Antimicrobial peptides

Abstract

Disclosed herein are methods of diagnosing, selecting, monitoring, and treating a subject having Alzheimer's disease (AD) or suspected of having AD based on an antimicrobial peptide (AMP) present at a different level than in a control individual.

Description

Cross-references to related applications

[0001] This application claims the benefit and priority of U.S. Provisional Application Serial No. 63 / 513,868, filed July 15, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This article describes methods for treating subjects with Alzheimer's disease (AD) involving measurements of antimicrobial peptides (AMPs) in biofluid samples from the subjects. The levels of these selected AMPs can be used for various aspects of AD treatment, such as selecting subjects for treatment, treating AD and AD-related symptoms, monitoring and / or adjusting treatment, and determining maintenance dosing regimens for subjects. Background Technology

[0003] Alzheimer's disease (AD) is a progressive, neurodegenerative disorder of unknown cause and the most common form of dementia in older adults. In 2006, there were 26.6 million cases of AD worldwide (range: 11.4-59.4 million) (Brookmeyer, R. et al., Forecasting the global burden of Alzheimer's Disease). Alzheimer Dement. [Alzheimer's Disease and Dementia] 2007; 3:186-91), and it is reported that more than 5 million people in the United States suffer from AD (Alzheimer's Association, Alzheimer's Association report, 2010 Alzheimer's disease facts and figures). Alzheimer's disease. stay] 2010;6:158-94). By 2050, the global prevalence of Alzheimer's disease (AD) is projected to reach 106.8 million (range: 47.2 million to 221.2 million), with an estimated prevalence of 11 million to 16 million in the United States alone. (Brookmeyer, see above, and 2010 Alzheimer's disease facts and figures, see above).

[0004] The disease typically involves a general decline in cognitive function, which progresses slowly and leaves terminally ill patients bedridden. AD patients typically survive only 3 to 10 years after symptom onset, although known survival extremes are 2 to 20 years. (Hebert, LE, et al., Alzheimer disease in the US population: prevalence estimates using the 2000 census.) Arch Neurol. [Neurology Literature] (2003; 60:1119-1122.) Although deaths caused by Alzheimer's disease (AD) are significantly underestimated because death certificates rarely attribute death to AD, AD remains the seventh leading cause of death in the United States and the fifth leading cause of death among Americans over the age of 65. (Alzheimer's Association report. 2010 Alzheimer's disease facts and figures.) Alzheimer Dement. [Alzheimer's Disease and Dementia] 2010; 6:158-94. AD represents a heavy economic burden for industrialized countries, with significant impacts on healthcare systems and national treasuries, as well as on participants and their families. In the United States alone, total costs were estimated at $172 billion in 2010, including $123 billion spent on Medicare and Medicaid.

[0005] Histologically, the disease is characterized by neuroinflammatory plaques, primarily found in the associative cortex, limbic system, and basal ganglia. The main component of these plaques is amyloid-β peptide (Aβ). Aβ exists in various conformational states: monomers, oligomers, primary fibrils, and insoluble fibrils. The mechanistic relationship between Alzheimer's disease onset and Aβ production remains unclear. However, several anti-Aβ antibodies are currently undergoing clinical trials as potential therapeutic agents for Alzheimer's disease.

[0006] Despite recent developments in treatments for Alzheimer's disease (AD), including those targeting Aβ, there remains a need for improved AD diagnosis and better treatment monitoring, including more specific biomarkers that can be used to diagnose AD in subjects, predict disease prognosis, monitor disease progression, and indicate treatment efficacy. Selecting relevant and robust biomarkers from the numerous biomolecules associated with AD remains challenging.

[0007] Recent studies have shown that antimicrobial peptides can serve as biomarkers for diagnosing Alzheimer's disease (AD) (Bruno et al., Antibiotics, 2022, 11:6, 726). Antimicrobial peptides (AMPs) are small (12-50 amino acids), charged, cationic, and usually amphiphilic peptides that provide the first line of defense against bacteria, fungi, parasites, and viruses by oligomerizing to form protofibrillary "nanonets" that trap invading pathogens. AMPs are expressed at high levels in the brain and other immune-privileged organs where adaptive immunity is limited. Most AMPs are synthesized as polymeric precursors, which release small (12-50 amino acids) active peptides upon proteolysis. Removal of the signal peptide can be a post-translational or co-translational process, and traditional DNA and RNA sequencing-based methods may not be suitable for studying AMP peptides.

[0008] A pathological feature of Alzheimer's disease (AD) is the activation of the innate immune system. Increasing evidence suggests that Aβ is an effector molecule of the innate immune system and also acts as an antimicrobial peptide, with its oligomerization mediating pathogen interception to prevent infection, as described in "Antimicrobial Protection Hypothesis of AD" (Moir et al., Alzheimer's & Dementia. 2018;14: 1602-1614). 1-42 The AMP exhibits compelling structural similarity to viral fusion domains and sequence similarity to specific bacterial bacteriocin families. This opens the door to new research into identifying novel AMPs capable of influencing neurological disorders.

[0009] AMPs are also activated by inflammation. The “infection hypothesis” for AD proposes that the weakening of the blood-brain barrier (BBB) ​​and immune system in older subjects, combined with infection from microbes, leads to chronic neuroinflammation. Although specific pathogens causing AD have not been identified, the co-occurrence of multiple pathogens in the brains of AD subjects and the role of Aβ as an antimicrobial peptide suggest that chronic neuroinflammation may be a contributing factor to the pathogenesis (Vigasova et al., Microbial Cell Factories, 2021; 20: 25). In an inflammatory state, the production of Aβ and phosphorylated tau increases, which may lead to the aggregation of these proteins into tangles and plaques, subsequently resulting in neurodegeneration. Consistent with the infection hypothesis, antimicrobial peptides (AMPs) may mediate the processes of aggregation and / or neurodegeneration. Some AMPs (e.g., lactoferrin and cysteine ​​protease inhibitors) interact with Aβ and are found in amyloid plaques. In addition, lactoferrin, cysteine ​​protease inhibitors, and other AMPs have shown increased expression in saliva, blood, serum, and / or CSF obtained from AD patients (Bruno et al., Antibiotics, 2022, 11, 726). While this data is promising, further analysis of the overall diagnostic potential of AMPs is still needed, as well as the identification of highly specific AMPs that can be used for the diagnosis of AD.

[0010] This article discloses a method for diagnosing, monitoring, and treating improvements in AD patients based on identifying AMP levels that show strong differential expression compared to control individuals. Summary of the Invention

[0011] One aspect of this disclosure relates to a method for selecting a subject for treatment with an Alzheimer's disease (AD) therapy, the method comprising: a) obtaining a measurement of the level of at least one antimicrobial peptide (AMP) in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) selecting the subject for treatment if the level of the at least one AMP changes compared to a control sample, for example, compared to the AMP level in an individual without Alzheimer's disease (AD), optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lecanemab) or an anti-tau antibody (e.g., E2814).

[0012] This disclosure relates to a method for selecting a subject to be treated with an AD therapy, the method comprising: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), clusterin (CLUS) (Clusterin-A), chromogranin-1 (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) selecting the subject to be treated if the level of the at least one AMP is altered compared to a control sample, for example, compared to the AMP level in an individual without Alzheimer's disease (AD), optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0013] In some embodiments, AMP is a peptide listed in Table 10.

[0014] In some embodiments, the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease. In some embodiments, the subject has early-stage AD or mild to moderate AD. In some embodiments, the subject is selected for treatment if their AMP levels are increased compared to a control.

[0015] In some embodiments, if a subject's AMP levels are lower than those of a control, that subject is selected for treatment.

[0016] Another aspect of this disclosure relates to a method for monitoring treatment efficacy in subjects receiving treatment including a therapeutically effective dose of an AD therapy, the method comprising: a) obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF, or a blood sample from the subject prior to the treatment, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF, or a blood sample from the subject during or after the treatment; and c) comparing the first AMP level with the second AMP level, wherein a change in the second AMP level compared to the first AMP level is an indicator of treatment efficacy, optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0017] Another aspect of this disclosure relates to a method for monitoring the efficacy of treatment in subjects receiving AD therapy, including a therapeutically effective dose, the method comprising: a) prior to the treatment, obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory glucomannan-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) during or after the treatment, obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; and c) The first AMP level is compared with the second AMP level, wherein the change in the second AMP level compared with the first AMP level is an indicator of therapeutic efficacy, optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0018] In some embodiments, AMP is a peptide listed in Table 10.

[0019] In some embodiments, a decrease in the second AMP level compared to the first AMP level indicates therapeutic efficacy. In some embodiments, no decrease in the second AMP level compared to the first AMP level indicates therapeutic ineffectiveness. In some embodiments, a decrease in the second AMP level compared to the first AMP level indicates therapeutic ineffectiveness. In some embodiments, no decrease in the second AMP level compared to the first AMP level indicates therapeutic efficacy.

[0020] This disclosure relates to a method for adjusting a treatment regimen in a subject receiving treatment including an effective dose of an AD therapy, the method comprising: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is selected from any of those listed in Table 10; b) comparing the level of the at least one AMP with the AMP level concentration in a control sample, such as an individual without Alzheimer's disease (AD); and c) if the level of the at least one AMP is different from that in a control sample, such as in an individual without Alzheimer's disease (AD), then adjusting the treatment regimen, for example, by changing the dose size, frequency of administration, and / or route of administration of the anti-Aβ protofibrillary antibody, optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0021] This disclosure relates to a method for adjusting a treatment regimen in a subject receiving a therapeutically effective dose of AD therapy, the method comprising: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) comparing the level of the at least one AMP with the AMP level concentration in a control sample, such as an individual without Alzheimer's disease (AD); and c) If the level of at least one AMP differs from that of a control sample, such as from the AMP level in an individual without Alzheimer's disease (AD), the treatment regimen may be adjusted, for example, by changing the dose size, frequency of administration, and / or route of administration of the anti-Aβ primary fibrillary antibody, optionally wherein the AD therapy is an anti-Aβ primary fibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0022] In some embodiments, AMP is a peptide listed in Table 10.

[0023] In some embodiments, if the AMP level is higher than the control, the treatment regimen is adjusted. In some embodiments, if the AMP level is lower than the control, the treatment regimen is adjusted.

[0024] This disclosure relates to a method for detecting a decrease in brain Aβ levels in a subject receiving treatment including a therapeutically effective dose of an AD therapy, the method comprising: a) prior to the treatment, obtaining a measurement of a first AMP level in a first biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) during or after the treatment, obtaining a measurement of a second AMP level in a second biological fluid sample, such as CSF or a blood sample, from the subject; and c) comparing the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject; optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab).

[0025] This disclosure relates to a method for detecting a decrease in brain Aβ levels in a subject receiving treatment including a therapeutically effective dose of AD therapy, the method comprising: a) prior to the treatment, obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) during or after the treatment, obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; and c) The first AMP level and the second AMP level are compared, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject; optionally, the AD therapy is an anti-Aβ primary fibrillary antibody.

[0026] In some embodiments, AMP is a peptide listed in Table 10.

[0027] In some embodiments, a decrease in AMP levels in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject. In some embodiments, an increase in AMP levels in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject.

[0028] This disclosure relates to a method for detecting a reduction in brain tau levels (e.g., a reduction in tau tangles) in a subject receiving treatment including a therapeutically effective dose of an AD therapy, the method comprising: a) obtaining a measurement of a first AMP level in a first biological fluid sample, such as CSF, or a blood sample from the subject prior to the treatment, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biological fluid sample, such as CSF, or a blood sample from the subject during or after the treatment; and c) comparing the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a reduction in brain tau levels in the subject; optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0029] This disclosure relates to a method for detecting a reduction in brain tau levels (e.g., a reduction in tau tangles) in a subject receiving treatment including a therapeutically effective dose of AD therapy, the method comprising: a) prior to the treatment, obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) during or after the treatment, obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; and c) The first AMP level and the second AMP level are compared, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject; optionally, the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0030] In some embodiments, AMP is a peptide listed in Table 10.

[0031] In some embodiments, a decrease in AMP levels in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject. In some embodiments, an increase in AMP levels in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject.

[0032] In some embodiments, a decrease in brain tau levels is a reduction in tau tangles.

[0033] This disclosure relates to a method for reducing tau tangles in subjects who have Alzheimer's disease (AD), are suspected of having Alzheimer's disease, or are at risk of developing Alzheimer's disease, the method comprising: a) obtaining a measurement of a first AMP level in a biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) if the first AMP level is elevated compared to a control sample, such as compared to AMP levels in an individual without Alzheimer's disease (AD), administering to the subject treatment comprising a therapeutically effective dose of an anti-tau proficiency antibody; and c) obtaining a measurement of a second AMP level, wherein a change in the second AMP level compared to the first AMP level indicates a reduction in tau tangles, optionally wherein the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and containing SEQ ID NO: The three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) of the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2) and SEQ ID NO: 20 (LCDR3).

[0034] This disclosure relates to a method for reducing tau tangles in subjects with Alzheimer's disease (AD), suspected Alzheimer's disease, or at risk of developing Alzheimer's disease, the method comprising: a) obtaining a measurement of a first AMP level in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), clump protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) if the first AMP level is elevated compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), administering to the subject treatment comprising a therapeutically effective dose of an anti-tau proficiency antibody; and c) A second AMP level measurement is obtained, wherein the change in the second AMP level compared to the first AMP level indicates a reduction in tau tangles, optionally wherein the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0035] This disclosure relates to a method for treating a subject who has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease, the method comprising: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) if the level of the at least one AMP changes compared to a control sample, such as compared to the AMP level in an individual without Alzheimer's disease (AD), administering to the subject treatment comprising a therapeutically effective dose of an AD therapy, optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0036] This disclosure relates to a method for treating subjects with Alzheimer's disease (AD), suspected Alzheimer's disease, or at risk of developing Alzheimer's disease, the method comprising: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); and b) If the level of at least one AMP is altered compared to a control sample, such as compared to the AMP level in an individual without Alzheimer's disease (AD), the subject is given treatment including a therapeutically effective dose of an AD therapy, optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0037] In some embodiments, AMP is a peptide listed in Table 10.

[0038] In some embodiments, AD therapy is administered if AMP levels increase compared to a control sample. In some embodiments, AD therapy is administered if AMP levels decrease compared to a control sample.

[0039] In some embodiments, the method of treating a subject includes steps a) obtaining a measurement of the level of at least one AMP in a biofluid sample, such as CSF or a blood sample, from the subject; and b) if the level of the at least one AMP is elevated compared to a control sample, then after administering treatment to the subject including a therapeutically effective dose of an anti-tau antibody, applying the following additional steps: c) obtaining an additional measurement of the level of the at least one AMP (e.g., an additional AMP level) in a second biofluid sample, such as CSF or a blood sample, from the subject; d) determining that the additional AMP level has changed relative to the level of the at least one AMP obtained before administering the AD therapy; and e) administering an additional therapeutically effective dose of the AD therapy to the subject, optionally wherein the AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

[0040] In some embodiments, an additional therapeutically effective dose is administered according to a maintenance dosing regimen.

[0041] In some embodiments, treatment includes administering a therapeutically effective dose of AD therapy according to an initial dosing regimen, optionally followed by switching the subject to a maintenance dosing regimen.

[0042] In some embodiments, a subject is switched from an initial dosing regimen to a maintenance dosing regimen when an additional measurement of AMP levels in a separate biological fluid sample, such as CSF or blood sample, differs from a threshold level observed, for example, in a control sample from an individual who does not have AD.

[0043] In some embodiments, subjects are switched when AMP levels are below a threshold. In some embodiments, subjects are switched when AMP levels are above a threshold.

[0044] In some embodiments, AMP levels are quantified by LC / MS.

[0045] In some embodiments, the biofluid sample is CSF.

[0046] In some embodiments, subjects show changes and / or differences in measurements of one or more additional biomarkers associated with AD pathology prior to treatment.

[0047] In some embodiments, the variation and / or difference in the measured values ​​are selected from: a) an increase in amyloid protein in the brain, for example, as measured by amyloid PET (e.g., a percentage measure of about 20-40, for example, a percentage measure of about 20-32), b) an increase in tau in the brain, for example, as measured by positron emission tomography (PET), c) Decreased levels of the Aβ1-42 / 1-40 ratio in cerebrospinal fluid and / or decreased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranulin and / or neurofilament light chains (NfL), and d) Decreased levels of the Aβ1-42 / 1-40 ratio in serum or plasma and / or increased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0048] In some embodiments, subjects show changes and / or differences in measurements of one or more additional biomarkers associated with AD pathology during and / or after treatment.

[0049] In some embodiments, the variation and / or difference in the measured values ​​are selected from: a) a decrease in amyloid protein in the brain, for example, as measured by amyloid PET (e.g., a percentage measure of about 20-40, for example, a percentage measure of about 20-32), b) a decrease in tau in the brain, for example, as measured by positron emission tomography (PET), c) Increased levels of the Aβ1-42 / 1-40 ratio in cerebrospinal fluid and / or decreased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranulin and / or neurofilament light chains (NfL), and d) Increased levels of the Aβ1-42 / 1-40 ratio in serum or plasma and / or decreased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0050] In some embodiments, treatment a) delays clinical decline, as determined by ADCOMS; b) delays clinical decline, as determined by ADAS MCI-ADL; c) delays clinical decline, as determined by modified iADRS; d) delays clinical decline, as determined by CDR-SB; or e) delays clinical decline, as determined by ADAS-Cog.

[0051] In some embodiments, the subject has a gene mutation for dominant Alzheimer's disease, for example, wherein the subject has a gene mutation in at least one of three genes—PSEN1, PSEN2, or APP. In some embodiments, the subject has a mutation in APP.

[0052] In some embodiments, the subject has a family history of Alzheimer's disease, for example, a family member was diagnosed with Alzheimer's disease before the age of 60.

[0053] In some embodiments, the subject is ApoE4 positive. In some embodiments, the subject is 65 to 80 years old. In some embodiments, the subject is 55 to 64 years old and has at least one of the following risk factors: (i) a first-degree relative diagnosed with dementia before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid protein levels as measured by PET or cerebrospinal fluid (CSF) prior to administration.

[0054] In some embodiments, the subject is amyloid-positive.

[0055] In some embodiments, CSF assessments based on PET, Aβ(1-42) CSF assessment, total tau CSF assessment, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231) CSF assessment, phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) ratio, MTBR-tau243, MRI, and retinal amylose are used. The subject was amyloid-positive based on amyloid accumulation and / or blood biomarker assessments (e.g., plasma Aβ1-42 / 1-40 ratio, total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217, and / or tau231 / np-tau231) ratios and / or MTBR-tau243).

[0056] In some embodiments, the subjects had Alzheimer's disease.

[0057] In some embodiments, the subjects had early-stage Alzheimer's disease.

[0058] In some embodiments, the subject has been diagnosed with a) Alzheimer's disease-related mild cognitive impairment – ​​moderate probability, and / or has been diagnosed with mild Alzheimer's dementia; b) Alzheimer's disease-related mild cognitive impairment – ​​moderate probability according to the National Institute of Aging - Alzheimer's Association (NIA-AA) Core Clinical Guidelines; c) Alzheimer's disease-related mild cognitive impairment – ​​moderate probability according to a pre-treatment CDR total score of 0.5 and a Memory Box score of 0.5 or higher; d) Alzheimer's disease-related mild cognitive impairment—moderate probability—is indicated by, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year prior to treatment, as confirmed by an informed person; e) mild Alzheimer's disease dementia is indicated according to the NIA-AA core clinical guidelines for possible Alzheimer's disease dementia; or f) mild Alzheimer's disease dementia is indicated according to a CDR score of 0.5 to 1.0 and a memory frame score of 0.5 or higher prior to treatment.

[0059] In some embodiments, the subject is suspected of having Alzheimer's disease (AD). In some embodiments, the subject is at risk of developing AD.

[0060] In some embodiments, subjects at risk of developing AD have pre-AD (early AD).

[0061] In some embodiments, the subject did not have cognitive impairment.

[0062] In some embodiments, the anti-Aβ primary fibrillary antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0063] In some embodiments, the anti-Aβ protofibrillary antibody is lencanezumab.

[0064] In some embodiments, the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0065] In some embodiments, the anti-tau antibody is E2814.

[0066] In some embodiments, the antimicrobial peptide comprises any one of SEQ ID NO: 27-50.

[0067] Listed Examples 1. A method for treating AD in a subject who has or is suspected of having Alzheimer's disease (AD), the method comprising: Determine the altered levels of at least one antimicrobial peptide (AMP) in a subject's biological fluid, such as cerebrospinal fluid (CSF), compared to a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10, and The subject is given a therapeutically effective dose of an AD therapy, such as anti-amyloid beta (Aβ) therapy, for example, an anti-Aβ protofibrillary antibody.

[0068] 2. A method for treating AD in a subject who has or is suspected of having Alzheimer's disease (AD), the method comprising: Determine the altered levels of at least one antimicrobial peptide (AMP) in a biological fluid, such as cerebrospinal fluid (CSF), from a subject compared to a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulocyte-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-ribosomal protein eS31 fusion protein (RS27A), polyubiquitin-B (UBB), and polyubiquitin-C (UBC), and The subject is given a therapeutically effective dose of an AD therapy, such as anti-amyloid beta (Aβ) therapy, for example, an anti-Aβ protofibrillary antibody.

[0069] 3. The method as described in Example 2, wherein the antimicrobial peptide is one of the peptides listed in Table 10.

[0070] 4. The method as described in any one of Examples 1-3, wherein the antimicrobial peptide comprises any one of SEQ ID NO: 13-36.

[0071] 5. The method as described in Example 1, wherein the subject has cognitive impairment.

[0072] 6. The method as described in Example 1, wherein the subject has one or more of the following: a t-tau level in CSF above 400 ng / L, an Aβ1-42 level in CSF below 550 ng / L, and an Aβ1-42 / Aβ1-40 ratio in CSF below 0.065.

[0073] 7. The method as described in Example 1, wherein the control is the level of AMP in a biological fluid (e.g., CSF) from an individual who does not have Alzheimer's disease.

[0074] 8. The method as described in Example 1, wherein the anti-Aβ primary fibrillary antibody is lencanezumab.

[0075] 9. A method for treating AD in a subject who has or is suspected of having Alzheimer's disease (AD), the method comprising: Determine the first level of at least one antimicrobial peptide (AMP) in a biological fluid such as cerebrospinal fluid (CSF) from the subject, wherein the first level of the AMP in the subject's CSF is altered compared to a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10. The subject was given a first therapeutically effective dose of an AD therapy, such as anti-amyloid beta (Aβ) therapy, such as an anti-Aβ protofibrillary antibody; Determine the second level of this AMP from the subject's CSF; and If there is a change from the first level of the AMP to the second level of the AMP, then administer a second therapeutically effective dose of the AD therapy.

[0076] 10. The method as described in Example 9, wherein the antimicrobial peptide comprises any one of SEQ ID NO: 13-36.

[0077] 11. The method as described in Example 9, wherein the subject has cognitive impairment.

[0078] 12. The method as described in Example 9, wherein the subject has one or more of the following: a t-tau level in CSF above 400 ng / L, an Aβ1-42 level in CSF below 550 ng / L, and an Aβ1-42 / Aβ1-40 ratio in CSF below 0.065.

[0079] 13. The method as described in Example 9, wherein the control is the level of AMP in a biological fluid (e.g., CSF) from an individual who does not have Alzheimer's disease.

[0080] 14. The method as described in Example 9, wherein the anti-Aβ primary fibrillary antibody is lencanezumab.

[0081] 15. A method for monitoring the efficacy of treatment in subjects who have or are suspected of having AD, the method comprising: Determine the first level of at least one antimicrobial peptide (AMP) in a biological fluid such as cerebrospinal fluid (CSF) from the subject, wherein the first level of the AMP in the subject's CSF is altered compared to a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10. The subject was administered a first therapeutically effective dose of an AD therapy, such as anti-amyloid beta (Aβ) therapy, for example, an anti-Aβ primary fibrillary antibody; and A second level of the AMP was measured in the subject's CSF, wherein the second level of the AMP, which differed from the first level, indicated that the treatment was effective.

[0082] 16. The method as described in Example 15, wherein the antimicrobial peptide comprises any one of SEQ ID NO: 13-36.

[0083] 17. The method as described in Example 15, wherein the subject has cognitive impairment.

[0084] 18. The method as described in Example 15, wherein the subject has one or more of the following: a t-tau level in CSF above 400 ng / L, an Aβ1-42 level in CSF below 550 ng / L, and an Aβ1-42 / Aβ1-40 ratio in CSF below 0.065.

[0085] 19. The method as described in Example 15, wherein the control is the level of AMP in a biological fluid (e.g., CSF) from an individual who does not have Alzheimer's disease.

[0086] 20. The method as described in Example 15, wherein the anti-Aβ primary fibrillary antibody is lencanezumab.

[0087] 21. A method for diagnosing AD in a subject, the method comprising: Determine the levels of one or more antimicrobial peptides (AMPs) in biological fluids, such as cerebrospinal fluid (CSF), from the subject, wherein the AMP is selected from any of those listed in Table 10, and The level of AMP is compared with that of a control, for example, from the CSF of an individual who has not been diagnosed with AD, wherein the change in the level of AMP in the subject's CSF compared to the control indicates that the subject has AD.

[0088] 22. The method as described in Example 21, wherein the antimicrobial peptide comprises any one of SEQ ID NO: 13-36.

[0089] 23. The method as described in Example 21, wherein the subject has cognitive impairment.

[0090] 24. The method as described in Example 21, wherein the subject has one or more of the following: a t-tau level in CSF above 400 ng / L, an Aβ1-42 level in CSF below 550 ng / L, and an Aβ1-42 / Aβ1-40 ratio in CSF below 0.065.

[0091] 25. The method as described in Example 21, wherein the control is the level of AMP in a biological fluid (e.g., CSF) from an individual who does not have Alzheimer's disease. Attached Figure Description

[0092] Figure 1 shows the cohort demographics ( Figure 1A ) and research methods ( Figure 1B An overview of ( ).

[0093] Figure 2 A de novo-assisted procedure is shown for identifying differential expression (q<0.2) of 24 AMPs in CSF of Aβ+ dementia subjects.

[0094] Figure 3 This is a volcano plot of 320 CSF peptides used in subjects with cognitive impairment. 24 / 320 CSF AMP peptides were differentially regulated in subjects compared with Aβ+ (AD) versus Aβ- (non-AD) (q<0.2).

[0095] Figure 4 A heatmap showing 24 significant changes in AMP (q<0.2) in Aβ+ (AD) and Aβ- (non-AD) dementia subjects is presented.

[0096] Figure 5 shows the clustering proteins in CSF from Aβ-driven dementia ( Figure 5A ) and chromogranin A ( Figure 5B Box plot showing increased expression of antimicrobial peptides in proteins.

[0097] Figure 6 shows a MEGENA data-driven peptide co-expression network consisting of 642 modules. Figure 6A CMGA peptides represent a pivotal point in the c1_16 and c1_179 modules and exhibit a high correlation with the dementia-associated neurosecretory protein VGF. Figure 6B Genetic ontology analysis of the c1_16 module protein revealed enrichment in many neurodegenerative pathways. Figure 6C ). Detailed Implementation

[0098] Alzheimer's disease (AD) is characterized by progressive cognitive decline, accompanied by pathological features of brain structure and function. One hallmark of AD is the formation of insoluble aggregates composed of amyloid-β (Aβ) plaques or tau neurofibrillary tangles (NFTs) (also known as tau or fibrillary tangles). Each of Aβ and tau has been proposed to play a central or even pathogenic role in the pathogenesis of AD. Aβ plaques and tau tangles act independently or synergistically, leading to synaptic dysfunction, loss of neural connectivity, neuronal death, and other related pathologies.

[0099] One such pathology is chronic neuroinflammation, which can provide a link between Aβ plaques and NFTs (Chen and Yu, Journal of Neuroinflammation, 2023. 20:165). In the brain, innate immune cells (such as microglia and astrocytes) contribute to chronic inflammation, for example, through sustained activation by producing high levels of pro-inflammatory factors. Innate immune cells appear to be activated by Aβ and tau in feedback loops and enhance their activation. In a theory called the "Antimicrobial Protection Hypothesis" (Moir et al., Alzheimer's Dementia, 2018; 14: 1602-1614), Aβ deposition may be an innate immune response to attacks, for example, by microbial pathogens, as Aβ oligomers can trap pathogens to prevent infection. Aβ aggregates can be degraded and phagocytosed by microglia. However, in AD, when Aβ levels are elevated, microglia are in a state of chronic activation, which in turn leads to a decrease in Aβ clearance, further activating microglia and ultimately resulting in tangles formation and neurodegeneration (Prosswimmer et al., Scientific Reports, 2024.14:5376).

[0100] The findings on Aβ are consistent with studies on other antimicrobial peptides involved in plaque and tangle pathology (Bruno et al., Antibiotics, 2022; 11:726). In addition to Aβ, lactoferrin, defensins, cysteine ​​protease inhibitors, thymosin β4, LL37, histamine, and casein-rich proteins have been reported to exhibit antimicrobial activity and have been found in plaques or biofluids from AD patients. Bruno et al. (2022, see above) suggest that these AMPs could be used as biomarkers for the diagnosis of AD.

[0101] Identifying additional AMPs that have an improved association with AD can provide biomarkers for different stages of the disease and / or multiple pathologies. The identification of these AMPs is complicated by the challenges in confirming the identity of peptides in biological fluids and in determining their levels as strongly correlated with disease development.

[0102] This article discloses a novel AMP that can be used in a variety of methods for diagnosing, monitoring, and treating AD patients based on AMP levels in biofluid samples such as CSF or blood.

[0103] This disclosure relates to methods for diagnosing Alzheimer's disease (AD), treating AD, and / or monitoring the efficacy of treatment based on the determination of the level of at least one antimicrobial peptide (AMP) in a biofluid from a subject who has or is suspected of having AD.

[0104] One aspect of this disclosure relates to an AMP selected from the 24 AMPs listed in Table 10, any of which can be measured (alone or in combination) at any step in treating a subject with AD, suspected of having AD, or at risk of developing AD. In some embodiments, an AMP can be used to select a subject for treatment with a therapeutically effective dose of AD therapy (e.g., anti-amyloid beta (Aβ) therapy, such as anti-Aβ protofibrillary antibody), to treat the subject with AD therapy, to reduce brain Aβ levels by administering AD therapy, to reduce brain tau levels by administering AD therapy, to monitor treatment efficacy, and / or to modify the treatment regimen including the administration of AD therapy.

[0105] In some embodiments, AMP is selected from Table 10. Table 10 provides the sequences of AMP and the human proteins they map to. In some embodiments, AMP is a peptide of cluster protein (CLUS), for example, a peptide containing amino acids 69-79, 155-167, 259-276, 363-371, 386-395, 388-408, 391-408, or 418-425 of cluster protein. In some embodiments, AMP is a peptide of chromogranin A (CMGA), for example, a peptide containing amino acids 19-27, 20-46, 21-27, or 78-88 of CMGA.

[0106] In some embodiments, AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC). In some embodiments, AMP is selected from Table 10.

[0107] In some embodiments, the level of AMP (e.g., concentration, expression, quantity, etc.) in a biofluid sample from a subject is increased relative to a control (e.g., AMP level from an individual without AD). In some embodiments, AMP in a biofluid sample from a subject may be upregulated.

[0108] In some embodiments, the level of AMP (e.g., concentration, expression, quantity, etc.) in a biofluid sample from a subject is reduced relative to a control (e.g., AMP level from an individual without AD). In some embodiments, AMP in a biofluid sample from a subject may be downregulated.

[0109] In some embodiments, the difference between AMP levels in a biofluid sample from a subject and AMP levels in a biofluid sample from a control is used in the methods disclosed herein.

[0110] 1. Selecting subjects for treatment One aspect of this disclosure relates to a method for selecting a subject for treatment including an AD therapy, wherein the method comprises: a) obtaining a measurement of the level of at least one antimicrobial peptide (AMP) in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) selecting the subject for treatment if the level of the at least one AMP is altered compared to a control sample, such as compared to the AMP level in an individual without Alzheimer's disease (AD).

[0111] Another aspect of this disclosure relates to a method for selecting a subject for treatment including AD therapy, wherein the method includes a) obtaining a measurement of the level of at least one antimicrobial peptide (AMP) in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); and b) selecting the subject for treatment if the level of the at least one antimicrobial peptide (AMP) is altered compared to a control sample, for example, compared to the AMP level in an individual without Alzheimer's disease (AD).

[0112] In some embodiments, AMP is a peptide listed in Table 10.

[0113] In some embodiments, levels of two or more AMPs (e.g., from the AMPs listed in Table 10) may be obtained from a biological fluid sample, such as CSF, or a blood sample from the subject, and compared to the levels of two or more AMPs in a control sample (e.g., in an individual without AD). For example, levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to the levels in the control sample. In some embodiments, the level of at least one of the two or more AMPs may show a change (e.g., increase or decrease) compared to the level of the same AMP in the control sample.

[0114] In some embodiments, the level of at least one AMP from the subject is increased compared to the control.

[0115] In some embodiments, the level of at least one AMP from the subject is reduced compared to the control.

[0116] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0117] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0118] The level of at least one AMP in a biological fluid (e.g., CSF) from a subject can be compared to the level of at least one AMP in a control. In some embodiments, the control is the level of AMP in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0119] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0120] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid beta (Aβ) treatment, such as an anti-Aβ protofibrillary antibody. In some embodiments, the anti-Aβ protofibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ protofibrillary antibody is lencanezumab (also known as BAN2401). In some embodiments, AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, heavy chain variable region, light chain variable region, or constant region according to SEQ ID NOs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0121] In some embodiments, the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease. For example, the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or changes in the levels of one or more biomarkers other than AMP (e.g., MTBR-tau243, Aβ42, Aβ40, Aβ42 / 40 ratio, total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), p-tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231 ratio, and / or MTBR-tau243) indicating that the subject may have AD. In some embodiments, individuals may have additional risk factors for developing Alzheimer's disease (AD), such as family history, genetic background, sex, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors (e.g., smoking, alcohol consumption, or restriction of physical activity). In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early AD. In some embodiments, the subject has pre-AD. In some embodiments, the subject is amyloid-positive. In some embodiments, the subject is amyloid-positive and has cognitive impairment.

[0122] 2. Monitor treatment efficacy This disclosure relates to a method for monitoring treatment efficacy in subjects receiving treatment including therapeutically effective doses of AD therapy, wherein the method includes a) obtaining a first measurement of AMP levels in a biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a second measurement of AMP levels in a biofluid sample, such as CSF or a blood sample, from the subject during or after the treatment; and c) comparing the first AMP level with the second AMP level, wherein a change in the ratio of the second AMP level to the first AMP level is an indicator of treatment efficacy.

[0123] This disclosure relates to a method for monitoring treatment efficacy in subjects receiving AD therapy, including therapeutically effective doses, wherein the method includes a) obtaining a first measurement of AMP levels in a biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory glucomannan-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) obtaining a second measurement of AMP levels in a second biofluid sample, such as CSF or a blood sample, from the subject during or after the treatment; and c) comparing the first AMP level with the second AMP level, wherein a change in the second AMP level compared to the first AMP level is an indicator of treatment efficacy.

[0124] In some embodiments, AMP is a peptide listed in Table 10.

[0125] In some embodiments, levels of two or more AMPs (e.g., from the AMPs listed in Table 10) may be obtained from a biological fluid sample, such as CSF, or a blood sample from a subject, and compared to the levels of two or more AMPs in a control sample (e.g., in an individual without AD). For example, levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to the levels in the control sample. In some embodiments, the level of at least one of the two or more AMPs may show a change (e.g., increase or decrease) compared to the level of the same AMP in the control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase while the other may decrease).

[0126] In some embodiments, the first AMP level will show a change (e.g., increase or decrease) compared to the second AMP level from the subject after treatment.

[0127] In some embodiments, the first AMP level from the subject increases compared to the second AMP level, and this indicates that the treatment is effective.

[0128] In some embodiments, the first AMP level from the subject is reduced compared to the second AMP level, and this indicates that the treatment is ineffective.

[0129] In some embodiments, the first AMP level from the subject increases compared to the second AMP level, and this indicates that the treatment is ineffective.

[0130] In some embodiments, the first AMP level from the subject is reduced compared to the second AMP level, and this indicates that the treatment is effective.

[0131] In some embodiments, the first AMP level from the subject showed no change compared to the second AMP level, and this indicated that the treatment was effective.

[0132] In some embodiments, the first AMP level from the subject showed no change compared to the second AMP level, and this indicated that the treatment was ineffective.

[0133] In some embodiments, the first AMP level measurement may be obtained from the subject prior to treatment. In some embodiments, the first AMP level measurement is the AMP level measurement in a subject who has started treatment without a prior measurement of AMP level.

[0134] In some embodiments, step b) of the method for monitoring treatment efficacy, obtaining a second measurement of the AMP level in a second biofluid sample, such as CSF or blood sample, from the subject during or after the treatment; and step c) comparing the first AMP level with the second AMP level, may be repeated at least once to continue monitoring treatment efficacy over time. In an exemplary instance, the method further includes, after step c), obtaining a measurement of a third AMP level in a third biofluid sample, such as CSF or blood sample, from the subject at a time point after obtaining the second biofluid sample, and comparing the third AMP level with an earlier measurement of the AMP level (e.g., the first and / or second AMP levels), wherein the change in the third AMP level compared to the earlier AMP level is an indicator of treatment efficacy. In some embodiments, steps b) and c) may be repeated as long as the subject receives treatment. In some embodiments, steps b) and c) may be repeated periodically (e.g., weekly, bi-weekly, monthly, quarterly, semi-annually, or annually).

[0135] In some embodiments, the method for monitoring treatment efficacy may further include, after step c), a further step d) to modify the treatment by administering a modified treatment comprising an additional therapeutically effective dose of AD therapy. For example, if the treatment is ineffective, the dose may be modified by increasing the dose size, increasing the frequency of administration, and / or changing the route of administration. In some embodiments, additional therapeutic agents may be added, for example, if the AD therapy includes an anti-Aβ protofibrillary antibody (e.g., lencanezumab), an anti-tau antibody (e.g., E2814) may be added. Conversely, if the treatment is effective, the dose may be modified by decreasing the dose size, increasing the frequency of administration, and / or changing the route of administration. In some embodiments, the subject may be switched from treatment administered according to a treatment dosing regimen to treatment administered according to a maintenance dosing regimen. In some embodiments, treatment may be discontinued. In some embodiments, steps b) and c) may be repeated as long as the subject receives treatment, for example, after the subject has received modified treatment. In some embodiments, steps b) and c) may be repeated if the subject no longer receives treatment, for example, to continue monitoring treatment efficacy after treatment has been discontinued.

[0136] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0137] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0138] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control. In some embodiments, the control is the AMP level in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0139] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0140] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid β (Aβ) treatment, such as an anti-Aβ primary fibrillary antibody. In some embodiments, the anti-Aβ primary fibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ primary fibrillary antibody is lencanezumab (also known as BAN2401).

[0141] In some embodiments, the AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NO: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0142] In some embodiments, the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease. For example, the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or changes in the levels of one or more biomarkers other than AMP (e.g., MTBR-tau243, Aβ42, Aβ40, Aβ42 / 40 ratio, total tau and / or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) that indicate the subject may have AD. In some embodiments In some embodiments, individuals may have additional risk factors for developing Alzheimer's disease (AD), such as family history, genetic background, sex, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors (e.g., smoking, alcohol consumption, or restriction of physical activity). In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early AD. In some embodiments, the subject has pre-AD. In some embodiments, the subject is amyloid-positive. In some embodiments, the subject is amyloid-positive and has cognitive impairment.

[0143] 3. Adjust the treatment plan This disclosure relates to a method for adjusting a treatment regimen in a subject receiving treatment including an effective dose of an AD therapy, wherein the method comprises: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is selected from any of those listed in Table 10; b) comparing the level of at least one AMP with the AMP level in a control sample, such as an individual without Alzheimer's disease (AD); and c) if the AMP level differs from the control sample, adjusting the treatment regimen, for example, by adjusting the dose size, frequency of administration, and / or route of administration.

[0144] Another aspect of this disclosure relates to a method for adjusting a treatment regimen in a subject receiving treatment including an effective dose of AD therapy, wherein the method includes a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) comparing the level of at least one AMP with the AMP level in a control sample, such as an individual without Alzheimer's disease (AD); and c) if the AMP level differs from the control sample, adjusting the treatment regimen, for example, by adjusting the dose size, frequency of administration, and / or route of administration.

[0145] In some embodiments, AMP is a peptide listed in Table 10.

[0146] In some embodiments, levels of two or more AMPs (e.g., from the AMPs listed in Table 10) may be obtained from a biological fluid sample, such as CSF, or a blood sample from a subject, and compared to the levels of two or more AMPs in a control sample (e.g., in an individual without AD). For example, levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to the levels in the control sample. In some embodiments, the level of at least one of the two or more AMPs may show a change (e.g., increase or decrease) compared to the level of the same AMP in the control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase while the other may decrease).

[0147] In some embodiments, the control sample is a measurement of AMP levels obtained from a biological fluid sample, such as CSF or a blood sample, from a control subject (e.g., at least one of the same AMPs measured in the subject). The control subject may be an individual who does not have AD. In some embodiments, the control sample is a measurement of previous AMP levels obtained from a biological fluid sample, such as CSF or a blood sample, from a subject receiving treatment. For example, the control sample may be obtained from the subject before treatment or at an earlier time during the treatment process (before the steps of the method are performed).

[0148] In some embodiments, AMP levels may be measured prior to treatment. In some embodiments, AMP levels are measured in subjects who have begun treatment without prior measurements of AMP levels.

[0149] In some embodiments, a treatment regimen (also referred to as a "dosing regimen" or "treatment dosing regimen") includes a schedule specifying the dose of AD therapy administered per unit time, including the number of doses within a given time period and the elapsed time between doses. In some embodiments, a treatment regimen includes administering AD therapy at a specified dose according to a schedule (e.g., on a repetitive basis).

[0150] In some embodiments, if the AMP level is higher than that of the control sample, adjusting the treatment regimen may include increasing the dose of AD therapy, increasing the frequency of AD therapy administration, and / or changing the route of AD therapy administration. In some embodiments, additional therapeutic agents may be added.

[0151] In some embodiments, if the AMP level is lower than that of the control sample, adjusting the treatment regimen may include reducing the dose, reducing the frequency of administration, and / or changing the route of administration.

[0152] In some embodiments, a subject may be switched from treatment comprising administering an AD therapy (e.g., an initial dose) at a therapeutically effective dose according to an initial dosing regimen to treatment comprising administering an AD therapy (e.g., a maintenance dose) at a therapeutically effective dose according to a maintenance dosing regimen.

[0153] In some embodiments, treatment may be stopped.

[0154] In some embodiments, the steps a) of adjusting the treatment regimen, namely obtaining a measurement of the level of at least one AMP in a biofluid sample, such as CSF or a blood sample, from the subject, and b) comparing the level of at least one AMP with the AMP level in a control sample, such as an individual without Alzheimer's disease (AD), may be repeated at least once to monitor the efficacy of the adjusted treatment regimen and optionally further adjust the treatment regimen. In an exemplary instance, the method further includes, after step c), obtaining additional measurements of the level of at least one AMP in another biofluid sample, such as CSF or a blood sample, from the subject at a time point after adjusting the treatment regimen, and comparing the additional measurements with measurements of the level of at least one AMP obtained before adjusting the treatment regimen or with the AMP level in a control sample (e.g., an individual without AD). In some embodiments, if the additional measurements of the level of at least one AMP are still different from those in the control sample, the treatment may be further adjusted. Steps a) and b) may be repeated as long as the subject receives treatment or the adjusted treatment. In some embodiments, if the subject no longer receives treatment, steps b) and c) may be repeated, for example, to continue monitoring the efficacy of treatment after treatment has been discontinued. In some embodiments, steps b) and c) may be repeated periodically (e.g., weekly, bi-weekly, monthly, quarterly, semi-annually, or annually).

[0155] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0156] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0157] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control. In some embodiments, the control is the AMP level in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0158] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0159] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid beta (Aβ) treatment, such as an anti-Aβ protofibrillary antibody. In some embodiments, the anti-Aβ protofibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ protofibrillary antibody is lencanezumab (also known as BAN2401). In some embodiments, AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, heavy chain variable region, light chain variable region, or constant region according to SEQ ID NOs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0160] In some embodiments, the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease. For example, the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or changes in the levels of one or more biomarkers other than AMP (e.g., MTBR-tau243, Aβ42, Aβ40, Aβ42 / 40 ratio, total tau and / or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) that indicate the subject may have AD. In some embodiments In some embodiments, individuals may have additional risk factors for developing Alzheimer's disease (AD), such as family history, genetic background, sex, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors (e.g., smoking, alcohol consumption, or restriction of physical activity). In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early AD. In some embodiments, the subject has pre-AD. In some embodiments, the subject is amyloid-positive. In some embodiments, the subject is amyloid-positive and has cognitive impairment.

[0161] 4. Detect a decrease in brain Aβ or brain tau levels. This disclosure relates to a method for detecting a decrease in brain Aβ levels in a subject receiving treatment including a therapeutically effective dose of AD therapy, wherein the method comprises: a) obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject prior to the treatment, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject during or after the treatment; and c) comparing the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject.

[0162] This disclosure relates to a method for detecting a decrease in brain Aβ levels in a subject receiving treatment including a therapeutically effective dose of AD therapy, wherein the method comprises: a) obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject prior to the treatment, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory glucomannan-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject during or after the treatment; and c) comparing the first AMP level with the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject.

[0163] In some embodiments, AMP is a peptide listed in Table 10.

[0164] In some embodiments, levels of two or more AMPs (e.g., from the AMPs listed in Table 10) may be obtained from a biological fluid sample, such as CSF, or a blood sample from a subject, and compared to the levels of two or more AMPs in a control sample (e.g., in an individual without AD). For example, levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to the levels in the control sample. In some embodiments, the level of at least one of the two or more AMPs may show a change (e.g., increase or decrease) compared to the level of the same AMP in the control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase while the other may decrease).

[0165] In some embodiments, the first AMP level will show a change (e.g., increase or decrease) compared to the second AMP level from the subject after treatment.

[0166] In some embodiments, the first AMP level from the subject increases compared to the second AMP level, and this indicates a decrease in brain Aβ levels.

[0167] In some embodiments, the first AMP level from the subject is reduced compared to the second AMP level, and this indicates a decrease in brain Aβ levels.

[0168] In some embodiments, the first AMP level from the subject is increased compared to the second AMP level, and this indicates that the brain Aβ level is not decreased.

[0169] In some embodiments, the first AMP level from the subject is reduced compared to the second AMP level, and this indicates that the brain Aβ level is not reduced.

[0170] This disclosure relates to a method for detecting a reduction in brain tau levels (e.g., a reduction in tau tangles) in a subject receiving treatment including a therapeutically effective dose of an anti-tau antibody, wherein the method comprises: a) obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject prior to treatment with the anti-tau antibody, wherein the AMP is selected from any of those listed in Table 10; b) obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject during or after the treatment; and c) comparing the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a reduction in brain Aβ levels in the subject.

[0171] This disclosure relates to a method for detecting a decrease in brain tau levels in a subject receiving treatment including a therapeutically effective dose of AD therapy, wherein the method comprises: a) obtaining a measurement of a first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject prior to the treatment, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) obtaining a measurement of a second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject during or after the treatment; and c) comparing the first AMP level with the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject.

[0172] In some embodiments, the first AMP level from the subject increases compared to the second AMP level, and this indicates a decrease in brain tau levels.

[0173] In some embodiments, a decrease in brain tau levels is a reduction in tau tangles.

[0174] In some embodiments, the first AMP level from the subject is reduced compared to the second AMP level, and this indicates a reduction in brain tau levels.

[0175] In some embodiments, the first AMP level from the subject increases compared to the second AMP level, and this indicates that the brain tau level is not reduced.

[0176] In some embodiments, the first AMP level from the subject is reduced compared to the second AMP level, and this indicates that the brain tau level is not reduced.

[0177] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0178] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0179] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control (e.g., at least one AMP of the same type measured in the subject). In some embodiments, the control is the level of AMP in the CSF of an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0180] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0181] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid beta (Aβ) treatment, such as an anti-Aβ protofibrillary antibody. In some embodiments, the anti-Aβ protofibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ protofibrillary antibody is lencanezumab (also known as BAN2401). In some embodiments, AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, heavy chain variable region, light chain variable region, or constant region according to SEQ ID NOs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0182] In some embodiments, the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease. For example, the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or changes in the levels of one or more biomarkers other than AMP (e.g., MTBR-tau243, Aβ42, Aβ40, Aβ42 / 40 ratio, total tau and / or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) that indicate the subject may have AD. In some embodiments In some embodiments, individuals may have additional risk factors for developing Alzheimer's disease (AD), such as family history, genetic background, sex, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors (e.g., smoking, alcohol consumption, or restriction of physical activity). In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early AD. In some embodiments, the subject has pre-AD. In some embodiments, the subject is amyloid-positive. In some embodiments, the subject is amyloid-positive and has cognitive impairment.

[0183] 5. Methods to reduce tau tangles Another aspect of this disclosure relates to a method for reducing tau tangles in subjects with Alzheimer's disease (AD), suspected Alzheimer's disease, or at risk of developing Alzheimer's disease, the method comprising: a) obtaining a measurement of a first AMP level in a biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) administering treatment to the subject, comprising a therapeutically effective dose of an anti-tau profibrillary antibody, if the first AMP level is altered compared to a control sample, such as compared to AMP levels in an individual without Alzheimer's disease (AD); and c) obtaining a measurement of a second AMP level, wherein a change in the second AMP level compared to the first AMP level indicates a reduction in tau tangles, optionally wherein the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and containing SEQ ID NO: The three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) of the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2) and SEQ ID NO: 20 (LCDR3).

[0184] Another aspect of this disclosure relates to a method for reducing tau tangles in subjects with Alzheimer's disease (AD), suspected Alzheimer's disease, or at risk of developing Alzheimer's disease, the method comprising: a) obtaining a measurement of a first AMP level in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), clump protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); b) if the first AMP level is altered compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), administering to the subject treatment including a therapeutically effective dose of an anti-tau proficiency antibody; and c) A second AMP level measurement is obtained, wherein the change in the second AMP level compared to the first AMP level indicates a reduction in tau tangles, optionally wherein the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0185] In some embodiments, AMP is a peptide listed in Table 10.

[0186] In some embodiments, levels of two or more AMPs (e.g., from the AMPs listed in Table 10) may be obtained from a biological fluid sample, such as CSF, or a blood sample from a subject, and compared to the levels of two or more AMPs in a control sample (e.g., in an individual without AD). For example, levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs may be obtained from the subject and compared to the levels in the control sample. In some embodiments, the level of at least one of the two or more AMPs may show a change (e.g., increase or decrease) compared to the level of the same AMP in the control sample. Changes in the two or more AMPs may be independent of each other (e.g., one may increase while the other may decrease). In some embodiments, tau tangles are reduced by preventing, reducing, and / or slowing the formation of new tau tangles; and / or promoting, increasing, and / or accelerating the breakdown of existing tau tangles, as demonstrated by a decrease in AMP levels in samples collected after treatment. In some embodiments, tau tangles can be measured by tau PET imaging (e.g., using radioligands). In some embodiments, tau PET imaging can be used, for example, in conjunction with changes in AMP levels (e.g., increases or decreases in AMP levels) to establish and / or confirm a reduction in tau tangles.

[0187] In various embodiments, a method for identifying tau tangles in a subject includes a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject; b) identifying tau tangles in the subject if the level of at least one AMP is altered compared to a control sample, such as compared to the AMP level in an individual without Alzheimer's disease (AD).

[0188] In some embodiments, treatment comprising a therapeutically effective dose of an anti-tau antibody (e.g., E2814) may be administered to a subject who has been identified with tau tangles. In some embodiments, treatment comprising a therapeutically effective dose of an anti-Aβ proficiency antibody (e.g., lencanezumab) may be administered to a subject who has been identified with tau tangles. In some embodiments, measurements of additional levels of at least one AMP may be obtained from additional biological fluid samples (e.g., additional CSF or blood samples) to determine whether treatment has altered the level of at least one AMP. In some embodiments, changes in the level of at least one AMP over time indicate that treatment reduces tau tangles. In some embodiments, the efficacy of treatment (e.g., anti-tau antibody administered in combination with anti-Aβ proficiency antibody) may be determined by additional measurements of the level of at least one AMP in biological fluid samples (e.g., CSF or blood samples) obtained in the subject during the treatment period, and optionally, treatment may be adjusted. In some embodiments, the subject may be switched to a maintenance dose of AD therapy, such as a maintenance dose of an anti-tau antibody or a maintenance dose of an anti-Aβ proficiency antibody.

[0189] In some embodiments, the first AMP level will show a change (e.g., increase or decrease) compared to the second AMP level from the subject after treatment.

[0190] In some embodiments, the first AMP level from the subject increases compared to the second AMP level, and this indicates a reduction in tau tangles.

[0191] In some embodiments, the first AMP level from the subject is reduced compared to the second AMP level, and this indicates a reduction in tau tangles.

[0192] In some embodiments, the first AMP level from the subject increases compared to the second AMP level, and this indicates that tau tangles have not decreased.

[0193] In some embodiments, the first AMP level from the subject is lower than the second AMP level, and this indicates that tau tangles have not decreased.

[0194] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0195] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0196] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control (e.g., at least one AMP of the same type measured in the subject). In some embodiments, the control is the level of AMP in the CSF of an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0197] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0198] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid beta (Aβ) treatment, such as an anti-Aβ protofibrillary antibody. In some embodiments, the anti-Aβ protofibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ protofibrillary antibody is lencanezumab (also known as BAN2401). In some embodiments, AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, heavy chain variable region, light chain variable region, or constant region according to SEQ ID NOs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0199] In some embodiments, the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease. For example, the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or changes in the levels of one or more biomarkers other than AMP (e.g., MTBR-tau243, Aβ42, Aβ40, Aβ42 / 40 ratio, total tau and / or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) that indicate the subject may have AD. In some embodiments In some embodiments, individuals may have additional risk factors for developing Alzheimer's disease (AD), such as family history, genetic background, sex, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors (e.g., smoking, alcohol consumption, or restriction of physical activity). In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early AD. In some embodiments, the subject has pre-AD. In some embodiments, the subject is amyloid-positive. In some embodiments, the subject is amyloid-positive and has cognitive impairment.

[0200] 6. Methods of treating subjects This disclosure relates to a method for treating a subject with Alzheimer's disease (AD), suspected of having Alzheimer's disease, or at risk of developing Alzheimer's disease, wherein the method comprises: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) administering treatment to the subject, including a therapeutically effective dose of an AD therapy, if the level of at least one AMP is altered compared to a control sample, such as compared to the AMP level in an individual without Alzheimer's disease (AD).

[0201] This disclosure relates to a method for treating a subject with Alzheimer's disease (AD), suspected of having Alzheimer's disease, or at risk of developing Alzheimer's disease, wherein the method comprises: a) obtaining a measurement of the level of at least one AMP in a biological fluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); and b) administering treatment to the subject, including a therapeutically effective dose of an AD therapy, if the level of at least one AMP is altered compared to a control sample, for example, compared to the AMP level in an individual without Alzheimer's disease (AD).

[0202] In some embodiments, AMP is a peptide listed in Table 10.

[0203] In some embodiments, levels of two or more AMPs (e.g., from the AMPs listed in Table 10) in a biological fluid sample, such as CSF, or a blood sample from the subject can be obtained and compared with the levels of two or more AMPs in a control sample (e.g., in an individual without AD). For example, levels of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 AMPs from the subject can be obtained and compared with the levels in a control sample.

[0204] In some embodiments, the level of at least one of two or more AMPs will show a change (e.g., increase or decrease) compared to the level of the same AMP in a control sample. The changes in the two or more AMPs can be independent of each other (e.g., one can increase while the other can decrease).

[0205] In some embodiments, the first AMP level will show a change (e.g., increase or decrease) compared to the second AMP level from the subject after treatment. In some embodiments, the AMP level from the subject increases compared to the control. In some embodiments, the AMP level from the subject decreases compared to the control.

[0206] In some embodiments, the disorder (e.g., disease) is Alzheimer's disease (AD). In some embodiments, the disorder is mild AD. In some embodiments, the disorder is early AD. In some embodiments, the disorder is moderate AD. In some embodiments, the disorder is severe AD. In some embodiments, the disorder is pre-AD. In some embodiments, the disorder is a neurological disorder (e.g., a neurodegenerative disorder or disease) characterized by containing soluble and / or insoluble Aβ aggregates containing an Aβ peptide. Exemplary disorders include, but are not limited to, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and Lewy body dementia.

[0207] In some embodiments, treating a disorder includes at least one of the following: inhibiting the disorder, slowing its progression, delaying its progression, preventing its development, reversing its progression (e.g., reversing tau accumulation), preventing the onset or development of the disorder, alleviating or improving one or more symptoms or one or more underlying conditions of the disorder, curing the disorder, improving one or more clinical indicators, or preventing the recurrence of one or more symptoms of the disorder. In some embodiments, treating a disorder includes at least one of the following: reducing brain Aβ levels, reducing brain tau levels, improving cognition, and altering biomarkers associated with AD pathology.

[0208] In some embodiments, the method for treating the disorder further includes the steps of monitoring treatment efficacy and / or adjusting the treatment regimen. In some embodiments, the method further includes, after step a) obtaining a measurement of AMP levels in a biofluid sample, such as CSF or a blood sample, from the subject; and b) administering treatment to the subject comprising a therapeutically effective dose of AD therapy, applying the following additional steps: c) obtaining an additional measurement of the level of at least one AMP (e.g., an additional AMP level) in a second biofluid sample, such as CSF or a blood sample, from the subject; d) determining that the additional AMP level has changed compared to the level of at least one AMP obtained before administering the AD therapy; and e) administering an additional therapeutically effective dose of the AD therapy to the subject.

[0209] In some embodiments, the first AMP level is increased compared to the second AMP level.

[0210] In some embodiments, the first AMP level is reduced compared to the second AMP level.

[0211] In some embodiments, the additional therapeutically effective dose is an adjusted dose (e.g., an adjustment in dose size, frequency of administration, and / or route of administration compared to the initial treatment administered to the subject). In some embodiments, the additional therapeutically effective dose is an adjusted dose administered as part of an initial dosing regimen, wherein both the initial treatment administered to the subject and the additional therapeutically effective dose are part of the initial dosing regimen.

[0212] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0213] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0214] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control. In some embodiments, the control is the AMP level in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0215] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0216] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid beta (Aβ) treatment, such as an anti-Aβ protofibrillary antibody. In some embodiments, the anti-Aβ protofibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ protofibrillary antibody is lencanezumab (also known as BAN2401). In some embodiments, AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, heavy chain variable region, light chain variable region, or constant region according to SEQ ID NOs: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0217] In some embodiments, the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease. For example, the subject may have symptoms of AD, such as cognitive impairment or high levels of amyloid PET or tau PET, or changes in the levels of one or more biomarkers other than AMP (e.g., MTBR-tau243, Aβ42, Aβ40, Aβ42 / 40 ratio, total tau and / or phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) that indicate the subject may have AD. In some embodiments In some embodiments, individuals may have additional risk factors for developing Alzheimer's disease (AD), such as family history, genetic background, sex, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors (e.g., smoking, alcohol consumption, or restriction of physical activity). In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early AD. In some embodiments, the subject has pre-AD. In some embodiments, the subject is amyloid-positive. In some embodiments, the subject is amyloid-positive and has cognitive impairment.

[0218] In some embodiments, the AD therapies disclosed herein (e.g., anti-tau antibodies such as E2814 or antibodies containing a CDR and / or variable domain from E2814, and / or anti-Aβ protofibrillary antibodies such as lencanezumab or antibodies containing a CDR and / or variable domain from lencanezumab) are included in a pharmaceutical composition for treating subjects with Alzheimer's disease (AD), suspected of having Alzheimer's disease, or at risk of having Alzheimer's disease, wherein the level of at least one AMP in a biological fluid sample (e.g., CSF or blood sample) from the subject is altered (e.g., increased or decreased) compared to a control sample, such as compared to the level of at least one AMP (e.g., the same at least one AMP measured in the subject) in an individual without Alzheimer's disease (AD). In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier.

[0219] In some embodiments, the AD therapies disclosed herein (e.g., anti-tau antibodies such as E2814 or antibodies containing a CDR and / or variable domain from E2814, and / or anti-Aβ protofibrillary antibodies such as lencanezumab or antibodies containing a CDR and / or variable domain from lencanezumab) are used to manufacture a medicine for treating subjects with Alzheimer's disease (AD), suspected of having Alzheimer's disease, or at risk of having Alzheimer's disease, wherein the level of at least one AMP concentration in a biological fluid sample (e.g., CSF or blood sample) from the subject is elevated compared to a control sample, such as compared to the level of at least one AMP concentration (e.g., the same at least one AMP measured in the subject) in an individual without Alzheimer's disease (AD).

[0220] In some embodiments, (e.g., anti-tau antibodies such as E2814 or antibodies containing a CDR and / or variable domain from E2814, and / or anti-Aβ protofibrillary antibodies such as lencanezumab or antibodies containing a CDR and / or variable domain from lencanezumab) are used to treat subjects with Alzheimer's disease (AD), suspected Alzheimer's disease, or at risk of having Alzheimer's disease, wherein the level of at least one AMP in a biological fluid sample (e.g., CSF or blood sample) from the subject is elevated compared to a control sample, such as compared to the level of at least one AMP (e.g., the same at least one AMP measured in the subject) in an individual without Alzheimer's disease (AD).

[0221] 7. Treatment methods for Alzheimer's disease One aspect of this disclosure relates to a method for treating Alzheimer's disease (AD) in a subject who has or is suspected of having AD, the method comprising: determining the level of alteration of at least one antimicrobial peptide (AMP) in a biological fluid, such as cerebrospinal fluid (CSF), of the subject compared with a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10; and administering to the subject a therapeutically effective dose of an AD therapy, such as anti-amyloid β (Aβ) therapy, for example, an anti-Aβ primary fibrillary antibody.

[0222] Another aspect of this disclosure relates to a method for treating Alzheimer's disease (AD) in a subject who has or is suspected of having AD, the method comprising: determining the level of alteration of at least one antimicrobial peptide (AMP) in a biological fluid, such as cerebrospinal fluid (CSF), from the subject compared to a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); and administering to the subject a therapeutically effective dose of an AD therapy, such as anti-amyloid-β (Aβ) therapy, for example, an anti-Aβ primary fibrillary antibody.

[0223] A protein may have other names, or it may be named after the gene that encodes it. For example, secretory granulin-1 (SCG1) can also be called SgI, SCG1, secretory granulin B, or chromogranin B. The RPS27A gene can be called ribosomal protein S27a, ubiquitin carboxy-extended protein 80, UBCEP80, ubiquitin-40S ribosomal protein S27a, UBCEP1, Uba80, or UBA80.

[0224] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0225] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0226] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control. In some embodiments, the control is the AMP level in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0227] In some embodiments, a change in AMP levels in the biofluid is an increase in AMP levels. For example, subjects with or suspected of having AD may have increased AMP levels in the biofluid compared to AMP levels in a control. In some embodiments, a change in AMP levels in the biofluid is a decrease in AMP levels; for example, subjects with or suspected of having AD may have increased AMP levels in the biofluid compared to AMP levels in a control.

[0228] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0229] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid β (Aβ) treatment, such as an anti-Aβ primary fibrillary antibody. In some embodiments, the anti-Aβ primary fibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ primary fibrillary antibody is lencanezumab (also known as BAN2401).

[0230] In some embodiments, the AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NO: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0231] 8. Assess treatment efficacy AMP levels can be obtained at different time points. For example, AMP levels in a subject's biological fluid can be determined at two or more time points, with the first time point being before AD treatment or early in the treatment regimen, and the second time point being later in the treatment regimen. Therefore, another aspect of this disclosure relates to a method for treating Alzheimer's disease (AD) in a subject who has or is suspected of having AD, the method comprising determining a first level of at least one antimicrobial peptide (AMP) in a biological fluid, such as cerebrospinal fluid (CSF), from the subject, wherein the first level of the AMP in the subject's CSF is altered compared to a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10; administering to the subject a first therapeutically effective dose of an AD therapy, such as anti-amyloid β (Aβ) therapy, for example, an anti-Aβ primary fibrillary antibody; determining a second level of the AMP in the subject's CSF; and, if a change from the first level of the AMP to the second level of the AMP is present, administering a second therapeutically effective dose of the AD therapy.

[0232] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0233] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0234] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control. In some embodiments, the control is the AMP level in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0235] In some embodiments, a change in AMP levels in the biofluid is an increase in AMP levels. For example, subjects with or suspected of having AD may have increased AMP levels in the biofluid compared to AMP levels in a control. In some embodiments, a change in AMP levels in the biofluid is a decrease in AMP levels; for example, subjects with or suspected of having AD may have increased AMP levels in the biofluid compared to AMP levels in a control.

[0236] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0237] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid β (Aβ) treatment, such as an anti-Aβ primary fibrillary antibody. In some embodiments, the anti-Aβ primary fibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ primary fibrillary antibody is lencanezumab (also known as BAN2401).

[0238] Another aspect of this disclosure relates to a method for monitoring the efficacy of treatment in subjects who have or are suspected of having Alzheimer's disease (AD), the method comprising determining a first level of at least one antimicrobial peptide (AMP) in a biological fluid, such as cerebrospinal fluid (CSF), from the subject, wherein the first level of the AMP in the subject's CSF is altered compared to a control, such as CSF from an individual not diagnosed with AD, wherein the AMP is selected from any of those listed in Table 10; administering to the subject a first therapeutically effective dose of an AD therapy, such as anti-amyloid beta (Aβ) therapy, such as an anti-Aβ primary fibrillary antibody; and measuring a second level of the AMP in the subject's CSF, wherein the second level of the AMP, which differs from the first level, indicates therapeutic efficacy.

[0239] In some embodiments, if the difference between a first level and a second level of AMP indicates that treatment is effective, the treatment may be modified. For example, the treatment may be reduced, e.g., in terms of the dosage and / or frequency of administration. In some embodiments, if the first level and the second level of AMP differ, the treatment may not be modified. For example, treatment may continue.

[0240] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0241] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0242] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control. In some embodiments, the control is the AMP level in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0243] In some embodiments, a change in AMP levels in the biofluid is an increase in AMP levels. For example, subjects with or suspected of having AD may have increased AMP levels in the biofluid compared to AMP levels in a control. In some embodiments, a change in AMP levels in the biofluid is a decrease in AMP levels; for example, subjects with or suspected of having AD may have increased AMP levels in the biofluid compared to AMP levels in a control.

[0244] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0245] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid β (Aβ) treatment, such as an anti-Aβ primary fibrillary antibody. In some embodiments, the anti-Aβ primary fibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ primary fibrillary antibody is lencanezumab (also known as BAN2401).

[0246] In some embodiments, the AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NO: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0247] 9. Methods for diagnosing AD This disclosure relates to a method for diagnosing AD in a subject, the method comprising determining the level of one or more antimicrobial peptides (AMPs) in a biological fluid, such as cerebrospinal fluid (CSF), from the subject, wherein the AMPs are selected from any of those listed in Table 10, and comparing the level of the AMPs with that of a control, such as CSF from an individual not diagnosed with AD, wherein a change in the level of AMPs in the subject's CSF compared to the control indicates that the subject has AD.

[0248] In some embodiments, the AMP is about 10-100 amino acids long, for example, about 12-50 amino acids long. The peptide can correspond to any region of the full-length protein. In some embodiments, the AMP comprises any one of SEQ ID NO: 27-50.

[0249] In some embodiments, subjects with or suspected of having AD experience cognitive impairment. For example, an individual may have dementia. Subjects may be Aβ+, for example, determined by measurements of Aβ levels in biological fluids, or by imaging such as amyloid PET imaging. In some embodiments, subjects have one or more of the following: t-tau levels above 400 ng / L CSF, Aβ1-42 levels below 550 ng / L CSF, and an Aβ1-42 / Aβ1-40 ratio below 0.065 CSF.

[0250] AMP levels in a biological fluid (e.g., CSF) from a subject can be compared to AMP levels in a control. In some embodiments, the control is the AMP level in CSF from an individual who does not have Alzheimer's disease. In some embodiments, the individual has not been diagnosed with AD. In some embodiments, the individual has cognitive impairment. For example, the individual may have dementia. In some embodiments, the individual is Aβ-. In some embodiments, the individual does not have AD.

[0251] In some embodiments, the biofluid is cerebrospinal fluid (CSF). In some embodiments, the biofluid is blood. In some embodiments, the biofluid is one or more of the following: CSF, blood, serum, plasma, saliva, tears, sweat, or any other biofluid that can be collected from the body.

[0252] AD therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy is an anti-amyloid β (Aβ) treatment, such as an anti-Aβ primary fibrillary antibody. In some embodiments, the anti-Aβ primary fibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ primary fibrillary antibody is lencanezumab (also known as BAN2401).

[0253] In some embodiments, the AD therapy is an anti-tau antibody. In some embodiments, the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NO: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0254] Alzheimer's disease treatment Alzheimer's disease (AD) therapy can be any treatment or therapeutic agent administered to a subject to alleviate symptoms and / or progression of AD. In some embodiments, AD therapy can be any treatment that delays the progression of amyloid pathology, tau pathology, and / or clinical symptoms in a subject who has AD, is suspected of having AD, or is at risk of developing AD.

[0255] In some embodiments, AD therapy is administered to the subject based on measurements of antimicrobial peptides (AMP) in a biofluid sample from the subject.

[0256] In some embodiments, AD therapy includes antibodies.

[0257] In some embodiments, AD therapy is an anti-Aβ protofibrillary antibody (e.g., lencanezumab). In some embodiments, AD therapy is an anti-tau antibody (e.g., E2814).

[0258] In some embodiments, AD therapy is a combination of anti-Aβ protofibrillary antibodies (e.g., lencanezumab) and anti-tau antibodies (e.g., E2814).

[0259] In some embodiments, AD therapy may be administered according to an initial dosing regimen and optionally a maintenance dosing regimen. Exemplary dosing regimens for lencanezumab, E2814, and combinations thereof are disclosed in WO 2023 / 111618, WO 2023 / 114586, and PCT / US2024 / 033125, which are incorporated herein by reference.

[0260] a. Anti-Aβ primary fibrillary antibody In some embodiments, when the AMP level from a biofluid sample (e.g., a CSF sample or a blood sample) differs from the AMP level from a control (e.g., a biofluid sample from a subject who does not have AD), an AD therapy including anti-amyloid β (Aβ) treatment (e.g., an anti-Aβ protofibrillary antibody) may be administered.

[0261] In some embodiments, the anti-Aβ primary fibrillary antibody comprises a CDR, variable region, heavy chain, light chain, or constant region according to SEQ ID NOs: 1-12 listed in Tables 1-4. In some embodiments, the anti-Aβ primary fibrillary antibody is lencanezumab (also known as BAN2401).

[0262] In some embodiments, the anti-Aβ primary fibrillary antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3) (Table 1). In some embodiments, the anti-Aβ primary fibrillary antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 7 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 8 (Table 2). In some embodiments, the anti-Aβ primary fibrillary antibody comprises a human heavy chain and light chain variable region framework. In some embodiments, the anti-Aβ primary fibrillary antibody comprises a human IgG1 heavy chain constant region and a human Igκ light chain constant region. In some embodiments, the anti-Aβ protofibrillary antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10 (Table 3). In the context of antibody sequence or structure, “CDR” as used herein refers to the complementary determining region that provides the major determinant for antigen binding. Typically, there are six CDRs at the antigen binding site: three of the VH (HCDR1, HCDR2, HCDR3) and three of the VL (LCDR1, LCDR2, LCDR3). CDRs can be determined according to the Kabat numbering scheme. These CDRs can be determined according to the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Maryland, 1991, hereinafter referred to as the “Kabat Report”).

[0263] In some embodiments, at least one anti-Aβ primary fibrillary antibody comprises a human constant region. In some embodiments, the human constant region of at least one anti-Aβ primary fibrillary antibody comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variants thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in this disclosure. In some embodiments, the heavy chain constant region is selected from IgG1 and its allelic variants. The amino acid sequence of the human IgG1 constant region is known in the art and is shown in SEQ ID NO: 11 (Table 4).

[0264] In some embodiments, the human constant region of at least one anti-Aβ antibody comprises a light chain constant region selected from the κ-λ chain constant region and any allelic variants thereof as discussed in the Kabat report. Any one or more of such sequences may be used in this disclosure. In some embodiments, the light chain constant region is selected from κ and its allelic variants. The amino acid sequence of the human κ chain constant region is known in the art and is shown in SEQ ID NO: 12 (Table 4).

[0265] b. Anti-tau antibody In some embodiments, when the AMP level from a biofluid sample (e.g., a CSF sample or a blood sample) differs from the AMP level from a control (e.g., a biofluid sample from a subject who does not have AD), an AD therapy including anti-tau treatment (e.g., an anti-tau antibody) may be administered.

[0266] In some embodiments, the anti-tau antibody comprises a CDR, a heavy chain variable region, a light chain variable region, or a constant region according to SEQ ID NO: 15-24 in Tables 6-8. In some embodiments, the anti-tau antibody is E2814.

[0267] In some embodiments, the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3), as defined by Kabat (Table 6). In some embodiments, the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from the heavy chain variable region of SEQ ID NO: 21 and the light chain variable region of SEQ ID NO: 22 (e.g., as defined by Kabat or IMGT). In some embodiments, the anti-tau antibody comprises the heavy chain variable region of SEQ ID NO: 21 and the light chain variable region of SEQ ID NO: 22 (Table 7).

[0268] In some embodiments, the anti-tau antibody comprises a human constant region. In some embodiments, the human constant region comprises a heavy chain constant region selected from: IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allele variations thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in this disclosure. In some embodiments, the heavy chain constant region comprises SEQ ID NO: 23 (Table 8).

[0269] In some embodiments, the human constant region of the anti-tau antibody comprises a light chain constant region selected from the κ and λ chain constant regions, as well as any allelic variations thereof as discussed in the Kabat report. Any one or more of such sequences may be used in this disclosure. In some embodiments, the light chain constant region comprises SEQ ID NO: 24 (Table 8).

[0270] In some embodiments, the anti-tau antibody comprises E2814 or an antigen-binding fragment thereof. E2814 is disclosed in US2019 / 0112364 A1, the entire contents of which are incorporated herein by reference, and that patent discloses E2814 as clone 7G6-HCzu25 / LCzu18, the sequence of which is incorporated herein by reference.

[0271] In some embodiments, the anti-tau antibody is any of those disclosed in US 2019 / 0112364 A1, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the anti-tau antibody comprises the CDR and / or variable region sequence from antibody clone 7G6-HCzu25 / LCzu18 disclosed in US 2019 / 0112364 A1, these sequences being incorporated herein by reference. In some embodiments, the anti-tau antibody is produced by antibody-generating cells deposited on October 11, 2017, at the American Type Culture Collection (10801 University Blvd., Manassas, Va. 20110-2209) with accession number PTA-124524.

[0272] Other biomarkers In some embodiments, in addition to changes in the levels of one or more AMPs, subjects show changes and / or differences in measurements of one or more biomarkers associated with AD pathology before and / or during AD treatment (e.g., the treatment disclosed herein).

[0273] In some embodiments, the change and / or difference in the measured value is selected from (a) an increase in amyloid protein in the brain, for example, as measured by amyloid PET (e.g., a percentage measure of about 20-40, for example, a percentage measure of about 20-32), (b) an increase in tau in the brain, for example, as measured by positron emission tomography (PET), (c) Decreased levels of the Aβ1-42 / 1-40 ratio in cerebrospinal fluid and / or increased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranulin and / or neurofilament light chains (NfL), and (d) Decreased levels of the Aβ1-42 / 1-40 ratio in serum or plasma and / or increased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0274] In some embodiments, subjects show changes and / or differences in measurements of one or more biomarkers associated with AD pathology during and / or after treatment.

[0275] In some embodiments, the change and / or difference in the measured value is selected from (a) a decrease in amyloid protein in the brain, for example, as measured by amyloid PET (e.g., a percentage measure of about 20-40, for example, a percentage measure of about 20-32), (b) a decrease in tau in the brain, for example, as measured by positron emission tomography (PET), (c) Increased levels of the Aβ1-42 / 1-40 ratio in cerebrospinal fluid and / or decreased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranulin and / or neurofilament light chains (NfL), and (d) Increased levels of the Aβ1-42 / 1-40 ratio in serum or plasma and / or decreased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0276] amyloid PET PET imaging enables the visualization of amyloid plaques in the brain, plaques that were previously only detectable by examining the brain during autopsies. Amyloid PET is a valuable tool for diagnosing Alzheimer's disease (AD) and monitoring disease progression because of its high predictive accuracy for the presence of AD pathology. Amyloid PET can be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably blood or CSF markers, such as AMP in blood or CSF. In some embodiments, the AMP disclosed herein can be used to estimate (e.g., as a substitute value) amyloid PET measurements.

[0277] As used herein, the term "amyloid PET" refers to positron emission tomography (PET) of amyloid. In some embodiments, PET imaging (also known as PET scans) is performed to assess amyloid pathology (Hansson et al., Nature Medicine, 2021.27: 954-963; Therriault et al., Nature Reviews Neurology, 2024.20: 232-244). In some embodiments, amyloid PET is assessed using a PET tracer and the same tracer is used in subsequent assessments.

[0278] In some embodiments, PET imaging is used to evaluate amyloid β plaque levels in the brain. In some embodiments, PET imaging uses an amyloid PET tracer. In some embodiments, PET imaging uses flubetabenzene (e.g., 18F-fluorobetabenzene (Neuraceq®)), flubetapyr (e.g., 18F-fluorobetapyr (Amyvid®)), and / or flumetaphen (e.g., 18F-fluorometaphen (Vizamyl®)). In some embodiments, PET imaging uses a flubetapyr tracer. In some embodiments, PET imaging uses a flumetaphen tracer. In some embodiments, PET imaging uses a flubetabenzene tracer. In some other embodiments, different tracers may produce different results. In some embodiments, the correction average reduction threshold depends on the tracer used.

[0279] In some embodiments, the subject’s brain amyloid levels were determined by visual readings of amyloid PET images and expressed as the PET standard uptake ratio (SUVr value). In some embodiments, brain amyloid levels decreased following administration of AD therapy (e.g., anti-Aβ protofibrillary antibodies such as lencanezumab or anti-tau antibodies such as E2814), accompanied by changes in AMP measurements from Table 10.

[0280] Tau PET PET imaging enables the visualization of tau accumulations in the brain, which were previously only detectable by examining the brain during autopsy. Tau PET is a valuable tool for diagnosing AD and monitoring disease progression, particularly because tau NFT burden is closely correlated with the severity of clinical AD symptoms (Hansson et al., Nature Medicine, 2021.27: 954-963; Therriault et al., Nature Reviews Neurology, 2024.20: 232-244). Tau PET can be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably blood or CSF markers, such as AMP in blood or CSF. In some embodiments, the AMP disclosed herein can be used to estimate (e.g., as a substitute value) amyloid PET measurements.

[0281] As used herein, “tau PET” refers to tau positron emission tomography. In some embodiments, PET imaging (e.g., PET scans) is performed to assess tau pathology.

[0282] In some embodiments, tau PET is evaluated with a PET tracer and the same tracer is used in subsequent evaluations.

[0283] In some embodiments, the subject’s brain tau level is determined by visual readings of tau PET images and expressed as the PET standard uptake ratio (SUVr value). In some embodiments, brain tau levels decrease following administration of AD therapy (e.g., anti-Aβ protofibrillary antibodies such as lencanezumab or anti-tau antibodies such as E2814), accompanied by changes in AMP measurements from Table 10.

[0284] Subjects with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD Subjects treated in this study include those with or suspected of having Alzheimer's disease (AD). In some embodiments, subjects show changes (e.g., increases, decreases, changes in the rate and / or extent of increases, or changes in the rate and / or extent of decreases) in one or more biomarkers (e.g., AMPs described herein) associated with AD pathology compared to a reference measurement. In some embodiments, the reference measurement may be a measurement collected from the same subject, for example, at an earlier time point, or a measurement of the portion of the biomarker level in the subject's body, tissues, or fluids that does not change in response to AD pathology. In some embodiments, the reference measurement may be a measurement collected from another subject (e.g., a healthy control subject), or it may be the average of measurements collected from more than one reference subject.

[0285] In some embodiments, subjects may show changes and / or differences in measurements of AMP levels before treatment compared to a reference measurement, such as compared to earlier measurements in the subject or compared to control subjects who do not have AD, for example, an increase or decrease in AMP levels.

[0286] In some embodiments, compared to a reference measurement (e.g., a measurement from healthy controls), in addition to or instead of AMP levels, subjects may exhibit changes and / or differences in measurements of one or more biomarkers associated with AD pathology prior to treatment, such as one or more of the following: (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a percentage measure of about 20-40, e.g., about 20-32 percentage units); (b) Increased tau in the brain, for example, as measured by positron emission tomography (PET), (c) decreased levels of Aβ1-42 in cerebrospinal fluid (e.g., decreased Aβ1-42 / 1-40 ratio) and / or total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) ratios, MTBR-tau243, neurogranulin and / or neurofilament light chains (NfL), and (d) Decreased serum or plasma Aβ1-42 levels (e.g., decreased plasma or serum Aβ1-42 / 1-40 ratio) and / or total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231) ratios, MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL) levels. In some embodiments, subjects may exhibit changes in the ratio of phosphorylated to non-phosphorylated Tau 217 in plasma or serum (P-Tau217 / NP-Tau217 ratio, also known as P-Tau217R or pTau217R), for example, this ratio may be increased in subjects who have AD, are suspected of having AD, or are at risk of developing AD.Unbound by theory, the biomarkers disclosed in this paper can be effectively used to predict amyloid PET status (Rissman et al., 2024, Alzheimers & Dementia, 20(2): 1214-1224; Janelidze et al., 2022, Alzhimer's & Dementia, 18:283-293) and for the detection and diagnosis of AD (Hampel et al., 2023, Neuron, 111(18):2781-2799). In some embodiments, at least one of p-tau217 / np-tau217, Aβ42 / Aβ40, and p-tau181 / np-tau181 can be used to predict amyloid PET status. In some embodiments, measurements of p-tau217 and / or Aβ42 / Aβ40 can be used to predict amyloid PET status. In some embodiments, the combination of p-tau217 and Aβ42 / Aβ40 can be used to predict amyloid PET status. In some embodiments, the ratio of p-tau217 / np-tau217 and Aβ42 / Aβ40 can be combined to predict amyloid PET status.

[0287] In some embodiments, the subject is amyloid-positive, for example, as indicated by PET assessment, CSF assessment of Aβ(1-42), MRI, and / or retinal amyloid accumulation.

[0288] In some embodiments, the subject has AD, for example, is diagnosed with AD. For example, the subject has been diagnosed with (a) Alzheimer's disease-related mild cognitive impairment – ​​moderate probability, and / or has been diagnosed with mild Alzheimer's dementia; (b) Alzheimer's disease-related mild cognitive impairment – ​​moderate probability according to the National Institute on Aging and Alzheimer's Association (NIA-AA) Core Clinical Guidelines; (c) Alzheimer's disease-related mild cognitive impairment – ​​moderate probability according to a CDR total score of 0.5 and a memory frame score of 0.5 or higher before treatment; (d) Alzheimer's disease-related mild cognitive impairment – ​​moderate probability according to, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year before treatment, as confirmed by an informed party; (e) mild Alzheimer's dementia according to the NIA-AA Core Clinical Guidelines for possible Alzheimer's dementia; or (f) mild Alzheimer's dementia according to a CDR score of 0.5 to 1.0 and a memory frame score of 0.5 or higher before treatment.

[0289] In some embodiments, the subjects had early-stage AD. Subjects with early-stage AD may have symptoms ranging in severity from mild cognitive impairment of AD origin—moderate probability—to mild Alzheimer's dementia. In some embodiments, subjects with early-stage AD had an MMSE score of 22 to 30 and a total Clinical Dementia Rating Scale (CDR) score of 0.5 to 1.0.

[0290] In some embodiments, a subject has low tau PET levels in whole-brain measurements, such as those measured by tau PET. Low tau PET levels can refer to low levels of tau accumulation, such as low levels of cortical tau accumulation, as imaged by PET scan imaging. In some embodiments, a subject with low tau PET also has tau accumulation in certain brain regions (e.g., one or more early Braak areas or complex areas of regions where tau accumulates in early AD). In some embodiments, a subject may be classified as having low tau levels if the tau level measured by PET using an MK tracer (e.g., MK6240) is below about 1.1 (e.g., below about 1.0). In some embodiments, a patient may be classified as having low tau levels if the tau PET level measured using an MK tracer is below 1.06. In some embodiments, a patient may be classified as having intermediate tau levels if the tau PET level measured by an MK tracer is between about 1.1 and 3.0 (e.g., between 1.06 and 2.91). In some embodiments, a patient may be classified as having a high level of tau if the tau PET level, as measured by the MK tracer, is higher than about 3.0 (e.g., higher than 2.91).

[0291] In some embodiments, such as based on one or more biomarkers and / or cognitive symptoms of dementia, a subject is suspected of having AD.

[0292] In some embodiments, the subjects were at risk of developing AD but had not yet shown cognitive symptoms of dementia.

[0293] In some embodiments, the subject may have risk factors for AD, wherein these risk factors are associated with age or gene mutations. In some embodiments, the subject is ApoE4 positive. In some embodiments, the subject is at least 65 years old, for example, 65 to 80 years old. In some embodiments, the subject is 55 to 64 years old and has at least one of the following risk factors: (i) a first-degree relative diagnosed with dementia before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid protein as measured by PET or cerebrospinal fluid (CSF). In some embodiments, the subject at risk for AD has elevated brain amyloid protein, for example, as measured and / or confirmed by PET assessment, but does not exhibit any detectable cognitive symptoms. In some embodiments, subjects at risk of AD have the following variations relative to control subjects or populations: biomarkers, such as amyloid PET; levels of one or more of tau in the brain (e.g., as measured by positron emission tomography (PET)), Aβ1-42 in cerebrospinal fluid (or the Aβ1-42 / 1-40 ratio in cerebrospinal fluid), total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau). The ratio of 231), MTBR-tau243, neurogranulin, and neurofilament light chain (NfL), and / or changes in the levels of one or more of Aβ1-42 in serum or plasma (or the ratio of Aβ1-42 / 1-40), total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0294] In some embodiments, subjects at risk of developing Alzheimer's disease (AD) may have pre-AD (also known as preclinical AD, where the subject's cognition is not impaired, but amyloid protein in the brain is elevated, for example, based on changes in one or more biomarkers associated with AD pathology). For example, a subject may show changes in one or more biomarkers associated with AD pathology, but without cognitive impairment, for example, as measured by clinical symptoms of AD. In some embodiments, the subject's overall Clinical Dementia Rating (CDR) score is 0. In some embodiments, through educational adaptation, the subject's Mini-Mental State Examination (MMSE) score is greater than or equal to 27. In some embodiments, the subjects’ Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII) scores are better than the age-adjusted mean in the WMS-IV LMII by one standard deviation below; that is, a score greater than 15 for subjects aged 50 to 64 years, a score greater than 12 for subjects aged 65 to 69 years, a score greater than 11 for subjects aged 70 to 74 years, a score greater than 9 for subjects aged 75 to 79 years, and a score greater than 7 for subjects aged 80 to 90 years.

[0295] In some embodiments, the subject has a gene mutation for dominant Alzheimer's disease, for example, the subject has a gene mutation in at least one of three genes—PSEN1, PSEN2, or APP.

[0296] In some embodiments, the subject has a mutation in the APP.

[0297] In some embodiments, the subjects have dominant Alzheimer's disease (DIAD).

[0298] In some embodiments, the subject has mild to moderate AD, for example, where mild AD may be associated with a Mini-Mental State Examination (MMSE) score ≥ 20 and is characterized by forgetfulness and difficulty in activities of daily living (ADL). Moderate AD may be associated with an MMSE score of approximately 10–19 and is characterized by significant memory loss and a significant need for assistance with ADL.

[0299] definition The following are definitions of the terms used in this application.

[0300] Unless the context clearly indicates otherwise, as used herein, the singular terms “a / an” and “the” include plural references.

[0301] As used herein, the phrase “and / or” means “any one or both” of the elements that are combined, that is, elements that are combined in some cases and not combined in others. Therefore, as a non-limiting example, when “A and / or B” is used in conjunction with open-ended language such as “including,” in some embodiments it may refer only to A (optionally including elements other than B); in other embodiments it may refer only to B (optionally including elements other than A); in still other embodiments it may refer to both A and B (optionally including other elements); and so on.

[0302] As used herein, “at least one” means one or more elements in the list of elements, but is not required to include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether related to or unrelated to those specifically identified elements. Thus, as a non-limiting example, “at least one of A and B” (or equivalently, “at least one of A or B”, or equivalently, “at least one of A and / or B”) may, in one embodiment, mean at least one (optionally including more than one) A without B (and optionally including elements other than B); in another embodiment, mean at least one (optionally including more than one) B without A (and optionally including elements other than A); in yet another embodiment, mean at least one (optionally including more than one) A and at least one (optionally including more than one) B (and optionally including other elements); and so on.

[0303] As used herein, “about” when used in conjunction with a dose, amount, or ratio includes a specified dose, amount, or ratio, or a range of doses, amounts, or ratios, as recognized by one of ordinary skill in the art, to provide a therapeutic effect equivalent to those obtained from the specified dose, amount, or ratio. The term “about” may refer to an acceptable error in a particular value as determined by one of ordinary skill in the art, which in part depends on how those values ​​are measured or determined. In some embodiments, the term “about” means within 5% of a given value or range.

[0304] When a number is described alone or as part of a numerical range, it should be understood that the number can vary above and below the stated value by a deviation of up to + / - 10%.

[0305] When this document lists value ranges, it is intended to encompass all values ​​and subranges within that range. For example, “2.5 mg / kg to 10 mg / kg” is intended to encompass, for example, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 2.5 mg / kg to 3 mg / kg, 2.5 mg / kg to 4.5 mg / kg, 3 mg / kg to 4.5 mg / kg, 4.5 mg / kg to 8 mg / kg, 2.5 mg / kg to 9 mg / kg, etc.

[0306] As used herein, “corrected mean change from baseline” refers to the change in a biomarker value over time calculated using statistical analysis. In some embodiments, a linear mixed-effects model (MMRM) is used to account for at least one additional covariate to determine the corrected mean change from baseline.

[0307] As used in this article, antimicrobial peptides (AMPs) (also known as host defense peptides (HDPs)) are a class of peptides that can exhibit activity against pathogens (such as bacteria, viruses, and fungi) and certain cells (such as transformed cells, mutant cells, or cancer cells). AMPs can play a role in innate immune responses.

[0308] AMP level (also known as “AMP level”) refers to the concentration and / or quantity of AMP in a measured sample or subject.

[0309] Amyloid β 1-42 (Aβ42) refers to amyloid β monomers derived from amino acids 1 to 42 of the full-length protein (Table 5, SEQ ID NO: 13). Amyloid β 1-40 (Aβ1-40) refers to amyloid β monomers derived from amino acids 1 to 42 of the full-length protein (Table 5, SEQ ID NO: 14).

[0310] P-tau181 is human tau protein phosphorylated at threonine position 181. P-tau217 is human tau protein phosphorylated at threonine position 217. P-tau231 is human tau protein phosphorylated at threonine position 231. P-tau205 is human tau protein phosphorylated at threonine position 205.

[0311] As used in this article, total tau or t-tau is a measure of total tau in a sample (e.g., CSF sample, plasma sample, serum sample).

[0312] MTBR-tau 243 is a peptide fragment of tau that spans residues 243-254 in the microtubule-binding region of tau and is enriched in tau aggregates. MTBR-tau243 can be measured in biofluid samples (such as CSF or blood) and is correlated with tau tangles, tauPET, and cognitive impairment.

[0313] Patients with “preclinical AD” or “early AD” (also known as “asymptomatic” AD patients), as described in this article, are cognitively normal individuals with moderate or elevated levels of amyloid protein in their brains, and can be identified by the presence or absence of memory impairment and an asymptomatic phase of newly emerging episodic memory and executive function deficits. Cognitive normality can include individuals with a CDR of 0, or those within the normal range for cognitive test scores (MMSE, International Shopping List Task, Logical Memory, etc.). Preclinical AD occurs prior to significant irreversible neurodegeneration and cognitive impairment, and is typically characterized by the presence of in vivo molecular biomarkers of AD without clinical symptoms. Preclinical AD biomarkers that may indicate a future risk of developing Alzheimer's disease include, but are not limited to, one or more of the following: intermediate or elevated levels of amyloid protein in the brain as determined by amyloid PET (e.g., a percentage measurement of approximately 20-40, or approximately 20-32), fluorodeoxyglucose (FDG) PET, or tau positron emission tomography (PET); cerebrospinal fluid (CSF) levels of Aβ1-42 and / or the Aβ1-42 / 1-40 ratio; CSF levels of total tau; CSF levels of microtubule-binding zone (MTBR)-tau; CSF levels of neurogranulin; and CSF levels of neurofilament light chains (NfL). And blood biomarkers such as those measured in serum or plasma (e.g., levels of Aβ1-42, the ratio of the two forms of amyloid β peptide (Aβ1-42 / 1-40 ratio, e.g., between about 0.092 and 0.094 or below about 0.092), plasma levels of total tau (T-tau), levels of phosphorylated tau (P-tau or p-tau) isoforms (including tau phosphorylated at 181 (P-tau181), 205 (P-tau205), 217 (P-tau217), and 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)). For example, it has been found that subjects treated with elenbecestat (E2609), a β-amyloid precursor protein cleaving enzyme (BACE) inhibitor, showed the greatest reduction in cognitive decline during treatment, with baseline amyloid positron emission tomography (PET) uptake ratios (SUVr values) of 1.4 to 1.9.See Lynch, SY et al., “Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease,” poster p. 389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, it was found that subjects with baseline flubetapiprazole amyloid PET SUVr levels below 1.2 did not exhibit detectable sufficient cognitive decline, while subjects with SUVr levels above 1.6 showed a plateau effect, where amyloid levels had reached saturation and treatment did not induce changes in cognitive measures. See Dhadda, S. et al., “Baseline florbetapir amyloid PET standard update value ratio (SUVr) can predict clinical progression in prodromal Alzheimer's disease (pAD).” Poster p4-291, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA.

[0314] As used herein, “early AD” or “early Alzheimer’s disease” refers to a range of AD severity from moderate probability of AD-related mild cognitive impairment to mild Alzheimer’s dementia. Subjects with early AD include those with mild Alzheimer’s dementia as defined herein and those with mild cognitive impairment (MCI) due to moderate probability of AD as defined herein. In some embodiments, subjects with early AD have an MMSE score of 22 to 30 and a total Clinical Dementia Rating Scale (CDR) score of 0.5 to 1.0. Other methods for detecting early-stage AD disease may employ the following specified tests and assays, including the following National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical guidelines for possible Alzheimer's dementia: McKhann, GM et al., “The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.” Alzheimer Dement. [Alzheimer's Disease and Dementia] 2011; 7:263-9. Other methods include CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADASMCI-ADL, Modified iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, subjects with early AD have evidence of elevated or positive amyloid-beta protein levels in the brain. In some embodiments, elevated or positive amyloid-beta protein levels in the brain are indicated and / or confirmed by PET assessment. In some embodiments, elevated or positive amyloid-beta protein levels in the brain are indicated and / or confirmed by CSF assessment of biomarkers such as Aβ1-42 (e.g., water-soluble CSF biomarker analysis). In some embodiments, elevated or positive amyloid-beta protein levels in the brain are indicated and / or confirmed by measuring p-tau181 levels. In some embodiments, elevated or positive amyloid-beta protein levels in the brain are indicated and / or confirmed by MRI assessment.In some embodiments, retinal amyloid accumulation indicates elevated or positive amyloid load in the brain. In some embodiments, more than one assessment method is used.

[0315] "Amyloid" refers to unbranched fibrous tissue, typically extracellular and present in the body; additionally, the fibrous tissue binds to the dye Congo red and then exhibits green birefringence when observed between orthogonal polarizers. Amyloid-forming proteins have been identified and associated with serious diseases, including amyloid β-peptide (Aβ) associated with Alzheimer's disease (AD), islet amyloid polypeptide (IAPP) associated with type 2 diabetes, and prion protein (PrP) associated with spongiform encephalopathy. As used herein, "amyloid," "brain amyloid," and "amyloid β-peptide (Aβ)" are used interchangeably. Aβ exists in a variety of conformational states: monomers, oligomers (e.g., different forms of Aβ oligomers, such as dimers, trimers, tetramers, pentamers, hexamers, nonamers, and dodecamers), paranuclei (e.g., partially folded monomers forming nuclei for fibrillary elongation), primary fibrils (e.g., soluble, profibrillary intermediates), and insoluble fibrils (plaques). When Aβ monomers aggregate into insoluble fibrils, primary fibrils are formed as intermediate substances, and various soluble primary fibrils are associated with the pathogenesis of AD (Hampel et al., Mol Psychiatry, 2021: 26, 5481-550).

[0316] Aβ peptides typically exist in a dynamic and continuous conformational state, which means that species often evolve from monomeric Aβ into soluble Aβ aggregates. These aggregates range from low molecular weight oligomers to higher molecular weight protofibrils, and eventually develop into insoluble protofibrils (plaques).

[0317] In some embodiments, subjects have “elevated amyloid” or “moderate amyloid.” Those skilled in the art will recognize that amyloid levels from amyloid PET can be reported in “percentage units” (CL) using a percentage unit method. (Klunk WE et al., The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer's Dement. 2015; 11:1-15 e1-4). The percentage unit method measures tracers in the range of 0 CL to 100 CL, where 0 is considered the anchor point and represents the mean of young, healthy controls, and 100 CL represents the mean amyloid load present in subjects with mild to moderate severity of dementia due to AD. (Ibid.) As those skilled in the art will recognize, percentage unit thresholds can be varied, for example, improved based on new or additional scientific information. (See, for example, http: / / www.gaain.org / centiloid-project.) Elevated amyloid levels can be set relative to a baseline threshold in healthy controls determined according to methods known to those skilled in the art (POSA). For example, a percentage value of 32.5 can be used as the threshold for “elevated amyloid,” and a “moderate amyloid” level refers to Aβ amyloid PET in the range of 20–32.5 CL (e.g., 30 CL). In another example, a percentage value of 40 can be used as the threshold for “elevated amyloid,” and a “moderate amyloid” level refers to Aβ amyloid PET in the range of 20–40 CL.

[0318] Tau protein refers to tau protein, which belongs to the microtubule-associated protein (MAP) family and is primarily expressed in neurons and found in axons and dendrites. Tau protein plays a crucial role in the assembly of tubulin monomers into microtubules, which form the cytoskeleton and act as pathways for axonal transport. Tau protein is translated from a single gene located on chromosome 17, and through selective mRNA splicing, it forms six distinct tau isoforms in the central nervous system, five of which are found in the adult human brain. These isoforms differ in that they possess either three (R1, R3, and R4) or four (R1-R4) repeat regions in the C-terminal region, and the incidence of the microtubule-binding region (MTBR) is variable. The N-terminal amino-terminal domain, which establishes connections between microtubules and other parts of the cytoskeleton or the plasma membrane, has a variable incidence of 0, 1, or 2 inserts of 29 amino acids.

[0319] “Tau pathology” refers to the pathological forms of tau, such as intracellular fibrillary tangles and their components, described in Alzheimer’s disease (AD) and other neurodegenerative disorders as tau lesions. Hyperphosphorylated tau aggregates into insoluble paired helical filaments (PHFs), which accumulate in neurons to form neurofibrillary tangles (NFTs), a hallmark of tau pathology. In AD, NFTs occur with an increasing pattern of neuroanatomical features, typically defined according to Braak stages 1 through 6, closely associated with progressive neuronal loss and clinical decline. Extracellular tau seeds are also a pathological form of tau. Some tau seeds contain tau MTBRs.

[0320] As used in this article, participants with “mild Alzheimer’s dementia” or “mild AD dementia” were those who met the following National Institute on Aging and Alzheimer’s Association (NIA-AA) core clinical guidelines for possible Alzheimer’s dementia: McKhann, GM et al., “The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging - Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” Alzheimer Dement. [Alzheimer’s Disease and Dementia] 2011; 7:263-9. This study also included subjects with a CDR score of 0.5 to 1.0 and a memory frame score of 0.5 or higher at screening and baseline, as well as subjects who showed changes in their scores on the Wechsler Memory Scale-Modified Logical Memory Subscale II (WMS-R LM II).

[0321] As used in this article, subjects with “AD-related MCI – Moderate Probability” were identified according to the NIA-AA Core Clinical Criteria for Mild Cognitive Impairment of Alzheimer’s Disease – Moderate Probability (see McKhann, above). For example, subjects could be symptomatic but not demented, with amyloid pathology that resulted in lower heterogeneity from subjects with mild Alzheimer’s disease dementia and similarity in cognitive and functional decline, as measured by the ADCOMS Composite Clinical Scale as defined in this article. Subjects with a CDR score of 0.5 and a memory frame score of 0.5 or higher at screening and baseline were also included. Furthermore, subjects with a history of subjective memory decline and gradual onset and slow progression within the most recent year prior to screening, as confirmed by informed witnesses, were also included in this article. Memory decline and / or episodic memory impairment could be assessed by changes in scores on the Wechsler Memory Scale – Modified Logical Memory Subscale II (WMS-R LM II).

[0322] As used herein, “control subject,” “untreated AD subject,” or “untreated control subject” refers to a subject who has not received or has received treatment for Alzheimer’s disease. In some embodiments, the control subject has Alzheimer’s disease. In some embodiments, the control subject has early Alzheimer’s disease or pre-Alzheimer’s disease. In some embodiments, the control subject has Alzheimer’s disease and has not been treated with anti-Aβ proficiency antibodies.

[0323] The terms "patient" and "subject" are used interchangeably.

[0324] As used herein, “MMSE” refers to the Mini-Mental State Examination, a cognitive tool commonly used for screening purposes and also frequently used longitudinally in AD clinical trials. It has a 30-point scale where higher scores indicate lower levels of impairment and lower scores indicate higher levels of impairment, ranging from 0 (highest level of impairment) to 30 (no impairment). In some embodiments, seven items measuring time and place orientation, registration, recall, attention, language, and drawing may be assessed as part of the MMSE score. (Folstein, MF et al., “Mini-mental state. A practical method for grading the cognitive state of patients for the clinician.” J Psychiatr. Res. 1975; 12:189-98.) As used in this article, "ADAS-Cog" refers to the Alzheimer's Disease Assessment Scale-Cognitive. ADAS-Cog is a commonly used cognitive scale in Alzheimer's disease trials. It is a structural scale that evaluates memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming and comprehension), orientation, conceptual practice (placing a letter in an envelope), and constructive practice (copying geometric designs). (Rosen, WG et al., "A new rating scale for Alzheimer's disease." Am. J. Psychiatry 1984; 141:1356-64.) It can also obtain ratings for spoken language, language comprehension, difficulty in recalling words, ability to remember test instructions, maze and number cancellation. In some embodiments, ADAS-Cog refers to the Alzheimer's Disease Assessment Scale-Cognitive subscale. 14 (ADAS-Cog14). In some embodiments, a modified form may be used herein, and the scoring is from 0 to 90 points, where 0 indicates no impairment and 90 indicates the highest degree of impairment. In some embodiments, the ADAS-Cog14 task includes memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, conceptual practice (placing a letter in an envelope), construction practice (copying geometric designs), spoken language, language comprehension, difficulty recalling words, ability to remember test instructions, mazes, and number cancellation (Rosen et al., 1984).

[0325] As used in this article, “CDR-SB” refers to the Clinical Dementia Rating-Sum of Boxes. The CDR is a clinical scale that describes five degrees of impairment in performance across six functional categories: memory, orientation, judgment and problem-solving, group activities, family and hobbies, and personal care. (Berg, L. et al., “Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment.” Ann. Neurol. 1988; 23:477-84.) The sum of the box scores provides a measure of variability, with each category having a maximum possible score of 3 points, and the total score being the sum of the scores for each category, resulting in a total possible score from 0 to 18, where a higher score indicates a higher degree of impairment.

[0326] As used herein, the “CDR Total,” “Total CDR” score, and “Total Dementia Assessment CDR” score are used interchangeably. As used herein, the Total CDR score is an assessment of the degree of impairment obtained in each of the six functional categories of the six categories of the CDR scale, and is synthesized into a single total rating (range 0 to 3) for the Dementia CDR score, where 0 represents no cognitive impairment, 0.5 represents mild cognitive impairment, and 1–3 represent mild, moderate, and severe dementia, respectively. The Total CDR score can be used as a clinical measure of the severity of dementia. In some embodiments, the Total CDR score can be used to determine whether a patient has progressed or maintained a stage of Alzheimer's disease (AD), for example, a higher score on subsequent evaluations indicates AD progression, while no change in the score indicates no AD progression.

[0327] As used in this article, “ADCOMS” refers to the Alzheimer’s Disease Composite Scale, a composite clinical score based on four ADAS-Cog items (delayed word recall, orientation, word recognition, and difficulty in calling words), two Mini-Mental State Examination (MMSE) items (time orientation and drawing), and all six CDR-SB items (personal care, group affairs, family and hobbies, memory, orientation, and judgment and problem-solving), as seen in the example and Wang, J. et al., “ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials.” J Neurol. Neurosurg. Psychiatry. 2016; 87:993-999. ADCOMS was developed to be particularly sensitive to disease progression during the early stages of AD (i.e., prodromal AD or early AD).

[0328] In some embodiments, ADCOMS can be calculated using the following formula: in , and These are the item scores at time t corresponding to items from ADAS-cog, the reverse MMSE score, and CDR-SB, respectively (Wang, J. et al., “ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials”). ADCOMS is particularly sensitive to disease progression in the early stages of AD, i.e., during prodromal and mild AD.

[0329] As used in this article, “ADCS MCI-ADL” refers to the Alzheimer’s Disease Collaborative Study – Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL). The ADCS MCI-ADL is a clinical scale used to assess a patient’s ability level in six basic activities of daily living. Further examples are discussed in Kreutzer JS, DeLuca J., Caplan B. (eds.) Encyclopedia of Clinical Neuropsychology, Springer, New York, NY.

[0330] As used in this article, "modified iADRS" or "iADRS" refers to a composite tool that combines scores from ADAS Cog14 (all items) and ADCS MCI-ADL (all items). The modified iADRS score can be used to assess disease progression. Improved iADRS score = [-1(ADAS-cog14) +90] + ADCS MCI-ADL.

[0331] As used herein, “ApoE4 positive” subjects and “ApoE4 carriers” refer to subjects who possess the ε4 variant of the apolipoprotein E (APOE) gene. The ε4 variant is one of several major alleles of the apolipoprotein gene, which is generally responsible for lipid metabolism. It has been found that carriers of apolipoprotein E4 exhibit significantly higher amyloid retention rates compared to non-carriers. (Drzezga, A. et al., “Effect of APOE genotype on amyloid plaqueload and gray matter volume in Alzheimer disease.” Neurology. 2009; 72:1487-94.) In some embodiments, the subjects treated herein were alloconjugated carriers of the apolipoprotein E ε4 gene allele. In some embodiments, the subjects were alloconjugated carriers of the apolipoprotein E ε4 gene allele. The terms “ApoE4 negative” and “ApoE4 non-carrier” are used interchangeably.

[0332] As used herein, whether an early AD subject is “amyloid-positive” or “amyloid-negative” can be determined based on whether the subject has a positive amyloid load. In some embodiments, a subject is identified as amyloid-positive or amyloid-negative as indicated by longitudinal positron emission tomography (PET) assessment of an imaging agent (e.g., an amyloid imaging agent or a tau imaging agent) taken up in the brain. In some embodiments, an evaluation by tau PET imaging assessment determines whether a subject is amyloid-positive or amyloid-negative. In some embodiments, a subject is “amyloid-negative” if PETSUVr negativity is below a threshold determined for an amyloid PET tracer. In some embodiments, the amyloid PET tracer may be flubetabenzene (e.g., 18F-flubetabenzene (Neuraceq®)), flubetapyr (e.g., 18F-flubetapyr (Amyvid®)), and / or flumetaphen (e.g., 18F-flumetaphen (Vizamyl®)). In some embodiments, the PET SUVr threshold for the amyloid PET tracer is about 1.17, and measurements below this threshold indicate that the subject is “amyloid negative.” In some embodiments, the PET SUVr threshold for flubetapirid amyloid is about 1.17. In some embodiments, the PET SUVr threshold for flubetabenzyl amyloid is about 1.17. In some embodiments, the PET SUVr threshold for flumetafol amyloid is about 1.17. In some embodiments, a subject is determined to be amyloid positive or amyloid negative by evaluating the level of a biomarker (e.g., the Aβ42 / 40 ratio) in a sample from the subject, either alone or in combination with another method, such as a PET measurement of brain amyloid. In some embodiments, a subject is “amyloid negative” if the Aβ42 / 40 ratio in the sample is at or above 0.092–0.094, for example, at about 0.092. In some embodiments, a subject is “amyloid negative” if the Aβ42 / 40 ratio in the sample is above 0.092. In some embodiments, the presence of amyloid pathology is assessed by CSF evaluation using markers such as p-tau181, alone or in combination with another method, such as PET measurement of brain amyloid, to determine whether a subject is amyloid-positive or amyloid-negative. In some embodiments, qualitative visual readings from PET scans can be used to determine amyloid positivity and negativity by categorizing subjects based on PET image patterns as having “normal” or “abnormal” uptake. The reader will be trained and calibrated to identify brain PET images with abnormal or normal uptake patterns, or amyloid will be detected using semi-quantitative or quantitative methods.In some embodiments, a threshold is set to quantitatively determine whether Aβ brain load indicates a subject is amyloid-positive or amyloid-negative from biomarkers (e.g., serum or CSF) and / or PET scans. In some embodiments, an imaging method is used to determine whether a subject is amyloid-positive or amyloid-negative. Imaging methods can be used to determine, calculate, or predict whether a subject is amyloid-positive or amyloid-negative, even when the imaging method is not used to directly visualize amyloid. In some embodiments, the method uses MRI, and / or a combination of MRI and other imaging modalities such as PET. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by retinal amyloid accumulation. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by behavioral / cognitive phenotype.

[0333] As those skilled in the art will understand, digital, computer, and / or conventional (e.g., pen and paper) cognitive tests can be used to detect early cognitive changes that may indicate mild cognitive impairment and / or the risk of developing dementia, and therefore can be used to identify subjects who require treatments as disclosed herein. For example, such tests can screen for cognitive impairment and can potentially identify individuals with MCI. Artificial intelligence can be used to analyze cognitive test results to determine whether a case of mild cognitive impairment will progress to Alzheimer's disease within a year. Early diagnosis of symptoms before they begin can help physicians identify subjects who require treatments as disclosed herein earlier, potentially delaying the onset of neurodegenerative diseases or reducing their severity.

[0334] As used herein, the term "treatment" means any administration or application of a therapeutic agent for a subject's disease or disorder, and includes suppressing the disease, slowing disease progression, delaying progression, preventing its development, reversing disease progression (e.g., reversing the accumulation of Aβ fibrils), preventing the onset or development of the disease, alleviating or improving one or more symptoms or underlying conditions of the disease, curing the disease, improving one or more clinical indicators, or preventing the recurrence of one or more symptoms of the disease. In some embodiments, treatment of a subject's AD includes administration, for example, intravenous infusion of an anti-amyloid β (Aβ) primary fibrils antibody. In some embodiments, treatment of a subject's AD includes administration (e.g., intravenous infusion) of a therapeutically effective dose of an anti-amyloid β (Aβ) primary fibrils antibody.

[0335] As used herein, the term "infusion" refers to the active administration of one or more agents over a period of, for example, approximately 60 minutes. In some embodiments, the anti-amyloid β (Aβ) profibrillary antibody described herein is administered systemically to a human subject via infusion. In some embodiments, the anti-amyloid β (Aβ) profibrillary antibody is alternatively administered to a human subject, for example, via subcutaneous injection. In some embodiments, the subcutaneous injection is given once weekly. In some embodiments, the subcutaneous injection is given once every two weeks. In some embodiments, the anti-amyloid β (Aβ) profibrillary antibody is administered to a human subject via intravenous infusion.

[0336] In some embodiments, a maintenance dose is administered to the subject. As used herein, the term "maintenance dose" refers to the dose administered to the subject to maintain the desired therapeutic effect. In some embodiments, the maintenance dose is administered weekly, bi-weekly, monthly, bi-monthly, or bi-monthly (quarterly) or every 24 weeks (six-monthly or semi-annually). In some embodiments, the maintenance dose comprises anti-Aβ protofibrillary antibody. In some embodiments, the maintenance dose is administered as an intravenous infusion. In some embodiments, the intravenous infusion is a monthly dose of 10 mg / kg of lencanezumab. In some embodiments, the maintenance dose is administered subcutaneously, orally, or nasally. In some embodiments, the maintenance dose is administered subcutaneously.

[0337] In some embodiments, the maintenance dose is administered as a subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a bi-weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a monthly subcutaneous injection. In some embodiments, the maintenance dose is administered as a quarterly subcutaneous injection. In some embodiments, the maintenance dose is administered weekly or at a less frequent frequency, such as every two weeks, every four weeks, monthly, every six weeks, every eight weeks (2 months), every three months (quarterly), or every six months (half-yearly). In some embodiments, the maintenance dose is administered as a 500 mg, 360 mg, or 250 mg subcutaneous injection every two weeks. In some embodiments, the maintenance dose is administered as a 500 mg subcutaneous injection every two weeks, comprising two simultaneous (e.g., sequential) injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, the subcutaneous dose is administered as a single injection of 360 mg (e.g., 1 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, a 250 mg subcutaneous dose is administered as a single injection of 250 mg (e.g., 400 mg / 2 mL of 1 x 1.25 mL) of subcutaneous preparation. In some embodiments, the subcutaneous dose is administered via a vial-syringe method or via an autoinjector (AI). In some embodiments, a 500 mg, 360 mg, or 250 mg subcutaneous dose is administered using an autoinjector.

[0338] In some embodiments, the maintenance dose is administered once or multiple times. In some embodiments, the maintenance dose is administered at a lower dose than during an earlier treatment process, and / or at a lower frequency than during an earlier treatment process.

[0339] In some embodiments, after switching to a maintenance dose, the subject's biomarker levels may indicate an increase in amyloid levels in the brain. In some embodiments, after switching to a maintenance dose, the subject's biomarker levels may begin to deteriorate, such as an increase in the plasma Aβ42 / 40 ratio, indicating an increase in amyloid levels in the brain. In some embodiments, the Aβ42 / 40 ratio of subjects receiving a maintenance dose may decrease. In some embodiments, subjects receive a selected maintenance dose such that the subject's Aβ42 / 40 ratio may decrease, but the Aβ42 / 40 ratio may remain above an amyloid positivity threshold, for example, for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0340] In some embodiments, upon conversion to a maintenance dose, the levels of a subject's biomarker (e.g., MTBR-tau243 from a biological fluid sample (e.g., CSF or blood)) may increase. In some embodiments, upon conversion to a maintenance dose, the subject's biomarker levels may begin to deteriorate, such as an increase in MTBR-tau243 in CSF. In some embodiments, the subject receives a selected maintenance dose such that the subject's MTBR-tau243 concentration may decrease and be maintained at a level comparable to that of a healthy control for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0341] In some embodiments, after switching to a maintenance dose, a subject's biomarker levels (e.g., MTBR-tau243 concentration or tau PET level) may begin to increase or the rate of increase may increase. In some embodiments, such subjects may be transferred back to a treatment regimen. In some embodiments, for example, if the increase remains below the tau PET level or the rate of increase observed in control subjects with AD but not receiving anti-Aβ proficiency antibodies, the subject may maintain the maintenance dose.

[0342] As used herein, the term “prevention” means obtaining a favorable or desired outcome, including but not limited to preventive benefits. For preventive benefits, the composition may be administered to subjects at risk of developing Alzheimer’s disease; to subjects with one or more preclinical symptoms that are not clinical symptoms of Alzheimer’s disease; or to subjects reported to have one or more physical symptoms of Alzheimer’s disease, even though a clinical diagnosis of Alzheimer’s disease has not been performed. As used herein, “prevention” may further include therapeutic benefits, meaning the eradication or improvement of the latent condition being treated or one or more associated physical symptoms.

[0343] As used herein, the term “ARIA” refers to amyloid-associated imaging abnormality, such as that evaluated using MRI. In some embodiments, ARIA includes amyloid-associated imaging abnormality edema / effusion (ARIA-E). In some embodiments, ARIA includes amyloid-associated imaging abnormality hemorrhage (ARIA-H). In some embodiments, subjects with ARIA experience headache, confusion, and / or seizures, and these can be used to identify subjects with ARIA or to indicate further evaluation for ARIA. In some embodiments, ARIA is evaluated at specified intervals during treatment. In some embodiments, ARIA is evaluated when a subject experiences symptoms of ARIA. In some embodiments, the maximum serum concentration (Cmax) of anti-Aβ primary fibrillary antibody can be used as a predictor of ARIA-E risk. In some embodiments, the use of subcutaneous preparations reduces the risk of ARIA-E compared to IV administration (e.g., due to lower Cmax).

[0344] As used herein, the term “clinical decline” refers to a worsening of one or more clinical symptoms of AD. Methods for measuring clinical decline may employ the tests and assays specified herein. In some embodiments, clinical decline is determined by a worsening of ADCOMS. In some embodiments, clinical decline is determined by a worsening of MMSE. In some embodiments, clinical decline is determined by a worsening of ADAS-Cog. In some embodiments, clinical decline is determined by a worsening of FAQ. In some embodiments, clinical decline is determined by a worsening of CDR-SB. In some embodiments, clinical decline is determined by a worsening of Wechsler Memory Scale-IV Logical Memory (subscale) I and / or (subscale) II. In some embodiments, clinical decline is determined by a worsening of CDR score. In some embodiments, clinical decline refers to a worsening of one or more biomarkers of AD or brain measurements such as brain atrophy and / or amyloid accumulation (e.g., by PET or MRI).

[0345] As used herein, the term "blood sample" or "blood" refers to a sample of blood, including serum and / or plasma from human subjects. In some embodiments, blood will be collected from subjects to assess potential biomarkers for AD, which may include amyloid fragments and isotypes, tau, and other protein biomarkers (e.g., antimicrobial peptides, neurofilament light chains, or NfL) associated with AD diagnosis, amyloid or tau burden, or disease alterations. In some embodiments, subjects are required to fast before collection at weeks 96 and 216, if possible. In other embodiments and / or at other time points, fasting is not required. Levels of pre-AD biomarkers that may indicate the development of Alzheimer's disease include, but are not limited to, brain amyloid levels, cerebrospinal fluid Aβ1-42 levels, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranulin levels, and cerebrospinal fluid neurofilament light chain (NfL) levels.

[0346] sequence list Table 1. Amino acid sequences of monoclonal antibody (mAb) CDRs Table 2. Amino acid sequence of the mAb variable region Table 3. Amino acid sequences of mAb heavy and light chains Table 4. Amino acid sequence of the mAb constant region Table 5. Amino acid sequence of amyloid-β Table 6. Amino acid sequence of E2814 CDR Table 7. Amino acid sequence of the E2814 variable region Table 8. Amino acid sequence of the E2814 constant region Table 9. Amino acid sequence of Tau Table 10. Antimicrobial peptides This disclosure is further illustrated by the following examples, which should not be construed as restrictive. All references, patents, and published patent applications cited throughout this application, as well as the accompanying drawings, are incorporated herein by reference in their entirety for all purposes.

[0347] Example Example 1: Identification of antimicrobial peptides (AMP) Figure 1 shows the cohort demographics ( Figure 1A ) and cohort study methods ( Figure 1B CSF data were obtained from patients recruited from several memory clinics in western Sweden. All subjects had cognitive impairment. Mass spectrometry (MS) data obtained from the publicly available study (PRIDE archive PXD016278; Bader et al., Mol Syst Biol [Molecular Systems Biology], 2020;16(6):e9356) were used to compare peptides in CSF from subjects with cognitive impairment Aβ+ (AD) and Aβ- (non-AD) individuals. AD subjects were classified according to t-tau levels above 400 ng / L, Aβ1-42 levels below 550 ng / L, and an Aβ1-42 / Aβ1-40 ratio below 0.065. For patients classified as AD, at least one of the t-tau and Aβ criteria had to be met.

[0348] Analyze MS files using a new platform that integrates a de novo workflow. de novoA workflow based on AMP sequences and a custom human protein database were used to identify antimicrobial peptides in CSF samples. Non-trypsin peptides, hemitrypsin peptides, and complete trypsin peptides were selected. When AMPs are generated, they may not be complete trypsin peptides (e.g., the K and R amino acids are located at their ends, due to trypsin cleavage sites). Therefore, the strategy of selecting non-trypsin peptides and hemitrypsin peptides allows for the selection of different peptides, including those that do not have the K and R amino acids at the ends.

[0349] Figure 2 The procedure for obtaining 24 AMPs is shown. Starting with 39,447 peptides from de novo analysis, peptides mapped to the contaminant database were removed. From the remaining 36,409 peptides, non-AMP peptides were removed, leaving 815 AMPs. Peptides missing more than 75% of the data were excluded, leaving 547 AMPs. Peptides with zero variation were removed, leaving 485 AMPs. PTM adjustment was performed, leaving 320 AMPs. Of these, 24 AMPs were significant at q < 0.2. The sequences of the 24 AMPs, along with the fold change, p-value, Cohen's D value, and q-value for each AMP, are listed in Table 10. UniProt ID refers to the protein to which the peptide is mapped (e.g., the protein that produces the peptide), and AMP_ID refers to the ID number in the public AMP databases (dbAMP, https: / / awi.cuhk.edu.cn / dbAMP / , and UDAMP, https: / / aps.unmc.edu / ).

[0350] The original peak area intensity of the peptide was normalized by quantiles and transformed by log2 to reduce technical differences and ensure distribution symmetry.

[0351] After adjusting for age and sex, differentially expressed peptides were identified by analysis of covariance, with a significance criterion set at a false discovery rate of 20%.

[0352] Figure 3 This is a volcano plot of 320 CSF peptides used in subjects with cognitive impairment. 24 / 320 CSF AMP peptides were differentially regulated in subjects compared with Aβ+ (AD) versus Aβ- (non-AD) (q<0.2).

[0353] Figure 4 A heatmap showing 24 significant changes in AMP (q<0.2) in Aβ+ (AD) and Aβ- (non-AD) dementia subjects is presented.

[0354] Figure 5 shows the clustering proteins in CSF from Aβ-driven dementia ( Figure 5A ) and chromogranin A ( Figure 5B Box plot showing increased expression of antimicrobial peptides in proteins.

[0355] Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) was used to identify AMPs with the potential to regulate molecular changes in Alzheimer's disease (AD).

[0356] Figure 6 shows a MEGENA data-driven peptide co-expression network consisting of 642 modules. Figure 6A CMGA peptides represent a pivotal point in the C1_16 and C1_179 modules and exhibit a high correlation with the dementia-associated neurosecretory protein VGF. Figure 6B Genetic ontology analysis of the c1_16 module protein revealed enrichment in many neurodegenerative pathways. Figure 6C The most enriched pathways in module c1_16 are cell adhesion, phylogenetic development, nervous system development, regulation of nervous system development, and neurogenesis.

Claims

1. A method for selecting subjects to undergo treatment with Alzheimer's disease (AD) therapy, the method comprising: a) Obtain a measurement of the level of at least one antimicrobial peptide (AMP) in a biofluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is selected from any of those listed in Table 10; and b) If the level of at least one AMP is altered compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), then the subject is selected for treatment. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

2. A method for selecting subjects to undergo treatment with AD therapy, the method comprising: a) Obtain a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC). b) If the level of at least one AMP is altered compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), then the subject is selected for treatment. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

3. The method of claim 2, wherein the AMP is a peptide listed in Table 10.

4. The method of any one of claims 1-3, wherein the subject has Alzheimer's disease (AD), is suspected of having Alzheimer's disease, or is at risk of developing Alzheimer's disease.

5. The method of claim 4, wherein the subject has early AD or mild to moderate AD.

6. The method of any one of claims 1-5, wherein if the AMP level from the subject increases compared to the control, the subject is selected for treatment.

7. The method of any one of claims 1-5, wherein the subject is selected for treatment if the AMP level from the subject is reduced compared to the control.

8. A method for monitoring the efficacy of treatment in a subject receiving an AD therapy comprising a therapeutically effective dose, the method comprising: a) Prior to the treatment, a measurement of the first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) During or after the treatment, obtain a measurement of the second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; as well as c) Compare the first AMP level with the second AMP level, wherein the change in the second AMP level compared to the first AMP level is an indicator of therapeutic efficacy. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

9. A method for monitoring the efficacy of treatment in a subject receiving an AD therapy comprising a therapeutically effective dose, the method comprising: a) Prior to the treatment, a measurement of the first AMP level is obtained from a first biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC). b) During or after the treatment, obtain a measurement of the second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; as well as c) Compare the first AMP level with the second AMP level, wherein the change in the second AMP level compared to the first AMP level is an indicator of therapeutic efficacy. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

10. The method of claim 9, wherein the AMP is a peptide listed in Table 10.

11. The method of any one of claims 8-10, wherein a decrease in the second AMP level compared to the first AMP level indicates therapeutic efficacy.

12. The method of any one of claims 8-10, wherein the decrease in the second AMP level compared to the first AMP level does not indicate treatment ineffectiveness.

13. The method of claim 3, wherein a decrease in the second AMP level compared to the first AMP level indicates ineffective treatment.

14. The method of claim 3, wherein the second AMP level does not indicate therapeutic efficacy compared to the first AMP level.

15. A method for adjusting the treatment regimen in a subject receiving treatment comprising a therapeutically effective dose of AD therapy, the method comprising: a) Obtain a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) Compare the level of at least one AMP with the AMP level concentration in a control sample, such as an individual without Alzheimer's disease (AD); as well as c) If the level of at least one AMP differs from that in a control sample, for example, from the AMP level in an individual without Alzheimer's disease (AD), the treatment regimen may be adjusted, for example, by changing the dose, frequency, and / or route of administration of the anti-Aβ primary fibrillary antibody. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

16. A method for adjusting the treatment regimen in a subject receiving AD therapy, comprising: a) Obtain a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC). b) Compare the level of at least one AMP with the AMP level concentration in a control sample, such as an individual without Alzheimer's disease (AD); as well as c) If the level of at least one AMP differs from that in a control sample, for example, from the AMP level in an individual without Alzheimer's disease (AD), the treatment regimen may be adjusted, for example, by changing the dose, frequency, and / or route of administration of the anti-Aβ primary fibrillary antibody. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

17. The method of claim 16, wherein the AMP is a peptide listed in Table 10.

18. The method of any one of claims 15-17, wherein if the AMP level is higher than the control, the treatment regimen is adjusted.

19. The method of any one of claims 15-17, wherein if the AMP level is lower than the control, the treatment regimen is adjusted.

20. A method for detecting a decrease in brain Aβ levels in a subject receiving treatment comprising a therapeutically effective dose of AD therapy, the method comprising: a) Prior to the treatment, a measurement of the first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) During or after the treatment, obtain a measurement of the second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; as well as c) Compare the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject; Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab).

21. A method for detecting a decrease in brain Aβ levels in a subject receiving treatment including a therapeutically effective dose of AD therapy, the method comprising: a) Prior to the treatment, a measurement of the first AMP level is obtained from a first biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC). b) During or after the treatment, obtain a measurement of the second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; as well as c) Compare the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject; Optionally, the AD therapy described therein is an anti-Aβ primary fibrillary antibody.

22. The method of claim 21, wherein the AMP is a peptide listed in Table 10.

23. The method of any one of claims 20-22, wherein a decrease in AMP levels in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject.

24. The method of any one of claims 20-22, wherein an increase in AMP levels in the second sample relative to the first sample indicates a decrease in brain Aβ levels in the subject.

25. A method for detecting a reduction in brain tau levels (e.g., a reduction in tau tangles) in a subject receiving treatment comprising a therapeutically effective dose of AD therapy, said method comprising: a) Prior to the treatment, a measurement of the first AMP level in a first biofluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) During or after the treatment, obtain a measurement of the second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; as well as c) Compare the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject; Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

26. A method for detecting a reduction in brain tau levels (e.g., a reduction in tau tangles) in a subject receiving treatment comprising a therapeutically effective dose of AD therapy, said method comprising: a) Prior to the treatment, a measurement of the first AMP level is obtained from a first biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC). b) During or after the treatment, obtain a measurement of the second AMP level in a second biofluid sample, such as CSF or a blood sample, from the subject; as well as c) Compare the first AMP level and the second AMP level, wherein a change in the AMP level in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject; Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

27. The method of claim 26, wherein the AMP is a peptide listed in Table 10.

28. The method of any one of claims 25-27, wherein a decrease in AMP levels in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject.

29. The method of any one of claims 25-27, wherein an increase in AMP levels in the second sample relative to the first sample indicates a decrease in brain tau levels in the subject.

30. The method of any one of claims 25-29, wherein the reduction in brain tau levels is a reduction in tau tangles.

31. A method for reducing tau tangles in subjects with Alzheimer's disease (AD), suspected Alzheimer's disease, or at risk of developing Alzheimer's disease, the method comprising: a) Obtain a measurement of the first AMP level in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; b) If the first AMP level is elevated compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), then the subject is given treatment comprising a therapeutically effective dose of anti-tau proficiency antibody; and c) Obtain a measurement of a second AMP level in the biofluid sample, wherein the change in the second AMP level compared to the first AMP level indicates a reduction in tau entanglement. Optionally, the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

32. A method for reducing tau tangles in subjects who have Alzheimer's disease (AD), are suspected of having Alzheimer's disease, or are at risk of developing Alzheimer's disease, the method comprising: a) Obtain a measurement of the first AMP level in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC). b) If the first AMP level is elevated compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), then the subject is given treatment comprising a therapeutically effective dose of anti-tau proficiency antibody; and c) Obtain a measurement of a second AMP level in the biofluid sample, wherein the change in the second AMP level compared to the first AMP level indicates a reduction in tau entanglement. Optionally, the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

33. A method for treating a subject with Alzheimer's disease (AD), suspected of having Alzheimer's disease, or at risk of developing Alzheimer's disease, the method comprising: a) Obtain a measurement of the level of at least one AMP in a biological fluid sample, such as CSF or a blood sample, from the subject, wherein the AMP is selected from any of those listed in Table 10; as well as b) If the level of at least one AMP is altered compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), then the subject is given treatment comprising a therapeutically effective dose of an AD therapy. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

34. A method for treating a subject with Alzheimer's disease (AD), suspected of having Alzheimer's disease, or at risk of developing Alzheimer's disease, the method comprising: a) Obtain a measurement of the level of at least one AMP in a biofluid sample, such as CSF, or a blood sample from the subject, wherein the AMP is a peptide of a human protein selected from amyloid-β precursor protein (A4), β-2-microglobulin (B2MG), cluster protein (CLUS), chromogranin-A (CMGA), secretory granulin-1 (SCG1), ubiquitin-ribosomal protein eL40 fusion protein (RL40), ubiquitin-40S ribosomal protein S27A, polyubiquitin-B (UBB), and polyubiquitin-C (UBC); and b) If the level of at least one AMP is altered compared to a control sample, for example, compared to AMP levels in individuals without Alzheimer's disease (AD), then the subject is given treatment comprising a therapeutically effective dose of an AD therapy. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

35. The method of claim 34, wherein the AMP is a peptide listed in Table 10.

36. The method of any one of claims 33-35, wherein the AD therapy is administered if the AMP level increases compared to the control sample.

37. The method of any one of claims 33-35, wherein the AD therapy is administered if the AMP level is reduced compared to the control sample.

38. The method of any one of claims 33-37, further comprising: a) Obtain additional measurements of the level of at least one AMP (e.g., additional AMP levels) in a second biological fluid sample, such as CSF or a blood sample, from the subject; b) Determine that the additional AMP level has changed relative to the level of the at least one AMP obtained prior to the administration of the AD therapy; and c) Administer an additional therapeutically effective dose of the AD therapy to the subject. Optionally, the AD therapy described therein is an anti-Aβ protofibrillary antibody (e.g., lencanezumab) or an anti-tau antibody (e.g., E2814).

39. The method of claim 38, wherein the additional therapeutically effective dose is administered according to a maintenance dosing regimen.

40. The method of any one of claims 1-38, wherein the treatment comprises administering a therapeutically effective dose of the AD therapy according to an initial dosing regimen, optionally thereafter switching the subject to a maintenance dosing regimen.

41. The method of claim 40, wherein the subject is switched from an initial dosing regimen to a maintenance dosing regimen when an additional measurement of AMP levels in another biological fluid sample, such as CSF or blood sample, from the subject differs from a threshold, such as the level observed in a control sample from an individual without AD.

42. The method of claim 41, wherein the subject is converted when the AMP level is below the threshold.

43. The method of claim 41, wherein the subject is converted when the AMP level is above the threshold.

44. The method of any one of claims 1-43, wherein the AMP level is quantified by LC / MS.

45. The method of any one of claims 1-44, wherein the biofluid sample is CSF.

46. ​​The method of any one of claims 1-45, wherein the subject exhibits changes and / or differences in measurements of one or more additional biomarkers associated with AD pathology prior to treatment.

47. The method of claim 46, wherein the variation and / or difference of the measured value is selected from: a) Increased amyloid protein in the brain, for example, as measured by amyloid PET (e.g., a percentage measure of approximately 20-40, or approximately 20-32). b) Increased tau in the brain, for example, as measured by positron emission tomography (PET). c) Decreased levels of the Aβ1-42 / 1-40 ratio in cerebrospinal fluid and / or increased ratios of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranulin and / or neurofilament light chains (NfL), and d) Decreased levels of the Aβ1-42 / 1-40 ratio in serum or plasma and / or increased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

48. The method of any one of claims 1-45, wherein the subject exhibits changes and / or differences in measurements of one or more additional biomarkers associated with AD pathology during and / or after treatment.

49. The method of claim 48, wherein the variation and / or difference of the measured value is selected from: a) Decreased amyloid protein in the brain, for example, as measured by amyloid PET (e.g., a percentage measure of approximately 20-40, or approximately 20-32). b) Decreased tau in the brain, for example, as measured by positron emission tomography (PET). c) Increased levels of the Aβ1-42 / 1-40 ratio in cerebrospinal fluid and / or decreased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranulin and / or neurofilament light chains (NfL), and d) Increased levels of the Aβ1-42 / 1-40 ratio in serum or plasma and / or decreased levels of total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

50. The method of any one of claims 1-49, wherein the treatment a) Delay clinical decline, as determined by ADCOMS; b) Delay clinical decline, as determined by ADAS MCI-ADL; c) Delaying clinical decline, as determined by modified iADRS; d) Delay clinical decline, as determined by CDR-SB; or e) Delay clinical decline, as determined by ADAS-Cog.

51. The method of any one of claims 1-50, wherein the subject has a gene mutation for dominant Alzheimer's disease, for example, wherein the subject has a gene mutation in at least one of three genes—PSEN1, PSEN2, or APP.

52. The method of claim 51, wherein the subject has a mutation in the APP.

53. The method of any one of claims 1-52, wherein the subject has a family history of Alzheimer's disease, for example, a family member was diagnosed with Alzheimer's disease before the age of 60.

54. The method of any one of claims 1-53, wherein the subject is ApoE4 positive.

55. The method of any one of claims 1-54, wherein the subject is 65 to 80 years old.

56. The method of any one of claims 1-55, wherein the subject is 55 to 64 years old and has at least one risk factor selected from: (i) A first-degree relative who was diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Elevated brain amyloid protein levels as measured by PET or cerebrospinal fluid (CSF) prior to the administration.

57. The method of any one of claims 1-56, wherein the subject is amyloid-positive.

58. The method of claim 57, wherein the assessment is based on PET, CSF assessment of Aβ(1-42), CSF assessment of total tau, CSF assessment of phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217 and / or p-tau231), the ratio of phosphorylated tau to non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, MRI, and visual... Retinal amyloid accumulation, and / or assessment of blood biomarkers (e.g., plasma Aβ1-42 / 1-40 ratio, total tau, phosphorylated tau (e.g., p-tau181, p-tau205, p-tau217, and / or p-tau231), phosphorylated tau / non-phosphorylated tau (e.g., tau181 / np-tau181, tau205 / np-tau205, p-tau217 / np-tau217, and / or tau231 / np-tau231) ratio and / or MTBR-tau243, in which the subject is amyloid-positive.

59. The method of any one of claims 1-58, wherein the subject suffers from Alzheimer's disease.

60. The method of any one of claims 1-58, wherein the subject suffers from early Alzheimer's disease.

61. The method of any one of claims 1-560, wherein the subject has been diagnosed with... a) Mild cognitive impairment of Alzheimer's disease - moderate probability and / or already diagnosed with mild Alzheimer's dementia; b) According to the National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical guidelines, mild cognitive impairment of Alzheimer's disease - moderate probability; c) Based on a total CDR score of 0.5 and a memory frame score of 0.5 or higher before treatment, mild cognitive impairment of Alzheimer's disease is of moderate probability. d) Based on, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year prior to treatment, as confirmed by an informed person, mild cognitive impairment of Alzheimer's disease - moderate probability. e) Mild Alzheimer's disease dementia according to the NIA-AA core clinical guidelines for possible Alzheimer's dementia; or f) Mild Alzheimer's dementia based on a CDR score of 0.5 to 1.0 and a memory frame score of 0.5 or higher before treatment.

62. The method of any one of claims 1-56, wherein the subject is suspected of having AD.

63. The method of any one of claims 1-56, wherein the subject is a subject at risk of developing AD.

64. The method of claim 63, wherein the subject at risk of developing AD has pre-AD (early AD).

65. The method of claim 63 or 64, wherein the subject has no cognitive impairment.

66. The method of any one of claims 1-65, wherein the anti-Aβ primary fibrillary antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

67. The method of claim 66, wherein the anti-Aβ protofibrillary antibody is lencanezumab.

68. The method of any one of claims 1-65, wherein the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO:15 (HCDR1), SEQ ID NO:16 (HCDR2), and SEQ ID NO:17 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO:18 (LCDR1), SEQ ID NO:19 (LCDR2), and SEQ ID NO:20 (LCDR3).

69. The method of claim 68, wherein the anti-tau antibody is E2814.

70. The method of any one of claims 1-69, wherein the antimicrobial peptide comprises any one of SEQ ID NO: 27-50.

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