived from amino acids 294-305 of a tau sequence coupled to keyhole limpet hemocyanin over a 2-year treatment period.

[0238] Method: Patient Inclusion Criteria 1. The patient has a diagnosis of near-certain Alzheimer's disease according to the revised NIA-AA diagnostic criteria (McKhann 2011). 2. The patient has a total MMSE score of 20 to 26 at the time of screening. 3. The patient has brain MRI findings consistent with a diagnosis of Alzheimer's disease at the time of screening. 4. The patient has evidence of a pathophysiological process of AD as defined by one or both of the following at the time of the screening visit: a. Medial temporal lobe atrophy as assessed by brain MRI and by a Scheltens score of 2 or higher (rated on a scale of 0-4 on the side with more advanced atrophy). b. Positive AD biomarker signature in CSF (total tau protein > 400 pg / mL, pT181 tau protein > 60 pg / mL, Aβ42 < 600 pg / mL, and Aβ42:Aβ40 ratio < 0.089) 5. The patient has completed six years of formal primary education. 6. The patient was between 50 and 85 years old at the time of the screening visit. 7. The patient is fluent in the local language and possesses sufficient hearing and visual abilities to undergo neuropsychological testing. 8. The patient can read and understand the informed consent form. 9. The patient has been on stabilization therapy with an acetylcholinesterase inhibitor for at least three months prior to the screening visit. 10. If the patient is receiving memantine treatment, the dose regimen must have been stable for at least three months prior to the screening visit. 11. The patient has a Hachinski Ischemia Rating Scale score of 4 or less at the time of screening. 12. The caregiver must be someone who knows the patient well, can accompany the patient during research visits, and can participate in the patient's research evaluation as needed. 13. Female patients are eligible to participate in this study only if they have either been sterilized or have been postmenopausal for at least two years. 14. Male patients must either be sterilized, or their fertile female spouse / partner must use a highly effective method of contraception consisting of two forms of birth control (one of which must be a barrier method), starting from the screening visit and continuing throughout the entire study period. 15. The patient submits written informed consent.

[0239] Methods: Patient exclusion criteria 1. Pregnant or breastfeeding female patients. 2. The patient had participated in another clinical trial within three months prior to the screening visit. 3. The patient is unlikely to complete this clinical trial. 4. The patient is known to have an allergy to a vaccine component, either currently or in the past, if the principal investigator deems it relevant. 5. The patient is known to have MRI-incompatible internal metal prostheses or MRI-incompatible stent implants, or other conditions that make MRI imaging contraindicated, as determined by the principal investigator. 6. One of the following is detected by brain MRI: a) Infarction in the large vessel region; b) Two or more lacunar infarcts defined as localized CSF signal intensity lesions, each less than 1.5 cm in diameter; c) Any lacunar infarct located in a strategically important location, such as the thalamus, the hippocampus in either hemisphere, or the head of the left caudate nucleus. d) Convergent deep hemispheric white matter lesion (Fazekas grade 3); or e) Other localized lesions that may affect the patient's cognitive state, such as infectious diseases, space-occupying lesions, normal pressure hydrocephalus, or any other abnormalities associated with a major central nervous system disorder other than Alzheimer's disease. 7. The patient underwent surgery (under general anesthesia) within three months prior to screening, and / or has surgery (under general anesthesia) scheduled during the entire study period. 8. The patient has a history of a clinically significant autoimmune disease, and / or currently has one, or is currently or will be expected to receive immunosuppressive or immunomodulatory therapy in the future. 9. The patient has a recent history of cancer (most recent special treatment within 5 years prior to screening) (exceptions: basal cell carcinoma, cervical neoplasm in situ). 10. The patient had a myocardial infarction within the two years prior to the screening visit. 11. The patient has hepatitis B, C, HIV, or syphilis, as confirmed by serological testing. 12. The patient has an active infectious disease. 13. Presence and / or history of immunodeficiency. 14. Patients currently suffering from a clinically significant systemic disease that could worsen the patient's condition or affect the safety of patients in the study: * Poorly controlled congestive heart failure (NYHA ≥ 3) *BMI>40 *Poorly controlled diabetes (HbA1c > 7.5%) *Severe renal failure (eGFR<30mL / min) *Chronic liver disease - ALT (alanine aminotransferase) >66 U / L in women or >80 U / L in men, AST (aspartate aminotransferase) >82 U / L *Other clinically significant systemic diseases if the principal investigator deems them relevant. 15. Patients have hypothyroidism, defined as elevated TSH (thyroid-stimulating hormone) > 5.0 mIU / mL and / or FT4 level < 0.7 ng / dL. Patients whose hypothyroidism has been corrected are eligible for this study if their treatment has been stable for three months prior to study enrollment. 16. The patient has a valid diagnosis of a serious psychotic disorder, such as schizophrenia, any type of psychotic disorder, or bipolar affective disorder. 17. The patient had a current depressive episode (Geriatric Depression Rating Scale GDS ≥ 6 at Visit 01) or had a major depressive episode within the past year. 18. The patient has dementia resulting from metabolic or toxic encephalopathy or a systemic medical condition. 19. The patient has a history of alcohol or drug abuse or dependence within the past two years. 20. The patient has Wernicke's encephalopathy. 21. The patient has a history or evidence of any CNS disorder other than Alzheimer's disease that may cause dementia (e.g., infectious or inflammatory / demyelinating CNS conditions, Creutzfeldt-Jakob disease, Parkinson's disease, Huntington's disease, brain tumor, subdural hematoma). 22. The patient has a history of cerebrovascular disease (ischemic or hemorrhagic stroke) with evidence, or has a diagnosis of suspected, near-certain, or confirmed vascular dementia. 23. The patient has a history of or is currently diagnosed with epilepsy. 24. The patient is currently being treated with an experimental immunotherapy drug, including IVIG, and / or has been treated with such a drug within the three months prior to the screening visit. 25. The patient is currently receiving treatment with an experimental therapy for AD aimed at disease modification, and / or was treated within 3 months prior to the screening visit. 26. The patient is currently receiving or has previously received treatment with any active vaccine for Alzheimer's disease (AD). 27. The patient is currently being treated with immunosuppressants. 28. Changes to the dosage of previous and current medications taken by patients due to comorbidities related to their medical history within the 30 days prior to their screening visit, when deemed clinically relevant. 29. The patient has a vitamin B12 deficiency (serum vitamin B12 < 191 pg / mL).

[0240] Method: Protocol The clinical trial was conducted according to the schedule shown in Table 5.

[0241] [Table 6]

[0242] result: Patients were selected at screening visits and underwent baseline testing. The selected patients were aged 50–85 years and continuing stable doses of acetylcholinesterase inhibitors (and eventually memantine). Patients had MMSE scores of 20–26 at screening visits and had a diagnosis of Alzheimer's disease as defined by the NIAA-AA diagnostic criteria described in McKhann et al., Alzheimer's & Dementia, (2011) 7:263–269.

[0243] A total of 117 patients were selected for treatment with AADvac1, while 79 patients were selected for placebo treatment. Of these, 100 patients in the AADvac1 treatment group and 63 patients in the placebo treatment group completed this clinical trial. The demographic characteristics of the patients are shown in Table 6.

[0244] [Table 7]

[0245] At baseline, the patient population had the characteristics shown in Tables 7 to 12.

[0246] [Table 8]

[0247] [Table 9]

[0248] [Table 10]

[0249] [Table 11]

[0250] Tables 11A and 11B: Baseline demographic characteristics (FAS) of the patient population by age subgroup (50-67 years and 68-85 years).

[0251] [Table 12]

[0252] [Table 13]

[0253] Tables 12A and 12B: Baseline demographic characteristics (FAS) of the patient population by age subgroup (50-70 years and 71-85 years).

[0254] [Table 14]

[0255] [Table 15]

[0256] Example 2: Clinical Trial - Cognitive Test Cognitive tests were conducted according to the research schedule shown in Table 5. These cognitive tests included the Clinical Dementia Rating Scale - Total Item (CDR-SB) test, the Alzheimer's Disease Collaborative Study - Mild Cognitive Impairment and Activities of Daily Living (ADCS MCI ADL) questionnaire, the Mini-Mental State Examination (MMSE), and a custom cognitive battery that included the Cogstate International Shopping List task, the Cogstate One-Card Learning and One-Card Back tasks, the Letter Fluency Test and the Category Fluency Test, and the Number-Symbol Conversion Test.

[0257] Figure 1 shows the distribution of total MMSE scores in the patient population measured at the time of screening. Each patient's total score was tracked during the course of treatment. For example, Figure 2 shows the total MMSE scores of each patient over a 12-week time span from V01 to V05.

[0258] Treatment effectiveness was assessed by the mean change in CDR-SB score, ADCS-MCI-ADL score, or MMSE score from baseline to week 104. Treatment effectiveness was also assessed by the mean change in the standard (overall z score) of the custom cognitive battery from baseline to week 104.

[0259] Table 13A provides baseline CDR-SB scores, ADCS-MCI-ADL scores, and MMSE scores, as well as other patient demographic characteristics.

[0260] [Table 16]

[0261] Tables 13B and 13C show the patients' cognitive test results at week 104 compared to baseline.

[0262] [Table 17]

[0263] ANCOVA was also used to assess the mean difference in change from baseline to week 104 between the two treatment groups. ANCOVA modeled the change from baseline to week 104, including terms related to treatment group, pooled country, sex, age, years of education, ApoE4 status, baseline MRI hippocampal volume, and baseline CDR-SB. For endpoints other than CDR-SB, the baseline value of the given assessment was included as an ANCOVA term. From this ANCOVA model, the least squares mean treatment difference (AADvac1-placebo) was presented along with the 95% confidence interval and two-sided p-value for treatment effect. The least squares mean was estimated at the mean level of continuous covariates (age, years of education, baseline MRI hippocampal volume, baseline CDR-SB), and piecewise covariates (sex, pooled country, ApoE4) were weighted proportionally to the number of subjects at each level in the FAS at baseline. These covariates were adjusted for mean values ​​at the time (visit) and treatment interaction levels. The results are shown in Table 13C.

[0264] [Table 18]

[0265] The patient outcomes regarding the CDR-SB score can be further analyzed by subgroup, as shown in Table 14.

[0266] [Table 19]

[0267] Similarly, Figures 3 to 6 show the changes in CDR-SB scores from different age subgroups of patients as treatment progresses.

[0268] As shown in Figures 7 and 8, the ADCS-MCI-ADL scores were also evaluated during the study.

[0269] Example 3: Antibody response Blood samples were collected for antibody response testing according to the study schedule shown in Table 5. Antibody titers in patient plasma were analyzed by indirect ELISA and quantitative ELISA.

[0270] Method: Determination of human antibody titers by indirect ELISA The titer of vaccine-inducing antibodies was determined by indirect ELISA using serially diluted plasma samples. AADvac1 was immobilized at a final concentration of 5 μg / ml and KLH at a final concentration of 2.5 μg / ml on microtiter plates (high-binding strip plates, Greiner Bio One, Frickenhausen, Germany), and incubated at 37°C for 2 hours. After blocking with PBS-0.05% T...

Claims

[Claim 1] The invention described herein.

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