Compositions and methods for treating Alzheimer's disease

Abstract

Provided herein are compositions and methods for improving cognition in individuals with or at risk of developing Alzheimer's disease, including familial Alzheimer's disease, early-onset Alzheimer's disease, and intermediate-to-late stage Alzheimer's disease.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Patent Application No. 63 / 060553, filed on 3 August 2020, which is incorporated herein by reference in its entirety.

[0002] Sequence List This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The above ASCII copy, created on 21 July 2021, has the filename "50014_708_601_sequence_listing.txt" and a size of 14,845 bytes. [Background technology]

[0003] There is an urgent and unmet need to develop effective treatments for Alzheimer's disease, and an urgent and unmet need to maintain cognitive function in individuals who have Alzheimer's disease or are at risk of developing it. [Overview of the Initiative]

[0004] In some embodiments, methods for treating, preventing, or delaying the onset of Alzheimer's disease in subjects who need to be treated, prevented, or have their onset delayed are disclosed herein, the method comprising administering a composition containing ETP69 to the subject, wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 1 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 3 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 4 Alzheimer's disease. In some embodiments, at least one mutation associated with familial Alzheimer's disease includes mutations in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene. In some embodiments, the mutation in the APP gene encodes a mutation in the amino acid sequence of the amyloid precursor protein expressed from the APP gene. In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at valine 717 as described in SEQ ID NO: 1. In some embodiments, valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes mutations at the positions of lysine 670 and methionine 671 as described in SEQ ID NO: 1. In some embodiments, lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670 / 671NL). In some embodiments, mutations in the amyloid precursor protein amino acid sequence include a mutation at glutamate 693 as described in SEQ ID NO: 1. In some embodiments, mutations in the APP gene encode a deletion at the position of glutamate 693 in the amyloid precursor protein amino acid sequence.In some embodiments, glutamic acid 693 of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at threonine 714 as described in SEQ ID NO: 1. In some embodiments, threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at valine 715 as described in SEQ ID NO: 1. In some embodiments, valine 715 of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at isoleucine 716 as described in SEQ ID NO: 1. In some embodiments, isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). In some embodiments, the PSEN-1 gene mutation encodes a mutation in the presenilin-1 amino acid sequence expressed from the PSEN-1 gene. In some embodiments, the presenilin-1 amino acid sequence mutation includes mutations at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 as described in SEQ ID NO: 2. In some embodiments, methionine 146 is mutated to leucine (M146L), leucine 166 is mutated to proline (L166P), isoleucine 213 is mutated to threonine (I213T), arginine 278 is mutated to isoleucine (R278I), and alanine 246 is mutated to glutamate (A246E). In some embodiments, mutations in the PSEN-2 gene encode mutations in the presenilin-2 amino acid sequence expressed from the PSEN-2 gene. In some embodiments, mutations in the presenilin-2 amino acid sequence include mutations at asparagine 141 or methionine 239 as described in SEQ ID NO: 3. In some embodiments, asparagine 141 is mutated to isoleucine, and methionine 239 is mutated to valine.In some embodiments, the genetic risk factors associated with sporadic Alzheimer's disease include the subject being a carrier of the apolipoprotein (APOE)e4 allele. In some embodiments, the genetic risk factors associated with sporadic Alzheimer's disease include gene mutations. In some embodiments, the genes include ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C. In some embodiments, the subject has asymptomatic Alzheimer's disease. In some embodiments, the subjects are under approximately 25 years of age, under approximately 30 years of age, under approximately 35 years of age, under approximately 40 years of age, under approximately 45 years of age, under approximately 50 years of age, under approximately 55 years of age, under approximately 60 years of age, under approximately 65 years of age, or under approximately 70 years of age. In some embodiments, delaying the onset of Alzheimer's disease includes delaying the onset of at least one symptom of Alzheimer's disease. In some embodiments, the delay in the onset of at least one symptom is at least approximately 6 months, approximately 12 months, approximately 18 months, approximately 2 years, approximately 3 years, approximately 5 years, approximately 10 years, approximately 15 years, or approximately 20 years. In some embodiments, the symptoms include memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech impairment, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality. In some embodiments, the method improves the subject's memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech disorders, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality. In some embodiments, the treatment results in improvements in mental state tests and / or neuroimaging tests.In some embodiments, mental state tests include the Mini-Mental State Exam (MMSE), Mini-Cog test, Cantab Mobile test, Cognigram test, Cognivue test, or Cognision test, and Automated Neuropsychological Assessment Metrics (ANAM) tests. In some embodiments, improvement includes an improved score compared to a score obtained before administration of the composition. In some embodiments, neuroimaging tests include magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, improvement includes a reduced amount of β-amyloid deposition compared to the amount of β-amyloid deposition measured before administration of the composition.

[0005] In some embodiments, a method for improving cognition in a subject at risk of developing Alzheimer's disease is disclosed herein, the method comprising administering a composition comprising ETP69 to the subject, wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 1 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 3 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 4 Alzheimer's disease. In some embodiments, the at least one mutation associated with familial Alzheimer's disease includes mutations in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene. In some embodiments, mutations in the APP gene encode mutations in the amino acid sequence of the amyloid precursor protein expressed from the APP gene. In some embodiments, mutations in the amyloid precursor protein amino acid sequence include a mutation at valine 717 as described in SEQ ID NO: 1. In some embodiments, valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). In some embodiments, mutations in the amyloid precursor protein amino acid sequence include mutations at the positions of lysine 670 and methionine 671 as described in SEQ ID NO: 1. In some embodiments, lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670 / 671NL). In some embodiments, mutations in the amyloid precursor protein amino acid sequence include a mutation at glutamic acid 693 as described in SEQ ID NO: 1. In some embodiments, mutations in the APP gene encode a deletion at the position of glutamic acid 693 in the amyloid precursor protein amino acid sequence.In some embodiments, glutamic acid 693 of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at threonine 714 as described in SEQ ID NO: 1. In some embodiments, threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at valine 715 as described in SEQ ID NO: 1. In some embodiments, valine 715 of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at isoleucine 716 as described in SEQ ID NO: 1. In some embodiments, isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). In some embodiments, the PSEN-1 gene mutation encodes a mutation in the presenilin-1 amino acid sequence expressed from the PSEN-1 gene. In some embodiments, the presenilin-1 amino acid sequence mutation includes mutations at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 as described in SEQ ID NO: 2. In some embodiments, methionine 146 is mutated to leucine (M146L), leucine 166 is mutated to proline (L166P), isoleucine 213 is mutated to threonine (I213T), arginine 278 is mutated to isoleucine (R278I), and alanine 246 is mutated to glutamate (A246E). In some embodiments, mutations in the PSEN-2 gene encode mutations in the presenilin-2 amino acid sequence expressed from the PSEN-2 gene. In some embodiments, mutations in the presenilin-2 amino acid sequence include mutations at asparagine 141 or methionine 239 as described in SEQ ID NO: 3. In some embodiments, asparagine 141 is mutated to isoleucine, and methionine 239 is mutated to valine.In some embodiments, the genetic risk factors associated with sporadic Alzheimer's disease include the subject being a carrier of the apolipoprotein (APOE)e4 allele. In some embodiments, the genetic risk factors associated with sporadic Alzheimer's disease include gene mutations. In some embodiments, the genes include ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C. In some embodiments, the subject does not exhibit symptoms of Alzheimer's disease. In some embodiments, the subjects are under approximately 25 years of age, under approximately 30 years of age, under approximately 35 years of age, under approximately 40 years of age, under approximately 45 years of age, under approximately 50 years of age, under approximately 55 years of age, under approximately 60 years of age, under approximately 65 years of age, or under approximately 70 years of age. In some embodiments, the method improves the subject's memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech disorders, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality. In some embodiments, the treatment results in improvements in mental state tests and / or neuroimaging tests. In some embodiments, mental state tests include the Mini-Mental State Exam (MMSE), Mini-Cog test, Cantab Mobile test, Cognigram test, Cognivue test, or Cognision test and Automated Neuropsychological Assessment Metrics (ANAM) tests. In some embodiments, the improvement includes an improved score compared to a score obtained before administration of the composition. In some embodiments, the neuroimaging is magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, the improvement includes a reduced amount of β-amyloid deposition compared to the amount of β-amyloid deposition measured before administration of the composition.

[0006] In some embodiments, a method for improving the cognition of a subject who needs cognitive improvement is disclosed herein, comprising (a) obtaining the results of a genetic test of the subject for at least one mutation associated with familial Alzheimer's disease, and (b) administering to the subject a composition comprising ETP69 if the genetic test indicates that the subject has at least one mutation associated with familial Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 1 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 3 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 4 Alzheimer's disease. In some embodiments, the at least one mutation associated with familial Alzheimer's disease includes mutations in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene. In some embodiments, mutations in the APP gene encode mutations in the amino acid sequence of the amyloid precursor protein expressed from the APP gene. In some embodiments, mutations in the amyloid precursor protein amino acid sequence include a mutation at valine 717 as described in SEQ ID NO: 1. In some embodiments, valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). In some embodiments, mutations in the amyloid precursor protein amino acid sequence include mutations at the positions of lysine 670 and methionine 671 as described in SEQ ID NO: 1. In some embodiments, lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670 / 671NL). In some embodiments, mutations in the amyloid precursor protein amino acid sequence include a mutation at glutamic acid 693 as described in SEQ ID NO: 1. In some embodiments, mutations in the APP gene encode a deletion at the position of glutamic acid 693 in the amyloid precursor protein amino acid sequence.In some embodiments, glutamic acid 693 of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at threonine 714 as described in SEQ ID NO: 1. In some embodiments, threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at valine 715 as described in SEQ ID NO: 1. In some embodiments, valine 715 of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at isoleucine 716 as described in SEQ ID NO: 1. In some embodiments, isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). In some embodiments, the PSEN-1 gene mutation encodes a mutation in the presenilin-1 amino acid sequence expressed from the PSEN-1 gene. In some embodiments, the presenilin-1 amino acid sequence mutation includes mutations at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 as described in SEQ ID NO: 2. In some embodiments, methionine 146 is mutated to leucine (M146L), leucine 166 is mutated to proline (L166P), isoleucine 213 is mutated to threonine (I213T), arginine 278 is mutated to isoleucine (R278I), and alanine 246 is mutated to glutamate (A246E). In some embodiments, mutations in the PSEN-2 gene encode mutations in the presenilin-2 amino acid sequence expressed from the PSEN-2 gene. In some embodiments, mutations in the presenilin-2 amino acid sequence include mutations at asparagine 141 or methionine 239 as described in SEQ ID NO: 3. In some embodiments, asparagine 141 is mutated to isoleucine, and methionine 239 is mutated to valine.

[0007] In some embodiments, a method for improving the cognition of a subject who needs cognitive improvement is disclosed herein, comprising (a) obtaining the results of a genetic test of the subject for at least one mutation associated with sporadic Alzheimer's disease, and (b) administering to the subject a composition comprising ETP69 if the genetic test indicates that the subject has at least one mutation associated with sporadic Alzheimer's disease. In some embodiments, the at least one mutation associated with sporadic Alzheimer's disease includes a mutation in the apolipoprotein (APOE)e4 gene. In some embodiments, the mutation in the APOEe4 gene encodes a mutation in the apolipoprotein e4 amino acid sequence expressed from the APOEe4 gene. In some embodiments, the genetic risk factors associated with sporadic Alzheimer's disease include gene mutations. In some embodiments, the genes include ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C. [Brief explanation of the drawing]

[0008] The features and effects of the present invention will be understood by referring to the following embodiments for carrying out the invention, which describe exemplary embodiments in which the principles of the present invention are utilized, and the following accompanying drawings. [Figure 1] This is the chemical structure of the compound described herein. [Figure 2A] This is an experimental design that includes three cohorts. [Figure 2B] This is the experimental design for the first cohort. [Figure 2C] This is the experimental design for the second cohort. [Figure 2D] This is the experimental design for the third cohort. [Figure 3A] This is a graph showing the total number of intrusions in the Y-maze experiment. [Figure 3B] This is a graph showing the rate of spontaneous alternation of behavior in the Y-maze experiment. [Figure 4A] This is a graph showing the total number of intrusions in a visual X maze (color, E) experiment. [Figure 4B] This graph shows the rate of spontaneous alternation behavior in a visual X maze (color, E) experiment. [Figure 4C] Includes an illustration of the visual X maze (color, E) experiment used. [Figure 4D] This is a graph showing the total number of intrusions in a visual X-maze (contrast) experiment. [Figure 4E] This graph shows the rate of spontaneous alternation behavior in a visual X-maze (contrast) experiment. [Figure 4F] Includes an explanation using illustrations of the visual X maze (contrast) experiment used. [Figure 4G] This graph shows the blue light intrusion rate in a visual X-maze (color, intrusion) experiment. [Figure 4H] Includes illustrations of the visual X maze (color, intrusion) experiment used. [Figure 4I] This document includes a graph of the blue-white ratio in a visual X-maze (color, bidirectional) experiment, and an explanation using illustrations of the visual X-maze (color, bidirectional) experiment used. [Figure 4J] This document includes a graph of the red-to-white ratio in a visual X-maze (color, bidirectional) experiment, along with an explanation using the illustration of the visual X-maze (color, bidirectional) experiment used. [Figure 5A] Includes graphs of standing activity, total activity, and average speed in open field tests. [Figure 5B] This includes plots of wrong entries in the Barnes maze, as well as graphs of wrong entries and latency. [Figure 5C] Includes an explanation using illustrations from the Barnes maze test used. [Figure 6A] This is a plot of freezing behavior time in fear conditioning tests. [Figure 6B] Includes graphs of freezing behavior duration in fear conditioning tests. [Figure 7A]Includes images of Golgi-Cox stained neurons and dendritic projections in wild-type mice at 15 months of age. [Figure 7B] Includes images of Golgi-Cox stained neurons and dendritic projections in K1 wild-type mice at 18 months of age. [Figure 7C] Includes images of Golgi-Cox stained neurons and dendritic projections in K5 ADtg mice and K1 wild-type mice treated with ETP69 at 18 months of age. [Figure 7D] Includes images of Golgi-Cox stained neurons and dendritic projections in 18-month-old K5 ADtg mice treated with ETP69. [Figure 8] The experimental protocol used to test the effects of ETP69 on 18-month-old mice is shown. [Figure 9A] This shows the total number of entries into the Y-maze. [Figure 9B] This shows the alternation rate in a Y-maze. [Figure 10A] A schematic diagram of the visual stimulus X maze and the total number of entries into the visual stimulus X maze are shown. [Figure 10B] This shows the alternating behavior rate in the visual stimulus X maze. [Figure 10C] This shows the rate of movement in the maze with visual stimulus X. [Figure 10D] This shows the alternating behavior rate in the visual stimulus X maze. [Figure 10E] A schematic diagram and total number of intrusions are shown for the high-contrast visual stimulus X maze. [Figure 10F] This shows the alternating behavior rate in a high-contrast visual stimulus X maze. [Figure 11A] This shows a schematic diagram of the Barnes maze test and the number of errors during training. [Figure 11B] This shows the number of errors during the holding phase of the Barnes maze test. [Figure 11C] This shows the number of errors that occur during the inversion phase of the Barnes maze test. [Figure 11D] This shows the number of errors during training in mice that received a single injection. [Figure 11E] This shows the number of errors in training mice that received repeated injections. [Figure 11F] This shows a comparison of error rates in mice that received a single injection, an additional injection, or repeated injections. [Figure 11G] This shows the number of errors in the reversal phase of mice that received a single injection. [Figure 11H] This shows the number of errors in the reversal phase of mice that received repeated injections. [Figure 12] This shows the duration of freezing behavior that occurred in contextual fear conditioning tests. [Figure 13A] Representative sections of Golgi-Cox stained cingulate cortex (CC) from mice treated with ETP69 and DMSO are shown. [Figure 13B] This image shows a representative section of the hippocampal region (Hipp) of a mouse treated with ETP69, stained with Golgi-Cox. [Figure 13C] This shows the quantification of the number of dendritic spines and elongated spines in the cingulate cortex of mice treated with ETP69 and DMSO. [Figure 13D] This shows the quantification of the number of dendritic spines and elongated spines in the hippocampal region of mice treated with ETP69 and DMSO. [Figure 13E] This paper quantifies the ratio of elongated spines to all spines in the cingulate cortex (CC) and hippocampal region (Hipp) of mice treated with ETP69 and DMSO. [Figure 13F] This paper quantifies the ratio of elongated spines to all spines in the cingulate cortex (CC) and hippocampal region (Hipp) of mice treated with ETP69 and DMSO. [Figure 13G] This shows the correlation between the ratio of elongated spines to all spines and the number of errors during the holding phase of the Barnes maze test. [Figure 14A] This shows H3K9me3 signaling across the cortical layer. [Figure 14B] This shows H3K9me3 and DAPI staining in AD+ mice treated with ETP69 and DMSO. [Figure 14C]This paper shows the quantification of H3Kme3 and the H3K9me3 to actin ratio in the cingulate cortex (CC) and hippocampal region (Hipp) of mice treated with ETP69 and DMSO. [Figure 14D] Representative images of 6E10 and GFAP staining in AD+ mice treated with ETP69 and DMSO are shown. [Figure 14E] This shows the quantification of 6E10 in the cingulate cortex (CC) of mice treated with ETP69 and DMSO. [Figure 14F] This shows the quantification of GFAP in the cingulate cortex (CC) of mice treated with ETP69 and DMSO. [Figure 14G] This shows the quantification of the GFAP to actin ratio in the hippocampal region (Hipp) of mice treated with ETP69 and DMSO. [Figure 15] This document presents an experimental protocol for testing the effects of ETP69 in 14-month-old mice. [Figure 16A] A schematic diagram of the visual stimulus X maze and the total number of entries into the visual stimulus X maze are shown. [Figure 16B] This shows the alternating behavior rate in the visual stimulus X maze. [Figure 16C] This section provides an explanation using illustrations from the visual X maze experiment that was used. [Figure 16D] This shows the rate of movement in the maze with visual stimulus X. [Figure 17A] The results of fear conditioning tests in wild-type and AD+ mice treated with ETP69 and DMSO are shown. [Figure 17B] This study demonstrates the effect of ETP69 treatment on freezing behavior duration in fear conditioning tests. [Figure 18A] Representative images of H3K9me2, 6E10, and GFAP staining in mice administered DMSO and ETP69 are shown. [Figure 18B] This shows the quantification of H3K9me3 staining in mice administered DMSO and ETP69. [Figure 18C] This shows the quantification of 6E10 staining in mice administered DMSO and ETP69. [Figure 18D]This shows the quantification of GFAP staining in mice administered DMSO and ETP69. [Figure 18E] This shows the quantification of Iba1 staining in mice administered DMSO and ETP69. [Figure 19A] This figure shows a proteomics analysis comparing the brains of ETP-treated and untreated mice. The figure includes volcano plots of the most downregulated (left) and most upregulated (right) proteins. [Figure 19B] This shows an Ingenuity pathway analysis that demonstrates activation of the BDNF pathway. [Figure 20] This shows the results of the behavioral path analysis of the Ingenuity software. [Figure 21A] This shows the effect of ETP69 treatment on H3K9me3 staining in bone marrow monocyte cells. [Figure 21B] This shows the effect of ETP69 treatment on 6E10 staining in bone marrow monocyte cells. [Figure 21C] This shows the effect of ETP69 treatment on GFAP staining in bone marrow monocyte cells. [Figure 21D] Representative images of Iba-1 staining in AD+ mice treated with DMSO or ETP69 are shown. [Figure 21E] This shows the quantification of Iba-1 staining in AD+ mice treated with DMSO or ETP69. [Figure 21F] This shows a comparison between alternating activity rates and H3K9me3 staining. [Figure 21G] Representative staining for H3K9me3, NeuN, and DAPI in AD+ mice administered DMSO or ETP69 is shown. [Figure 21H] Representative staining for H3K9me3, CD45, Iba-1, 6E10, and DAPI in AD+ mice administered DMSO or ETP69 is shown. [Figure 21I] This shows the quantification of H3K9me3 staining in nerve cells of mice administered with ETP69 or DMSO. [Figure 21J]This shows the quantification of H3K9me3 staining in microglia of mice administered ETP69 or DMSO. [Figure 21K] Representative images of H3K9me3 and GFAP staining in AD+ mice administered DMSO or ETP69 are shown. [Figure 21L] This shows the quantification of H3K9me3 staining in astrocytes of mice administered ETP69 or DMSO. [Figure 22] Representative images of VGF, BDNF, and NCAM in 18-month-old AD+ mice are shown. [Figure 23] The experimental protocol used is shown below. [Figure 24A] This demonstrates an open field test. [Figure 24B] This paper presents a temporal analysis of standing behavior. [Figure 24C] This shows an analysis of the average standing-up behavior for each treatment group. [Figure 24D] This shows the quantification of standing behavior in each treatment group. [Figure 24E] This shows a time-series analysis of spontaneous momentum. [Figure 24F] This shows an analysis of the average spontaneous physical activity for each treatment group. [Figure 24G] This shows the quantification of spontaneous physical activity in each treatment group. [Figure 25A] This shows a color-mode visual stimulus X maze. [Figure 25B] This shows the total number of intrusions in the test. [Figure 25C] This shows the alternation rate of the treatment group. [Figure 25D] This shows the progression of alternation behavior rates associated with entry into mice treated with ETP69 or oraB. [Figure 25E] The Kaplan-Meier curve shows the percentage of mice that perform alternating behavior for the first time in response to an intrusion. [Figure 26A] This shows a visual stimulus X-maze in contrast mode. [Figure 26B] This shows the total number of intrusions in the test. [Figure 26C] This shows the alternation rate of the treatment group. [Figure 26D] This shows the progression of alternation behavior rates associated with entry into mice treated with ETP69 or oraB. [Figure 26E] The Kaplan-Meier curve shows the percentage of mice that perform alternating behavior for the first time in response to an intrusion. [Figure 27A] This shows the Barnes maze test. [Figure 27B] This shows the error counts for each WT and AD+ mouse administered with oraB or ETP69. [Figure 27C] This shows the average number of errors in the acquisition phase of WT and AD+ mice administered oraB or ETP69. [Figure 27D] This shows the average number of errors during the memory retention phase in WT and AD+ mice administered oraB or ETP69. [Figure 27E] This shows the average number of errors in the reversal phase of WT and AD+ mice administered oraB or ETP69. [Modes for carrying out the invention]

[0009] In the United States, more than 5.5 million people live with Alzheimer's disease, and tens of thousands have early-onset Alzheimer's. Alzheimer's disease can affect both the brain and the retina, and patients may experience cognitive impairment, behavioral impairment, and visual impairment. There is a need for treatments to prevent, delay, or treat Alzheimer's disease and associated cognitive and visual impairments, and the development of effective treatments and means to maintain cognitive function is essential.

[0010] Cognitive decline is a serious condition associated with neurodegenerative disorders and is generally age-dependent. Early-onset Alzheimer's disease presents with marked difficulties and severe conditions in which carriers of certain mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2) genes can develop Alzheimer's disease with 100% penetrant rate. In some cases, this early-onset disease is caused by increased production of neurotoxic amyloid-beta protein and is associated with inflammation, vascular pathology, or other adverse effects on histone methylation, gene expression, and synaptic loss.

[0011] Epigenetic modulation of certain synaptic proteins may be reversible, but could be the underlying cause of this decline. Histone 3 trimethylation is a promising target for pharmacological interventions that may counteract cognitive decline in the aging brain. Herein, evidence is provided that manipulating enzymes that regulate H3K9 trimethylation (H3K9me3) (using ETP69, an inhibitor of SUV39H1) can alter the chromatin state of the target and restore memory and synaptic function in the aging brain. Treatment with ETP69 may result in unique mechanisms for enhancing gene expression and restoring neuronal and synaptic activity. Treatment with ETP69 may prevent, delay, or treat Alzheimer's disease and Alzheimer's disease-associated cognitive and visual impairments. Some advantages of ETP69 include an improved safety and toxicity profile, availability, and safe formulation.

[0012] Histone tail methylation typically occurs at specific lysine residues, such as H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20, and can activate or repress transcription. Trimethylation of H3K9 (H3K9me3) can be a useful repressive histone mark and is associated with gene silencing. The establishment of H3K9me3 is influenced by the activity of SUV39H1, a histone methyltransferase that regulates H3K9 trimethylation in pericentric heterochromatin.

[0013] H3K9me3 can be an inhibitory histone mark and is typically associated with gene silencing. Several embodiments involve the role of histone H3K9me3 and its histone methyltransferase (SUV39H1) in mediating hippocampal memory function and in influencing the progression or onset of Alzheimer's disease. Pharmacological inhibition of SUV39H1 using selective inhibitors may reduce the level of H3K9me3 in the hippocampus of treated subjects and / or improve performance on object location memory tasks, fear conditioning tasks, or complex spatial environment learning tasks. Inhibition of SUV39H1 with ETP69 or another compound disclosed herein may induce an increase in the density of thin spines and stubby spines in the hippocampus of treated subjects, but not in the density of mushroom spines, and increases AMPA receptor levels, including GluR1, on the spine surface, which is a useful indicator of long-term potentiation (LTP). The establishment of H3K9me3 may depend on the activity of SUV39H1, a histone methyltransferase that regulates H3K9 trimethylation in pericentric heterochromatin. Therefore, regulating the function of enzymes that contribute to histone methylation may be a powerful means of compensating for age-related cognitive decline.

[0014] In some embodiments, methods for treating, preventing, or delaying the onset of Alzheimer's disease in subjects who need to be treated, prevented, or have their onset delayed are disclosed herein, comprising administering a composition containing ETP69 to the subject. In some embodiments, methods for improving the cognition of subjects at risk of developing Alzheimer's disease are disclosed herein, comprising administering a composition containing ETP69 to the subject.

[0015] In some embodiments, methods for treating amyloidosis in a subject are disclosed herein, comprising administering a composition containing ETP69 to the subject. The subject may have mutations associated with familial Alzheimer's disease or genetic risk factors associated with sporadic Alzheimer's disease. The administration may reduce the amyloidosis in the subject compared to a measured amyloidosis level obtained before administration.

[0016] In some embodiments, methods for modulating molecular markers in a subject are disclosed herein, which include administering a composition containing ETP69 to the subject. For example, the method may include modulating one or more proteins as shown in Figure 19A, Figure 19B, or Figure 20 (e.g., increasing or decreasing them compared to baseline). The subject may have mutations associated with familial Alzheimer's disease or genetic risk factors associated with sporadic Alzheimer's disease.

[0017] In some embodiments, methods for treating neuroinflammation in a subject are disclosed herein, comprising administering a composition containing ETP69 to the subject. The subject may have mutations associated with familial Alzheimer's disease or genetic risk factors associated with sporadic Alzheimer's disease. The administration may reduce the subject's neuroinflammation compared to amyloidosis measurements obtained prior to administration.

[0018] A. Compound This specification provides compounds used in methods for treating, preventing, or delaying the onset of Alzheimer's disease. In some embodiments, the compounds inhibit histone methyltransferase. In some embodiments, the compounds inhibit SUV39H1. In some embodiments, the compounds inhibit H3K9 trimethylation (H3K9me3). For example, some embodiments include the use of H3K9me3 modulation to enhance cognitive function in aging and to treat age-related impairments such as Alzheimer's disease.

[0019] In some embodiments, the compound comprises ETP69(Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile). In some embodiments, the compound consists of ETP69. The structure of ETP69 is shown in Figure 1. In some embodiments, the compound comprises ETP69 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound consists of ETP69 or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound comprises an analog of ETP69. In some embodiments, the compound is an analog of ETP69. In some embodiments, the compound comprises or consists of an analog of ETP69 or a pharmaceutically acceptable salt thereof. In some embodiments, the analog of ETP69 is of the following formula

[0021] [ka] It is a compound that has [a certain characteristic].

[0022] The symbol p can be 2, 3, or 4. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0023] R 1, R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , and / or R 18 is, independently of each other, hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0024] In some embodiments, R 1 is hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0025] In some embodiments, R 2 is hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0026] In some embodiments, R 3 These are hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0027] In some embodiments, R 4 These are hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0028] In some embodiments, R 5 These are hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0029] In some embodiments, R 6These are hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0030] In some embodiments, R 16 These are hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0031] In some embodiments, R 18 These are hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -Cl3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0032] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16, or R 18 is hydrogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is a halogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -N3. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -CF3. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -CCl3. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -CBr3. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -Cl3. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16or R 18 is -CN. In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 R 16 or R 18 is -CHO. In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 R 16 or R 18 is -OH. In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 R 16 or R 18 is -NH2. In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 R 16 or R 18 is -COOH. In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 R 16 or R 18 is -CONH2. In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 R 16 or R 18 is -NO2. In some embodiments, R 1 R 2 R 3 R 4 R 5 R 6 R 16, or R 18 is -SH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -SO2. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -SO2Cl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -SO3H. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -SO4H. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -SO2NH2. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -NHNH2. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R16 , or R 18 is -ONH2. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -NHC(O)NHNH2. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is a substituted or unsubstituted alkyl group. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 R is a substituted or unsubstituted heteroalkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is a substituted or unsubstituted cycloalkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 R is a substituted or unsubstituted aryl. In some embodiments, R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 16 , or R 18 These are substituted or unsubstituted heteroaryl compounds.

[0033] In some embodiments, the compound is used to manufacture a drug for the treatment of Alzheimer's disease. In some embodiments, the compound is used to manufacture a drug for the prevention of Alzheimer's disease. In some embodiments, the compound is used to manufacture a drug for delaying the onset of Alzheimer's disease.

[0034] B. Formulations In certain embodiments, the compounds described herein are administered as pure chemical substances. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or pharmaceutically acceptable carrier (also referred herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on a chosen route of administration.

[0035] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition of the present invention further comprises a pharmaceutically acceptable carrier.

[0036] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises physiological saline. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or physiological saline. In some embodiments, the composition comprises liposomes. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogels, or combinations thereof.

[0037] C. Treatment and prevention of Alzheimer's disease In some embodiments, methods for treating, preventing, or delaying the onset of Alzheimer's disease in subjects who need to treat, prevent, or delay the onset of Alzheimer's disease are disclosed herein. Some embodiments include treating Alzheimer's disease. Some embodiments include preventing Alzheimer's disease. Some embodiments include delaying the onset of Alzheimer's disease. Some embodiments include treating Alzheimer's disease or delaying its onset. Some embodiments include administering compositions described herein to subjects. For example, compositions may comprise ETP69 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects have at least one mutation associated with familial Alzheimer's disease. In some embodiments, subjects have at least one genetic risk factor associated with sporadic Alzheimer's disease. In some embodiments, subjects have (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. Some embodiments involve administering a composition comprising ETP69 to a subject having (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. Some embodiments disclose a method for treating, preventing, or delaying the onset of Alzheimer's disease in a subject who needs to be treated, prevented, or has their onset delayed, the method comprising administering a composition comprising ETP69 to the subject, the subject having (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease.

[0038] In some embodiments, methods for improving the cognition of subjects are disclosed herein. In some embodiments, subjects are at risk of developing Alzheimer's disease. Some embodiments involve improving the cognition of subjects at risk of developing Alzheimer's disease. Some embodiments involve administering compositions described herein to subjects. For example, compositions may comprise ETP69 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects have at least one mutation associated with familial Alzheimer's disease. In some embodiments, subjects have at least one genetic risk factor associated with sporadic Alzheimer's disease. In some embodiments, subjects have (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. Some embodiments involve administering a composition comprising ETP69 to subjects, wherein the subjects have (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. In some embodiments, methods for improving the cognition of subjects at risk of developing Alzheimer's disease are disclosed herein, the method comprising administering a composition comprising ETP69 to the subject, wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease.

[0039] In some embodiments, methods for improving the cognition of subjects who need cognitive improvement are disclosed herein. Some embodiments include obtaining the results of a genetic test. In some embodiments, the genetic test determines the presence of at least one mutation associated with familial Alzheimer's disease. In some embodiments, the genetic test results are for at least one mutation associated with familial Alzheimer's disease. The genetic test is for any or more mutations described herein associated with familial Alzheimer's disease. Some embodiments include obtaining the results of a genetic test of a subject for at least one mutation associated with familial Alzheimer's disease. In some embodiments, the genetic test indicates that the subject has at least one mutation associated with familial Alzheimer's disease. Some embodiments include administering a composition described herein to a subject. For example, the composition may comprise ETP69 or a pharmaceutically acceptable salt thereof. Some embodiments include administering a composition to a subject based on the results of a genetic test. Some embodiments include administering a composition to a subject if the genetic test indicates that the subject has at least one mutation associated with familial Alzheimer's disease. Some embodiments include administering a composition containing ETP69 to a subject if a genetic test indicates that the subject has at least one mutation associated with familial Alzheimer's disease. Some embodiments include (a) obtaining the results of a genetic test, and (b) administering the composition described herein to the subject based on the results of said genetic test. Some embodiments include (a) obtaining the results of a genetic test of a subject for at least one mutation associated with familial Alzheimer's disease, and (b) administering a composition containing ETP69 to the subject if the genetic test indicates that the subject has at least one mutation associated with familial Alzheimer's disease.In some embodiments, methods for improving the cognition of a subject who needs cognitive improvement are disclosed herein, the methods comprising (a) obtaining the results of a genetic test of the subject for at least one mutation associated with familial Alzheimer's disease, and (b) administering the subject a composition comprising ETP69 if the genetic test indicates that the subject has at least one mutation associated with familial Alzheimer's disease.

[0040] In some embodiments, methods for improving the cognition of subjects who need cognitive improvement are disclosed herein. Some embodiments include obtaining the results of a genetic test. In some embodiments, the genetic test determines the presence of at least one mutation associated with sporadic Alzheimer's disease. In some embodiments, the genetic test results are for at least one mutation associated with sporadic Alzheimer's disease. The genetic test is for any or more of the mutations described herein associated with sporadic Alzheimer's disease. Some embodiments include obtaining the results of a genetic test of a subject for at least one mutation associated with sporadic Alzheimer's disease. In some embodiments, the genetic test indicates that the subject has at least one mutation associated with sporadic Alzheimer's disease. Some embodiments include administering a composition described herein to a subject. For example, the composition may comprise ETP69 or a pharmaceutically acceptable salt thereof. Some embodiments include administering a composition to a subject based on the results of a genetic test. Some embodiments include administering a composition to a subject if the genetic test indicates that the subject has at least one mutation associated with sporadic Alzheimer's disease. Some embodiments include administering a composition containing ETP69 to a subject if a genetic test indicates that the subject has at least one mutation associated with sporadic Alzheimer's disease. Some embodiments include (a) obtaining the results of a genetic test, and (b) administering the composition described herein to the subject based on the results of said genetic test. Some embodiments include (a) obtaining the results of a genetic test of a subject for at least one mutation associated with sporadic Alzheimer's disease, and (b) administering a composition containing ETP69 to the subject if the genetic test indicates that the subject has at least one mutation associated with sporadic Alzheimer's disease.In some embodiments, methods for improving the cognition of a subject in need of cognitive improvement are disclosed herein, the methods comprising (a) obtaining the results of a genetic test of the subject for at least one mutation associated with sporadic Alzheimer's disease, and (b) administering the subject a composition comprising ETP69 if the genetic test indicates that the subject has at least one mutation associated with sporadic Alzheimer's disease.

[0041] D. Administration In some embodiments, administering a compound (e.g., ETP69) to a subject involves administering an effective amount of the compound sufficient to inhibit SUV39H1 in the subject. In some embodiments, the route of administration is intravenous, oral, subcutaneous, intraperitoneal, ocular, intraocular, intramuscular, interstitial, or intracranial. In some embodiments, the administration is systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is oral. In some embodiments, the administration includes injection. In some embodiments, the administration is subcutaneous. In some embodiments, the administration is intraperitoneal. In some embodiments, the administration is ocular. In some embodiments, the administration is intraocular. In some embodiments, the administration is intramuscular. In some embodiments, the administration is interstitial. In some embodiments, the administration is intracranial.

[0042] In some embodiments, administering the compound includes a single dose. In some embodiments, administering the compound includes multiple doses (e.g., two doses). For example, administration may include repeated doses at different time points. Repeated doses may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses, or more, or a range of doses defined by any two of the above-mentioned dose counts. In some embodiments, administration includes 11 doses.

[0043] E. Alzheimer's disease and mutations In some embodiments, methods for treating, preventing, or delaying the onset of a particular Alzheimer's disease are disclosed herein. In some embodiments, Alzheimer's disease is early-onset Alzheimer's disease. In some embodiments, Alzheimer's disease is late-onset Alzheimer's disease. In some embodiments, Alzheimer's disease is familial. In some embodiments, Alzheimer's disease is familial Alzheimer's disease. In some embodiments, early-onset Alzheimer's disease is familial Alzheimer's disease. In some embodiments, Alzheimer's disease is sporadic. In some embodiments, Alzheimer's disease is sporadic Alzheimer's disease.

[0044] Some embodiments relate to symptoms of Alzheimer's disease. In some embodiments, symptoms include memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech disorders, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality. In some embodiments, symptoms include memory impairment. In some embodiments, symptoms include difficulty concentrating. In some embodiments, symptoms include difficulty completing familiar tasks. In some embodiments, symptoms include confusion about time or place. In some embodiments, symptoms include difficulty understanding visual images and spatial relationships. In some embodiments, symptoms include speech disorders. In some embodiments, symptoms include misplacing objects. In some embodiments, symptoms include impaired or poor judgment. In some embodiments, symptoms include withdrawal. In some embodiments, symptoms include changes in mood or personality.

[0045] In some embodiments, methods for treating, preventing, or delaying the onset of familial Alzheimer's disease are disclosed herein. In some embodiments, familial Alzheimer's disease includes type 1 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 3 Alzheimer's disease. In some embodiments, familial Alzheimer's disease includes type 4 Alzheimer's disease.

[0046] In some embodiments, the subject has a mutation associated with Alzheimer's disease (e.g., familial or sporadic Alzheimer's disease). In some embodiments, the mutation is recessive. In some embodiments, the mutation is dominant. In some embodiments, the mutation is heterozygous. In some embodiments, the mutation is homozygous.

[0047] In some embodiments, the subject has one mutation associated with Alzheimer's disease. In some embodiments, the subject has two mutations associated with Alzheimer's disease. In some embodiments, the subject has three mutations associated with Alzheimer's disease. In some embodiments, the subject has four mutations associated with Alzheimer's disease. In some embodiments, the subject has five mutations associated with Alzheimer's disease. In some embodiments, the subject has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen mutations associated with Alzheimer's disease. In some embodiments, the subject has a range of mutations defined by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen mutations associated with Alzheimer's disease, or any two of the integers described above.

[0048] In some embodiments, the subject has at least one mutation associated with Alzheimer's disease. In some embodiments, the subject has at least two mutations associated with Alzheimer's disease. In some embodiments, the subject has at least three mutations associated with Alzheimer's disease. In some embodiments, the subject has at least four mutations associated with Alzheimer's disease. In some embodiments, the subject has at least five mutations associated with Alzheimer's disease. In some embodiments, the subject has at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, or at least fifteen mutations associated with Alzheimer's disease.

[0049] In some embodiments, the subject has one or fewer mutations associated with Alzheimer's disease. In some embodiments, the subject has two or fewer mutations associated with Alzheimer's disease. In some embodiments, the subject has three or fewer mutations associated with Alzheimer's disease. In some embodiments, the subject has four or fewer mutations associated with Alzheimer's disease. In some embodiments, the subject has five or fewer mutations associated with Alzheimer's disease. In some embodiments, the subject has one or fewer, two or fewer, three or fewer, four or fewer, five or fewer, six or fewer, seven or fewer, eight or fewer, nine or fewer, ten or fewer, eleven or fewer, twelve or fewer, thirteen or fewer, fourteen or fewer, or fifteen or fewer mutations associated with Alzheimer's disease.

[0050] In some embodiments, the subject has at least one mutation associated with familial Alzheimer's disease. In some embodiments, the at least one mutation associated with familial Alzheimer's disease includes mutations in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene. In some embodiments, the at least one mutation associated with familial Alzheimer's disease includes mutations in the amyloid precursor protein (APP) gene. In some embodiments, the at least one mutation associated with familial Alzheimer's disease includes mutations in the presenilin-1 (PSEN1) gene. In some embodiments, the at least one mutation associated with familial Alzheimer's disease includes mutations in the presenilin-2 (PSEN2) gene.

[0051] In some embodiments, mutations in the APP gene encode mutations in the amino acid sequence of the amyloid precursor protein expressed from the APP gene. In some embodiments, mutations in the amyloid precursor protein amino acid sequence include a mutation at lysine 670 as described in SEQ ID NO: 1. In some embodiments, lysine 670 is mutated to asparagine (K670N). In some embodiments, mutations in the amyloid precursor protein amino acid sequence include a mutation at methionine 671 as described in SEQ ID NO: 1. In some embodiments, methionine 671 is mutated to lysine (M671L). In some embodiments, mutations in the amyloid precursor protein amino acid sequence include mutations at the positions of lysine 670 and methionine 671 as described in SEQ ID NO: 1. In some embodiments, lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670 / 671NL, Swedish mutation).

[0052] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at alanine 673 as described in SEQ ID NO: 1. In some embodiments, alanine 673 in the amyloid precursor protein is mutated to valine (A673V).

[0053] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at histidine 677 as described in SEQ ID NO: 1. In some embodiments, histidine 677 in the amyloid precursor protein is mutated to arginine (H677R).

[0054] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at aspartic acid 678 as described in SEQ ID NO: 1. In some embodiments, aspartic acid 678 of the amyloid precursor protein is mutated to asparagine (D678N).

[0055] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at alanine 692 as described in SEQ ID NO: 1. In some embodiments, alanine 692 in the amyloid precursor protein is mutated to glycine (A692G).

[0056] In some embodiments, mutations in the amyloid precursor protein amino acid sequence include mutations at glutamate 693 as described in SEQ ID NO: 1. In some embodiments, mutations in the APP gene encode a deletion at the position of glutamate 693 in the amyloid precursor protein amino acid (E693Δ, Osaka mutation). In some embodiments, glutamate 693 in the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). In some embodiments, glutamate 693 in the amyloid precursor protein is mutated to glutamine (E693Q, Dutch mutation). In some embodiments, glutamate 693 in the amyloid precursor protein is mutated to glycine (E693G, Arctic mutation). In some embodiments, glutamate 693 in the amyloid precursor protein is mutated to lysine (E693K, Italian mutation).

[0057] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at aspartic acid 694 as described in SEQ ID NO: 1. In some embodiments, aspartic acid 694 of the amyloid precursor protein is mutated to asparagine (D694N, Iowa mutation).

[0058] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at alanine 713 as described in SEQ ID NO: 1. In some embodiments, alanine 713 of the amyloid precursor protein is mutated to threonine (A713T).

[0059] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at threonine 714 as described in SEQ ID NO: 1. In some embodiments, threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). In some embodiments, threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I, Austrian mutation). In some embodiments, threonine 714 of the amyloid precursor protein is mutated to alanine (T714A, Iranian mutation).

[0060] In some embodiments, the mutations in the amyloid precursor protein amino acid sequence include the mutation at valine 715 described in SEQ ID NO: 1. In some embodiments, valine 715 of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). In some embodiments, valine 715 of the amyloid precursor protein is mutated to methionine (V715M, French mutation). In some embodiments, valine 715 of the amyloid precursor protein is mutated to alanine (V715A, German mutation).

[0061] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at isoleucine 716 as described in SEQ ID NO: 1. In some embodiments, isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). In some embodiments, isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V). In some embodiments, isoleucine 716 of the amyloid precursor protein is mutated to phenylalanine (I716F, Florida mutation).

[0062] In some embodiments, the mutations in the amyloid precursor protein amino acid sequence include mutations at valine 717 as described in SEQ ID NO: 1. In some embodiments, valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). In some embodiments, valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I, London mutation). In some embodiments, valine 717 of the amyloid precursor protein is mutated to phenylalanine (V717F, Indiana mutation). In some embodiments, valine 717 of the amyloid precursor protein is mutated to glycine (V717G). In some embodiments, valine 717 of the amyloid precursor protein is mutated to leucine (V717L).

[0063] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at threonine 719 as described in SEQ ID NO: 1. In some embodiments, threonine 719 of the amyloid precursor protein is mutated to proline (T719P).

[0064] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes the mutation at leucine 723 described in SEQ ID NO: 1. In some embodiments, leucine 723 of the amyloid precursor protein is mutated to proline (L723P).

[0065] In some embodiments, the mutation in the amyloid precursor protein amino acid sequence includes a mutation at lysine 724 as described in SEQ ID NO: 1. In some embodiments, lysine 724 of the amyloid precursor protein is mutated to asparagine (K724N).

[0066] In some embodiments, mutations in the PSEN-1 gene encode mutations in the presenilin-1 amino acid sequence expressed from the PSEN-1 gene. In some embodiments, mutations in the presenilin-1 amino acid sequence include a mutation at methionine 146 as described in SEQ ID NO: 2. In some embodiments, methionine 146 is mutated to leucine (M146L). In some embodiments, mutations in the presenilin-1 amino acid sequence include a mutation at leucine 166 as described in SEQ ID NO: 2. In some embodiments, leucine 166 is mutated to proline (L166P). In some embodiments, mutations in the presenilin-1 amino acid sequence include a mutation at isoleucine 213 as described in SEQ ID NO: 2. In some embodiments, isoleucine 213 is mutated to threonine (I213T). In some embodiments, mutations in the presenilin-1 amino acid sequence include a mutation at arginine 278 as described in SEQ ID NO: 2. In some embodiments, arginine 278 is mutated to isoleucine (R278I). In some embodiments, the presenilin-1 amino acid sequence mutation includes a mutation at alanine 246 as described in SEQ ID NO: 2. In some embodiments, alanine 246 is mutated to glutamate (A246E). In some embodiments, the presenilin-1 amino acid sequence mutation includes a mutation at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 as described in SEQ ID NO: 2. In some embodiments, methionine 146 is mutated to leucine (M146L), leucine 166 is mutated to proline (L166P), isoleucine 213 is mutated to threonine (I213T), arginine 278 is mutated to isoleucine (R278I), or alanine 246 is mutated to glutamate (A246E). In some embodiments, methionine 146 is mutated to leucine (M146L), leucine 166 is mutated to proline (L166P), isoleucine 213 is mutated to threonine (I213T), arginine 278 is mutated to isoleucine (R278I), and alanine 246 is mutated to glutamic acid (A246E).

[0067] In some embodiments, mutations in the PSEN-2 gene encode mutations in the presenilin-2 amino acid sequence expressed from the PSEN-2 gene. In some embodiments, mutations in the presenilin-2 amino acid sequence include mutations at asparagine 141 or methionine 239 as described in SEQ ID NO: 3. In some embodiments, asparagine 141 is mutated to isoleucine (N141I) and methionine 239 is mutated to valine (M239V). In some embodiments, mutations in the presenilin-2 amino acid sequence include mutations at asparagine 141 as described in SEQ ID NO: 3. In some embodiments, asparagine 141 is mutated to isoleucine (N141I). In some embodiments, mutations in the presenilin-2 amino acid sequence include mutations at methionine 239 as described in SEQ ID NO: 3. In some embodiments, methionine 239 is mutated to valine (M239V).

[0068] In some embodiments, the subject has at least one mutation associated with sporadic Alzheimer's disease. In some embodiments, the at least one mutation associated with sporadic Alzheimer's disease includes a mutation in an apolipoprotein. In some embodiments, the at least one mutation associated with sporadic Alzheimer's disease includes a mutation in apolipoprotein e4. In some embodiments, the genetic risk factor associated with sporadic Alzheimer's disease includes the subject being a carrier of the apolipoprotein (APOE)e4 allele.

[0069] In some embodiments, genetic risk factors associated with sporadic Alzheimer's disease include gene mutations. In some embodiments, the gene includes ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, PTK2B, SORL1, ACE, TREM2, or UNC5C. In some embodiments, the gene includes ABCA7 (ATP-binding cassette subfamily A member 7). In some embodiments, the gene includes AKAP9 (A kinase anchor protein 9). In some embodiments, the gene includes BIN1 (bridging integrator 1). In some embodiments, the gene includes CASS4 (Cas scaffold protein family member 4). In some embodiments, the gene includes CD2AP (CD2-related protein). In some embodiments, the gene includes CD33 (sialic acid-binding Ig-like lectin 3). In some embodiments, the gene includes CLU (clusterin). In some embodiments, the gene includes EPHA1 (ephrin type A receptor 1). In some embodiments, the gene includes FERMT2 (fermitin family member 2). In some embodiments, the gene includes HLA-DRB5 / DRB1 (major histocompatibility complex, class II, DR β5). In some embodiments, the gene includes INPP5D (inositol polyphosphate-5-phosphatase). In some embodiments, the gene includes MEF2C (muscle cell enhancer factor 2C). In some embodiments, the gene includes MS4A6A / MS4A4E (transmembrane 4-domain A6A / transmembrane 4-domain A4E). In some embodiments, the gene includes PICALM (phosphatidylinositol-binding clathrin aggregate protein). In some embodiments, the gene includes PLD3 (phospholipase D). In some embodiments, the gene includes ACE (angiotensin-converting enzyme). In some embodiments, the gene includes PTK2B (protein tyrosine kinase 2β). In some embodiments, the gene includes SORL1 (soltirin-associated receptor 1).In some embodiments, the gene includes TREM2 (a trigger receptor 2 expressed in myeloid cells). In some embodiments, the gene includes UNC5C (Unc-5 Netrin receptor C).

[0070] In some embodiments, multiple genes associated with sporadic Alzheimer's disease are mutated in the target population.

[0071] In some embodiments, the subjects show altered expression of one or more proteins in Figure 19A compared to the control subjects. In some embodiments, the subjects show altered expression of one or more proteins in Figure 19B compared to the control subjects. In some embodiments, the subjects show altered expression of one or more proteins in Figure 20 compared to the control subjects. The control subjects may be subjects without Alzheimer's disease or subjects without genetic risk factors associated with sporadic Alzheimer's disease.

[0072] F. Target Some embodiments of the methods described herein involve administering a compound to a subject. Non-limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cat. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, mammal, dog, cat, cattle, rodent, mouse, rat, primate, or monkey. In some embodiments, the subject is a human. In some embodiments, the subject is a male. In some embodiments, the subject is a female.

[0073] In some embodiments, the subjects are 90 years of age or older. In some embodiments, the subjects are 85 years of age or older. In some embodiments, the subjects are 80 years of age or older. In some embodiments, the subjects are 70 years of age or older. In some embodiments, the subjects are 60 years of age or older. In some embodiments, the subjects are 50 years of age or older. In some embodiments, the subjects are 40 years of age or older. In some embodiments, the subjects are 30 years of age or older. In some embodiments, the subjects are 20 years of age or older. In some embodiments, the subjects are 10 years of age or older. In some embodiments, the subjects are 1 year of age or older. In some embodiments, the subjects are 0 years of age or older. In some embodiments, the subjects do not have symptoms of Alzheimer's disease. In some embodiments, the subjects are at least about 25 years of age, at least about 30 years of age, at least about 35 years of age, at least about 40 years of age, at least about 45 years of age, at least about 50 years of age, at least about 55 years of age, at least about 60 years of age, at least about 65 years of age, or at least about 70 years of age.

[0074] In some embodiments, the target age is 100 years or younger. In some embodiments, the target age is 90 years or younger. In some embodiments, the target age is 85 years or younger. In some embodiments, the target age is 80 years or younger. In some embodiments, the target age is 70 years or younger. In some embodiments, the target age is 60 years or younger. In some embodiments, the target age is 50 years or younger. In some embodiments, the target age is 40 years or younger. In some embodiments, the target age is 30 years or younger. In some embodiments, the target age is 20 years or younger. In some embodiments, the target age is 10 years or younger. In some embodiments, the target age is 1 year or younger. In some embodiments, the target age is approximately under 25 years old, approximately under 30 years old, approximately under 35 years old, approximately under 40 years old, approximately under 45 years old, approximately under 50 years old, approximately under 55 years old, approximately under 60 years old, approximately under 65 years old, or approximately under 70 years old.

[0075] In some embodiments, the target age range is 0 to 100 years. In some embodiments, the target age range is 20 to 90 years. In some embodiments, the target age range is 30 to 80 years. In some embodiments, the target age range is 40 to 75 years. In some embodiments, the target age range is 50 to 70 years. In some embodiments, the target age range is 40 to 85 years.

[0076] In some embodiments, the subject has Alzheimer's disease. In some embodiments, the subject is at risk of developing Alzheimer's disease. The subject may have mutations associated with familial Alzheimer's disease or genetic risk factors associated with sporadic Alzheimer's disease. In some embodiments, the subject has symptoms of Alzheimer's disease. In some embodiments, the subject does not have symptoms of Alzheimer's disease.

[0077] G. Baseline characteristics Some embodiments of the methods described herein include obtaining baseline measurements from a subject. For example, in some embodiments, the baseline measurements are obtained from the subject before treating the subject. In some embodiments, the baseline measurements are symptoms of Alzheimer's disease, such as the symptoms described herein. Non-limiting examples of baseline measurements include baseline memory measurements, baseline learning measurements, baseline spontaneous activity measurements, baseline neurostructural measurements, baseline neuroinflammation measurements, baseline amyloidosis measurements, or baseline biomarker measurements.

[0078] In some embodiments, baseline measurements include mental state assessments. In some embodiments, mental state assessments are short-term mental state examinations (MMSE), Mini-Cog tests, Cantab Mobile tests, Cognigram tests, Cognivue tests, or Cognision tests and automated neuropsychological assessment measures (ANAM) tests. In some embodiments, mental state assessments are short-term mental state examinations (MMSE). In some embodiments, mental state assessments are Mini-Cog tests. In some embodiments, mental state assessments are Cantab Mobile tests. In some embodiments, mental state assessments are Cognigram tests. In some embodiments, mental state assessments are Cognivue tests. In some embodiments, mental state assessments are Cognision tests and automated neuropsychological assessment measures (ANAM) tests. In some embodiments, baseline measurements include neuroimaging. In some embodiments, neuroimaging is magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, neuroimaging is MRI. In some embodiments, neuroimaging is CT.

[0079] In some embodiments, baseline measurements are obtained directly from the subject. In some embodiments, baseline measurements are obtained by observation, for example, by observation of the subject or the subject's tissue. In some embodiments, baseline measurements are obtained non-invasively using an imaging device. In some embodiments, baseline measurements are obtained from a sample derived from the subject. In some embodiments, baseline measurements are obtained from one or more tissue sections. In some embodiments, baseline measurements are obtained by performing an assay, such as an immunoassay, colorimetric assay, or fluorescence assay, on a sample obtained from the subject. In some embodiments, baseline measurements are obtained by an immunoassay, colorimetric assay, or fluorescence assay. In some embodiments, baseline measurements are obtained by PCR.

[0080] In some embodiments, the baseline measure is a baseline memory measure. In some embodiments, the baseline memory measure is a baseline spatial memory measure. In some embodiments, the baseline memory measure is a baseline hippocampus-dependent spatial memory measure. In some embodiments, the baseline spatial memory measure includes a fear-based test. In some embodiments, the baseline spatial memory measure includes a fear-conditioning test.

[0081] In some embodiments, the baseline measurement is a baseline learning measurement. In some embodiments, the baseline learning measurement is a baseline visual cognitive memory and visual cognitive learning measurement. In some embodiments, the baseline visual cognitive memory and visual cognitive learning measurement includes a color memory and color learning measurement. In some embodiments, the baseline visual cognitive memory and visual cognitive learning measurement includes a contrast memory and contrast learning measurement. In some embodiments, the baseline visual cognitive memory and visual cognitive learning measurement includes a transfer memory and transfer learning measurement. In some embodiments, the baseline visual cognitive memory and visual cognitive learning measurement includes a spatial memory and spatial learning measurement. In some embodiments, the baseline measurement is a baseline spontaneous activity measurement.

[0082] In some embodiments, baseline measurement is baseline neurostructural measurement. In some embodiments, baseline neurostructural measurement includes baseline spine integrity measurement. In some embodiments, baseline neurostructural measurement includes baseline dendritic spine measurement. In some embodiments, baseline dendritic spine measurement evaluates long thin filopodia spines, long thin spines, thin spines, stubby spines, wide-headed mushroom spines, and / or branched spines. In some embodiments, baseline neurostructural measurement includes baseline spine density measurement. In some embodiments, baseline neurostructural measurement includes synapse count. In some embodiments, baseline neurostructural measurement is performed by biopsy. In some embodiments, baseline neurostructural measurement is performed using staining such as Golgi-Cox staining. In some embodiments, baseline neurostructural measurement is performed using photographs. In some embodiments, baseline neural structure measurements are performed using microscopy.

[0083] In some embodiments, baseline measurement includes baseline neuroinflammation measurement. In some embodiments, baseline neuroinflammation measurement includes baseline activated immune activation or baseline reactive immune activation measurement. In some embodiments, baseline neuroinflammation measurement includes baseline activated immune cells or baseline reactive immune cells measurement. In some embodiments, baseline neuroinflammation measurement includes baseline reactive astrocyte measurement. In some embodiments, baseline neuroinflammation measurement includes baseline activated microglia measurement. In some embodiments, baseline neuroinflammation measurement includes baseline macrophage measurement. In some embodiments, baseline neuroinflammation measurement is obtained from tissue or fluid samples. In some embodiments, baseline neuroinflammation measurement is obtained by biopsy. In some embodiments, baseline neuroinflammation measurement is obtained by assays such as immunoassays, fluorescence-activated cell sorting (FACS), or histological evaluation.

[0084] In some embodiments, baseline measurement is baseline amyloidosis measurement. In some embodiments, baseline amyloidosis measurement includes baseline amyloid plaque measurement. In some embodiments, baseline amyloidosis measurement includes baseline amyloid-beta (Aβ) measurement. In some embodiments, baseline Aβ measurement includes baseline Aβ1-42 measurement. In some embodiments, baseline Aβ measurement includes baseline soluble Aβ measurement. In some embodiments, baseline Aβ measurement includes baseline soluble Aβ1-42 measurement. Baseline amyloidosis measurement may include baseline central nervous system (CNS) amyloidosis measurement. Baseline amyloidosis measurement may include baseline vascular amyloidosis measurement. In some embodiments, baseline amyloidosis measurement includes baseline concentration or volume. Baseline amyloidosis measurement (e.g., baseline amyloid plaque measurement) may be performed using an imaging device. Possible imaging devices include positron emission tomography (PET) systems. Baseline amyloidosis measurement may be performed by biopsy. Baseline amyloidosis measurement may be performed using spinal puncture (for example, if baseline amyloidosis measurement includes baseline cerebrospinal fluid (CSF) amyloidosis measurement). In some embodiments, baseline amyloidosis measurement is obtained by assay, such as an immunoassay.

[0085] In some embodiments, the baseline measurement is a baseline molecular marker measurement. In some embodiments, the baseline molecular marker measurement is a baseline histone trimethylation (H3K9me3) measurement. In some embodiments, the baseline molecular marker measurement is a baseline protein measurement. In some embodiments, the baseline molecular marker measurement is a baseline brain-derived neurotrophic factor (BDNF) measurement. In some embodiments, the baseline molecular marker measurement is a baseline Aβ measurement. In some embodiments, the baseline measurement includes a β-amyloid deposition measurement. In some embodiments, the baseline protein measurement is a baseline protein measurement as shown in Figure 19A. In some embodiments, the baseline protein measurement is a baseline protein measurement as shown in Figure 19B. In some embodiments, the baseline measurement is a baseline protein measurement as shown in Figure 20. In some embodiments, the baseline molecular marker measurement is measured by biopsy. In some embodiments, the baseline molecular marker measurement is measured using an immunoassay such as ELISA.

[0086] Some embodiments of the methods described herein involve taking a sample from a subject. In some embodiments, baseline measurements are taken with a sample taken from a subject. In some embodiments, the sample is taken from the subject before administration or before treatment of the subject with the composition described herein. In some embodiments, baseline measurements are taken with a sample taken from the subject before administering the composition to the subject.

[0087] In some embodiments, the sample contains a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood sample, a plasma sample, or a serum sample. In some embodiments, the sample contains blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample contains plasma. In some embodiments, the sample is a plasma sample. In some embodiments, the sample contains serum. In some embodiments, the sample is a serum sample. In some embodiments, the sample contains cerebrospinal fluid (CSF).

[0088] In some embodiments, the sample includes tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the sample includes nerve tissue. In some embodiments, the sample is a brain sample. In some embodiments, the sample is a hippocampal sample. In some embodiments, the sample includes nerve cells.

[0089] In some embodiments, the sample includes cells. Examples of cells include nerve cells. Examples of cells include brain cells. Examples of cells include brain macrophages, microglia, or astrocytes. In some embodiments, examples of cells include nerve cells. In some embodiments, examples of cells include macrophages. In some embodiments, examples of cells include microglia. In some embodiments, examples of cells include astrocytes.

[0090] H. Treatment effect In some embodiments, a composition or administration of a composition alters a measurement, such as a memory measurement, a learning measurement, a spontaneous activity measurement, a neurological structure measurement, a neuroinflammation measurement, an amyloidosis measurement, or a biomarker measurement, compared to a baseline measurement. In some embodiments, the measurement relates to the symptoms of Alzheimer's disease.

[0091] Some embodiments of the methods described herein involve obtaining measurements from a subject. For example, measurements may be obtained from a subject after it has been treated. In some embodiments, measurements are obtained from a second sample (e.g., a fluid or tissue sample as described herein) taken from the subject after the composition has been administered to the subject. In some embodiments, the measurement is an indication that the injury has been treated.

[0092] In some embodiments, the measurement is acquired directly from the subject. In some embodiments, the measurement is acquired non-invasively using an imaging device. In some embodiments, the measurement is acquired on a second sample derived from the subject. In some embodiments, the measurement is acquired on one or more tissue sections. In some embodiments, the measurement is acquired by performing an assay on a second sample obtained from the subject. In some embodiments, the measurement is acquired by an assay such as those described herein. In some embodiments, the assay is an immunoassay, colorimetric assay, fluorescence assay, or PCR assay. In some embodiments, the measurement is acquired by an assay such as an immunoassay, colorimetric assay, or fluorescence assay. In some embodiments, the measurement is acquired by PCR. In some embodiments, the measurement is acquired by histological examination. In some embodiments, the measurement is acquired by observation. In some embodiments, additional measurements are performed, for example, on a third, fourth, or fifth sample.

[0093] In some embodiments, measurements are taken within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are taken within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are taken within 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition. In some embodiments, measurements are taken 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are taken 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are taken one week, two weeks, three weeks, one month, two months, three months, six months, one year, two years, three years, four years, or five years after administration of the composition.

[0094] In some embodiments, the composition reduces the measured value compared to a baseline measurement. In some embodiments, the reduction is measured in a second tissue sample taken from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measured value decreases by about 2.5% or more, about 5% or more, or about 7.5% or more compared to a baseline measurement. In some embodiments, the measured value decreases by about 10% or more compared to a baseline measurement. In some embodiments, the measured value decreases by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more compared to a baseline measurement. In some embodiments, the measured value decreases by about 2.5% or less, about 5% or less, or about 7.5% or less compared to a baseline measurement. In some embodiments, the measured value decreases by about 10% or less compared to a baseline measurement. In some embodiments, the measured value decreases by approximately 20% or less, approximately 30% or less, approximately 40% or less, approximately 50% or less, approximately 60% or less, approximately 70% or less, approximately 80% or less, approximately 90% or less, or approximately 100% or less compared to the baseline measured value. In some embodiments, the measured value decreases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or within a range defined by either of the two above-mentioned percentages.

[0095] Some embodiments of the methods described herein include obtaining measurements from a.

[0096] In some embodiments, the composition increases the measured value compared to a baseline measurement. In some embodiments, the increase is measured in a second tissue sample taken from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measured value increases by about 2.5% or more, about 5% or more, or about 7.5% or more compared to a baseline measurement. In some embodiments, the measured value increases by about 10% or more compared to a baseline measurement. In some embodiments, the measured value increases by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more compared to a baseline measurement. In some embodiments, the measured value increases by about 100% or more, about 250% or more, about 500% or more, about 750% or more, or about 1000% or more compared to a baseline measurement. In some embodiments, the measured value increases by about 2.5% or less, about 5% or less, or about 7.5% or less compared to a baseline measurement. In some embodiments, the measured value increases by about 10% or less compared to the baseline measured value. In some embodiments, the measured value increases by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% or less compared to the baseline measured value. In some embodiments, the measured value increases by about 100%, about 250%, about 500%, about 750%, or about 1000% or less compared to the baseline measured value. In some embodiments, the measured value increases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or within the range defined by either of the two above-mentioned percentages.

[0097] In some embodiments, the measurement includes a mental state test. In some embodiments, the mental state test is the Short-Term Mental State Examination (MMSE), Mini-Cog test, Cantab Mobile test, Cognigram test, Cognivue test, or Cognision test and Automated Neuropsychological Assessment Measure (ANAM) test. In some embodiments, the measurement includes neuroimaging. In some embodiments, the neuroimaging is magnetic resonance imaging (MRI) or computed tomography (CT).

[0098] In some embodiments, the measurement is a memory measure. In some embodiments, the memory measure is a spatial memory measure. In some embodiments, the memory measure is a hippocampus-dependent spatial memory measure. In some embodiments, the spatial memory measure includes a fear-based test. In some embodiments, the spatial memory measure includes a fear-conditioning test. In some embodiments, the memory measure is improved. In some embodiments, the memory measure is increased.

[0099] In some embodiments, the measurement is a learning measurement. In some embodiments, the learning measurement is a measurement of visual cognitive memory and visual cognitive learning. In some embodiments, the measurement of visual cognitive memory and visual cognitive learning includes a measurement of color memory and color learning. In some embodiments, the measurement of visual cognitive memory and visual cognitive learning includes a measurement of contrast memory and contrast learning. In some embodiments, the measurement of visual cognitive memory and visual cognitive learning includes a measurement of transfer memory and transfer learning. In some embodiments, the measurement of visual cognitive memory and visual cognitive learning includes a measurement of spatial memory and spatial learning. In some embodiments, the learning measurement is improved. In some embodiments, the learning measurement is increased. In some embodiments, the measurement is a spontaneous activity measurement. In some embodiments, the spontaneous activity measurement is improved. In some embodiments, the spontaneous activity measurement is increased.

[0100] In some embodiments, the measurement is a neuronal structure measurement. In some embodiments, the neuronal structure measurement includes spine integrity measurement. In some embodiments, the neuronal structure measurement includes dendritic spine measurement. In some embodiments, dendritic spine measurement evaluates long thin filopodia spines, long thin spines, thin spines, stubby spines, wide-headed mushroom spines, and / or branched spines. In some embodiments, the neuronal structure measurement includes spine density measurement. In some embodiments, the neuronal structure measurement includes synapse count. In some embodiments, the neuronal structure measurement is performed using a biopsy. In some embodiments, the neuronal structure measurement is performed using staining such as Golgi-Cox staining. In some embodiments, the neuronal structure measurement is performed using a photograph. In some embodiments, the neuronal structure measurement is performed using microscopy. In some embodiments, the neuronal structure measurement is improved. In some embodiments, neural structure measurements (e.g., the number of synapses) are increased.

[0101] In some embodiments, the measurement includes neuroinflammation measurement. In some embodiments, the neuroinflammation measurement includes the measurement of activated immune activation or reactive immune activation. In some embodiments, the neuroinflammation measurement includes the measurement of activated immune cells or reactive immune cells. In some embodiments, the neuroinflammation measurement includes reactive astrocyte measurement. In some embodiments, the neuroinflammation measurement includes activated microglia measurement. In some embodiments, the neuroinflammation measurement includes macrophage measurement. In some embodiments, the neuroinflammation measurement is obtained from tissue or fluid samples. In some embodiments, the neuroinflammation measurement is obtained by biopsy. In some embodiments, the neuroinflammation measurement is obtained by assays such as immunoassays, fluorescence-activated cell sorting (FACS), or histological evaluation.

[0102] In some embodiments, the measurement is an amyloidosis measurement. In some embodiments, the amyloidosis measurement includes an amyloid plaque measurement. In some embodiments, the amyloidosis measurement includes an amyloid-beta (Aβ) measurement. In some embodiments, the Aβ measurement includes an Aβ 1-42 Measurement is included. In some embodiments, Aβ measurement includes soluble Aβ measurement. In some embodiments, Aβ measurement includes soluble Aβ 1-42 Measurement is included. Amyloidosis measurement may include central nervous system (CNS) amyloidosis measurement. Amyloidosis measurement may include vascular amyloidosis measurement. In some embodiments, amyloidosis measurement includes concentration or volume. Amyloidosis measurement (e.g., amyloid plaque measurement) may be performed using an imaging device. Possible imaging devices include positron emission tomography (PET) scanners. Amyloidosis measurement may be performed using a biopsy. Amyloidosis measurement may be performed using a spinal puncture (e.g., if amyloidosis measurement includes cerebrospinal fluid (CSF) amyloidosis measurement). In some embodiments, amyloidosis measurement is obtained by an assay such as an immunoassay.

[0103] In some embodiments, the measurement is a molecular marker measurement. In some embodiments, the molecular marker measurement is a histone trimethylation (H3K9me3) measurement. In some embodiments, the molecular marker measurement is a protein measurement. In some embodiments, the molecular marker measurement is a brain-derived neurotrophic factor (BDNF) measurement. In some embodiments, the molecular marker measurement is an Aβ measurement. In some embodiments, the measurement includes a β-amyloid deposition measurement. In some embodiments, the protein measurement is the protein measurement shown in Figure 19A. The protein measurement in Figure 19A may increase compared to the baseline measurement. The protein measurement in Figure 19A may decrease compared to the baseline measurement. In some embodiments, the protein measurement is the protein measurement shown in Figure 19B. The protein measurement in Figure 19B may increase compared to the baseline measurement. The protein measurement in Figure 19B may decrease compared to the baseline measurement. In some embodiments, the measurement is the protein measurement shown in Figure 20 or a protein measurement. The protein measurement in Figure 20 may increase compared to the baseline measurement. The protein measurement in Figure 20 may decrease compared to the baseline measurement. In some embodiments, molecular marker measurements are taken by biopsy. In some embodiments, molecular marker measurements are taken using an immunoassay such as ELISA. In some embodiments, molecular marker measurements increase. For example, BDNF levels may increase after treatment with a compound. In some embodiments, molecular marker measurements decrease. For example, H3K9me3 levels or Aβ levels may decrease after treatment with a compound.

[0104] In some embodiments, administration improves the symptoms of Alzheimer's disease. In some embodiments, administration reduces the symptoms of Alzheimer's disease. In some embodiments, administration prevents the symptoms of Alzheimer's disease. In some embodiments, administration delays the symptoms of Alzheimer's disease. In some embodiments, administration slows the progression of Alzheimer's disease.

[0105] This specification describes methods for delaying the onset of Alzheimer's disease. In some embodiments, delaying the onset of Alzheimer's disease includes delaying the onset of at least one symptom of Alzheimer's disease. In some embodiments, the delay in the onset of at least one symptom is at least about 6 months, about 12 months, about 18 months, about 2 years, about 3 years, about 5 years, about 10 years, about 15 years, or about 20 years. In some embodiments, the delay in the onset of at least one symptom is at least 6 months. In some embodiments, the delay in the onset of at least one symptom is at least 12 months. In some embodiments, the delay in the onset of at least one symptom is at least 18 months. In some embodiments, the delay in the onset of at least one symptom is at least 2 years. In some embodiments, the delay in the onset of at least one symptom is at least 3 years. In some embodiments, the delay in the onset of at least one symptom is at least 5 years. In some embodiments, the delay in the onset of at least one symptom is at least 10 years. In some embodiments, the delay in the onset of at least one symptom is at least 15 years. In some embodiments, the delay in the onset of at least one symptom is at least 20 years.

[0106] In some embodiments, the delay in the onset of Alzheimer's disease includes the delay in the onset of just one symptom of Alzheimer's disease. In some embodiments, the delay in the onset of just one symptom is about 6 months or less, about 12 months or less, about 18 months or less, about 2 years or less, about 3 years or less, about 5 years or less, about 10 years or less, about 15 years or less, or about 20 years or less. In some embodiments, the delay in the onset of just one symptom is 6 months or less. In some embodiments, the delay in the onset of just one symptom is 12 months or less. In some embodiments, the delay in the onset of just one symptom is 18 months or less. In some embodiments, the delay in the onset of just one symptom is 2 years or less. In some embodiments, the delay in the onset of just one symptom is 3 years or less. In some embodiments, the delay in the onset of just one symptom is 5 years or less. In some embodiments, the delay in the onset of just one symptom is 10 years or less. In some embodiments, the delay in the onset of just one symptom is 15 years or less. In some embodiments, the delay in the onset of just one symptom is less than 20 years.

[0107] This specification describes methods for delaying the onset of at least one symptom of Alzheimer's disease. In some embodiments, the symptom includes memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech impairment, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality. In some embodiments, the symptom includes memory impairment. In some embodiments, the symptom includes difficulty concentrating. In some embodiments, the symptom includes difficulty completing familiar tasks. In some embodiments, the symptom includes confusion about time or place. In some embodiments, the symptom includes difficulty understanding visual images and spatial relationships. In some embodiments, the symptom includes speech impairment. In some embodiments, the symptom includes misplacing objects. In some embodiments, the symptom includes impaired or poor judgment. In some embodiments, the symptom includes withdrawal. In some embodiments, the symptom includes changes in mood or personality.

[0108] In some embodiments, the method improves memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech disorders, misplacing objects, impaired or poor judgment, social withdrawal, and / or mood or personality changes. In some embodiments, the method improves memory impairment. In some embodiments, the method improves difficulty concentrating. In some embodiments, the method improves difficulty completing familiar tasks. In some embodiments, the method improves confusion about time or place. In some embodiments, the method improves difficulty understanding visual images. In some embodiments, the method improves difficulty understanding spatial relationships. In some embodiments, the method improves difficulty understanding visual images and spatial relationships. In some embodiments, the method improves speech disorders. In some embodiments, the method improves misplacing objects. In some embodiments, the method improves impaired or poor judgment. In some embodiments, the method improves social withdrawal. In some embodiments, the method improves mood or personality changes.

[0109] In some embodiments, the treatment results in improvement in mental state tests and / or neuroimaging tests. In some embodiments, the treatment results in improvement in mental state tests. In some embodiments, the mental state test is a short-term mental state examination (MMSE), a Mini-Cog test, a Cantab Mobile test, a Cognigram test, a Cognivue test, or a Cognision test and an Automated Neuropsychological Assessment Measure (ANAM) test. In some embodiments, the mental state test is a short-term mental state examination (MMSE). In some embodiments, the mental state test is a Mini-Cog test. In some embodiments, the mental state test is a Cantab Mobile test. In some embodiments, the mental state test is a Cognigram test. In some embodiments, the mental state test is a Cognivue test. In some embodiments, the mental state test is a Cognision test and an Automated Neuropsychological Assessment Measure (ANAM) test. In some embodiments, the improvement includes an improved score compared to the score obtained before administration of the composition.

[0110] In some embodiments, the procedure results in an improvement in neuroimaging. In some embodiments, the neuroimaging is magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, the neuroimaging is an MRI scan. In some embodiments, the neuroimaging is a CT scan.

[0111] In some embodiments, the improvement includes reduced β-amyloid deposition compared to the amount of β-amyloid deposition measured before administration of the composition.

[0112] definition Unless otherwise defined, all technical terms, notations, and other scientific or specialized terms used herein are intended to have the same meaning as generally understood by those skilled in the art relating to the claimed subject matter. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for immediate reference, but the inclusion of such definitions herein should not necessarily be interpreted as indicating a substantial difference from the commonly understood meaning in the art.

[0113] Throughout this application, various embodiments may be presented in scope form. It should be understood that scope form is merely for convenience and brevity and should not be interpreted as an inflexible limitation to the scope of this disclosure. Therefore, a scope description should be considered to specifically disclose all possible sub-ranges and individual numbers within that range. For example, a scope description such as 1-6 should be considered to specifically disclose sub-ranges, e.g., 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0114] As used herein and in the claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. For example, the term "sample" includes multiple samples (including mixtures thereof).

[0115] The terms “determine,” “measure,” “evaluate,” “judge,” “analyze,” and “analyze” are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element exists or not (e.g., detection). These terms may include quantitative determination, qualitative determination, or quantitative and qualitative determination. Evaluation may be relative or absolute. “To detect the presence of ~” may include determining whether something exists or not, depending on the context, in addition to determining the quantity of something that exists.

[0116] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts. Any pharmaceutically acceptable salt of any of the compounds described herein is intended to include any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0117] "Pharmacologically acceptable acid addition salts" refer to salts formed by inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, that retain the biological effects and properties of the free base and are not biologically or otherwise undesirable. Salts formed by organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanos, hydroxyalkanoics, alkanedioic acids, aromatic acids, aliphatic sulfonic acids, and aromatic sulfonic acids, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, are also included. Accordingly, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Salts of amino acids, such as arginates, glucons, and galacturons, are also intended. In some embodiments, acid addition salts of basic compounds are prepared by contacting a free base form with a sufficient amount of the desired acid to produce a salt, according to methods and techniques well known to those skilled in the art.

[0118] "Pharmacologically acceptable base addition salts" refer to salts that retain the biological effects and properties of a free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines, such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Examples of salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0119] The terms “subject” and “patient” may be used interchangeably herein. “Subject” may be a biological entity containing expressed genetic material. A biological entity may be a plant, an animal, or a microorganism, such as bacteria, viruses, fungi, and protozoa. A subject may be a mammal. A mammal may be a human. A subject may be diagnosed or suspected of being at high risk of disease. In some cases, a subject may not necessarily be diagnosed or suspected of being at high risk of disease.

[0120] As used herein, the term "approximately" refers to a number within ±10% of that number. The range of "approximately" refers to a range of -10% of its lowest value and +10% of its highest value.

[0121] As used herein, the terms “treatment” or “to treat” are used in relation to a pharmaceutical intervention or other interventional treatment plan aimed at achieving beneficial or desirable outcomes in a recipient. Beneficial or desirable outcomes include, but are not limited to, therapeutic and / or preventive effects. Therapeutic effects may refer to the eradication or improvement of symptoms or the underlying disease to be treated. Therapeutic effects may also be achieved by eradicating or improving one or more physiological symptoms associated with the underlying disease so that improvement is observed in the subject, even if the subject may still have the underlying disease. Preventive effects include delaying, preventing, or eliminating the onset of the disease or condition; delaying or eliminating the onset of symptoms of the disease or condition; slowing, stopping, or reversing the progression of the disease or condition; or any combination thereof. Subjects at risk of developing a particular disease, or who report one or more physiological symptoms of the disease, may receive treatment for preventive effects, even if they have not been diagnosed with the disease.

[0122] The headings used in this specification are for organizational purposes only and should not be interpreted as limiting the subjects described.

[0123] Sequence information Some embodiments include one or more nucleic acid sequences from Table 1.

[0124] [Table 1]

[0125] Embodiment Some embodiments include one or more of the following embodiments. 1. A method for treating, preventing, or delaying the onset of Alzheimer's disease in a subject who needs to be treated, prevented, or have the onset of Alzheimer's disease, the method comprising administering a composition comprising ETP69 to the subject, wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. 2. The method according to Embodiment 1, wherein the familial Alzheimer's disease includes type 1 Alzheimer's disease. 3. The method according to Embodiment 1, wherein the familial Alzheimer's disease includes type 3 Alzheimer's disease. 4. The method according to Embodiment 1, wherein the familial Alzheimer's disease includes type 4 Alzheimer's disease. 5. The method according to Embodiment 1, wherein the at least one mutation associated with familial Alzheimer's disease includes a mutation in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene. 6. The method according to Embodiment 5, wherein the mutation in the APP gene encodes a mutation in the amino acid sequence of the amyloid precursor protein expressed from the APP gene. 7. The method according to Embodiment 6, wherein the mutation in the amyloid precursor protein amino acid sequence includes the mutation at valine 717 described in SEQ ID NO: 1. 8. The method according to Embodiment 7, wherein the valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). 9. The method according to Embodiment 6, wherein the mutation in the amyloid precursor protein amino acid sequence includes mutations at the positions of lysine 670 and methionine 671 as described in SEQ ID NO: 1. 10. The method according to Embodiment 9, wherein lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670 / 671NL). 11. The method according to embodiment 6, wherein the mutation in the amyloid precursor protein amino acid sequence comprises the mutation at glutamic acid 693 set forth in SEQ ID NO: 1. 12. The method according to embodiment 6, wherein the mutation in the APP gene encodes a deletion at the position of glutamic acid 693 of the amyloid precursor protein amino acid. 13. The method according to embodiment 11, wherein the glutamic acid 693 of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). 14. The method according to embodiment 6, wherein the mutation in the amyloid precursor protein amino acid sequence comprises the mutation at threonine 714 set forth in SEQ ID NO: 1. 15. The method according to embodiment 14, wherein the threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). 16. The method according to embodiment 6, wherein the mutation in the amyloid precursor protein amino acid sequence comprises the mutation at valine 715 set forth in SEQ ID NO: 1. 17. The method according to embodiment 16, wherein the valine 715 of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). 18. The method according to embodiment 6, wherein the mutation in the amyloid precursor protein amino acid sequence comprises the mutation at isoleucine 716 set forth in SEQ ID NO: 1. 19. The method according to embodiment 18, wherein the isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). 20. The method according to embodiment 5, wherein the mutation in the PSEN-1 gene encodes a mutation in the presenilin-1 amino acid sequence expressed from the PSEN-1 gene. 21. The method according to embodiment 20, wherein the mutation in the presenilin-1 amino acid sequence comprises the mutation at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 set forth in SEQ ID NO: 2. 22. The method according to embodiment 21, wherein the methionine 146 is mutated to leucine (M146L), the leucine 166 is mutated to proline (L166P), the isoleucine 213 is mutated to threonine (I213T), the arginine 278 is mutated to isoleucine (R278I), and the alanine 246 is mutated to glutamic acid (A246E). 23. The method according to embodiment 2, wherein the mutation of the PSEN-2 gene encodes a mutation in the presenilin-2 amino acid sequence expressed from the PSEN-2 gene. 24. The method according to embodiment 23, wherein the mutation in the presenilin-2 amino acid sequence includes a mutation at asparagine 141 or methionine 239 as set forth in SEQ ID NO: 3. 25. The method according to embodiment 24, wherein the asparagine 141 is mutated to isoleucine and the methionine 239 is mutated to valine. 26. The method according to embodiment 1, wherein the genetic risk factor associated with sporadic Alzheimer's disease includes that the subject is a carrier of the apolipoprotein (APOE) e4 allele. 27. The method according to embodiment 1, wherein the genetic risk factor associated with sporadic Alzheimer's disease includes a gene mutation. 28. The method according to embodiment 27, wherein the gene includes ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C. 29. The method according to any one of embodiments 1 to 28, wherein the subject has asymptomatic Alzheimer's disease. 30. The method according to any one of embodiments 1 to 29, wherein the subject is less than about 25 years old, less than about 30 years old, less than about 35 years old, less than about 40 years old, less than about 45 years old, less than about 50 years old, less than about 55 years old, less than about 60 years old, less than about 65 years old, or less than about 70 years old. 31. The method according to any one of Embodiments 1 to 30, wherein delaying the onset of Alzheimer's disease includes delaying the onset of at least one symptom of Alzheimer's disease. 32. The method according to Embodiment 31, wherein the delay in the onset of at least one symptom is at least about 6 months, about 12 months, about 18 months, about 2 years, about 3 years, about 5 years, about 10 years, about 15 years, or about 20 years. 33. The method according to Embodiment 31 or 32, wherein the symptoms include memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual and spatial relationships, speech impairment, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality. 34. The method according to any one of Embodiments 1 to 28, wherein the method improves memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech impairment, misplacing objects, impaired or poor judgment, social withdrawal, and / or changes in mood or personality. 35. The method according to Embodiment 34, wherein the treatment results in improvement in mental state tests and / or neuroimaging tests. 36. The method according to Embodiment 35, wherein the mental state test is a short-term mental state test (MMSE), Mini-Cog test, Cantab Mobile test, Cognigram test, Cognivue test, or Cognision test and Automated Neuropsychological Assessment Measurement (ANAM) test. 37. The method according to Embodiment 36, wherein the improvement includes a score that is improved compared to a score obtained before administration of the composition. 38. The method according to Embodiment 35, wherein the neuroimaging examination is magnetic resonance imaging (MRI) or computed tomography (CT). 39. The method according to Embodiment 38, wherein the improvement includes a reduction in β-amyloid deposition compared to the amount of β-amyloid deposition measured before administration of the composition. 40. A method for improving the cognition of a subject at risk of developing Alzheimer's disease, the method comprising administering a composition comprising ETP69 to the subject, wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. 41. The method according to Embodiment 40, wherein the familial Alzheimer's disease includes type 1 Alzheimer's disease. 42. The method according to Embodiment 40, wherein the familial Alzheimer's disease includes type 3 Alzheimer's disease. 43. The method according to Embodiment 40, wherein the familial Alzheimer's disease includes type 4 Alzheimer's disease. 44. The method according to Embodiment 40, wherein the at least one mutation associated with familial Alzheimer's disease includes a mutation in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene. 45. The method according to Embodiment 44, wherein the mutation in the APP gene encodes a mutation in the amino acid sequence of the amyloid precursor protein expressed from the APP gene. 46. ​​The method according to Embodiment 45, wherein the mutation in the amyloid precursor protein amino acid sequence includes the mutation at valine 717 described in SEQ ID NO: 1. 47. The method according to Embodiment 46, wherein the valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). 48. The method according to Embodiment 45, wherein the mutation in the amyloid precursor protein amino acid sequence includes mutations at the positions of lysine 670 and methionine 671 as described in SEQ ID NO: 1. 49. The method according to Embodiment 45, wherein lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670 / 671NL). 50. The method according to Embodiment 45, wherein the mutation in the amyloid precursor protein amino acid sequence includes the mutation at glutamic acid 693 described in SEQ ID NO: 1. 51. The method according to Embodiment 45, wherein the mutation in the APP gene encodes a deletion at the position of glutamic acid 693 of the amyloid precursor protein amino acid. 52. The method according to Embodiment 51, wherein the glutamic acid 693 of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). 53. The method according to Embodiment 45, wherein the mutation in the amyloid precursor protein amino acid sequence includes a mutation at threonine 714 as described in SEQ ID NO: 1. 54. The method according to Embodiment 53, wherein the threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). 55. The method according to Embodiment 45, wherein the mutation in the amyloid precursor protein amino acid sequence includes the mutation at valine 715 described in SEQ ID NO: 1. 56. The method according to Embodiment 55, wherein the valine 715 of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). 57. The method according to Embodiment 45, wherein the mutation in the amyloid precursor protein amino acid sequence includes the mutation at isoleucine 716 described in SEQ ID NO: 1. 58. The method according to Embodiment 57, wherein the isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). 59. The method according to Embodiment 44, wherein the mutation in the PSEN-1 gene encodes a mutation in the presenilin-1 amino acid sequence expressed from the PSEN-1 gene. 60. The method according to Embodiment 59, wherein the mutation in the presenilin-1 amino acid sequence includes a mutation at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 as described in SEQ ID NO: 2. 61. The method according to Embodiment 60, wherein methionine 146 is mutated to leucine (M146L), leucine 166 is mutated to proline (L166P), isoleucine 213 is mutated to threonine (I213T), arginine 278 is mutated to isoleucine (R278I), and alanine 246 is mutated to glutamic acid (A246E). 62. The method according to Embodiment 44, wherein the mutation in the PSEN-2 gene encodes a mutation in the presenilin-2 amino acid sequence expressed from the PSEN-2 gene. 63. The method according to Embodiment 62, wherein the mutation in the presenilin-2 amino acid sequence includes a mutation in asparagine 141 or methionine 239 as described in SEQ ID NO: 3. 64. The method according to Embodiment 63, wherein asparagine 141 is mutated to isoleucine and methionine 239 is mutated to valine. 65. The method according to Embodiment 40, wherein the genetic risk factor associated with sporadic Alzheimer's disease is that the subject is a carrier of apolipoprotein (APOE)e4 allele. 66. The method according to Embodiment 40, wherein the genetic risk factor associated with sporadic Alzheimer's disease includes a gene mutation. 67. The method according to Embodiment 66, wherein the gene comprises ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C. 68. The method according to any one of embodiments 40 to 67, wherein the subject is asymptomatic Alzheimer's disease. 69. The method according to any one of Embodiments 40 to 68, wherein the subject is under approximately 25 years of age, under approximately 30 years of age, under approximately 35 years of age, under approximately 40 years of age, under approximately 45 years of age, under approximately 50 years of age, under approximately 55 years of age, under approximately 60 years of age, under approximately 65 years of age, or under approximately 70 years of age. 70. The method according to any one of Embodiments 40 to 69, wherein the method improves memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech impairment, misplacing objects, impaired or poor judgment, social withdrawal, and / or changes in mood or personality. 71. The method according to Embodiment 70, wherein the treatment results in improvement in mental state tests and / or neuroimaging tests. 72. The method according to Embodiment 71, wherein the mental state test is a short-term mental state test (MMSE), a Mini-Cog test, a Cantab Mobile test, a Cognigram test, a Cognivue test, or a Cognision test and an Automated Neuropsychological Assessment Measurement (ANAM) test. 73. The method according to Embodiment 72, wherein the improvement includes a score that is improved compared to a score obtained before administration of the composition. 74. The method according to Embodiment 71, wherein the neuroimaging examination is magnetic resonance imaging (MRI) or computed tomography (CT). 75. The method according to Embodiment 74, wherein the improvement includes a reduction in β-amyloid deposition compared to the amount of β-amyloid deposition measured before administration of the composition. 76. A method for improving the cognition of a subject in need of cognitive improvement, comprising: (a) obtaining the results of a genetic test of the subject for at least one mutation associated with familial Alzheimer's disease; and (b) administering to the subject a composition comprising ETP69 if the genetic test indicates that the subject has at least one mutation associated with familial Alzheimer's disease. 77. The method according to Embodiment 76, wherein the familial Alzheimer's disease includes type 1 Alzheimer's disease. 78. The method according to Embodiment 76, wherein the familial Alzheimer's disease includes type 3 Alzheimer's disease. 79. The method according to Embodiment 76, wherein the familial Alzheimer's disease includes type 4 Alzheimer's disease. 80. The method according to Embodiment 76, wherein the at least one mutation associated with familial Alzheimer's disease includes a mutation in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene. 81. The method according to Embodiment 80, wherein the mutation in the APP gene encodes a mutation in the amino acid sequence of the amyloid precursor protein expressed from the APP gene. 82. The method according to Embodiment 81, wherein the mutation in the amyloid precursor protein amino acid sequence includes the mutation at valine 717 described in SEQ ID NO: 1. 83. The method according to Embodiment 82, wherein the valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). 84. The method according to Embodiment 81, wherein the mutation in the amyloid precursor protein amino acid sequence includes mutations at the positions of lysine 670 and methionine 671 as described in SEQ ID NO: 1. 85. The method according to Embodiment 84, wherein lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670 / 671NL). 86. The method according to Embodiment 81, wherein the mutation in the amyloid precursor protein amino acid sequence includes the mutation at glutamic acid 693 described in SEQ ID NO: 1. 87. The method according to Embodiment 81, wherein the mutation in the APP gene encodes a deletion at the position of glutamic acid 693 of the amyloid precursor protein amino acid. 88. The method according to Embodiment 86, wherein the glutamic acid 693 of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). 89. The method according to Embodiment 81, wherein the mutation in the amyloid precursor protein amino acid sequence includes a mutation at threonine 714 as described in SEQ ID NO: 1. 90. The method according to embodiment 89, wherein the threonine 714 of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). 91. The method according to embodiment 81, wherein the mutation in the amino acid sequence of the amyloid precursor protein comprises a mutation at valine 715 described in SEQ ID NO: 1. 92. The method according to embodiment 91, wherein the valine 715 of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). 93. The method according to embodiment 81, wherein the mutation in the amino acid sequence of the amyloid precursor protein comprises a mutation at isoleucine 716 described in SEQ ID NO: 1. 94. The method according to embodiment 94, wherein the isoleucine 716 of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). 95. The method according to embodiment 80, wherein the mutation in the PSEN-1 gene encodes a mutation in the presenilin-1 amino acid sequence expressed from the PSEN-1 gene. 96. The method according to embodiment 95, wherein the mutation in the presenilin-1 amino acid sequence comprises a mutation at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 described in SEQ ID NO: 2. 97. The method according to embodiment 96, wherein the methionine 146 is mutated to leucine (M146L), the leucine 166 is mutated to proline (L166P), the isoleucine 213 is mutated to threonine (I213T), the arginine 278 is mutated to isoleucine (R278I), and the alanine 246 is mutated to glutamic acid (A246E). 98. The method according to embodiment 80, wherein the mutation in the PSEN-2 gene encodes a mutation in the presenilin-2 amino acid sequence expressed from the PSEN-2 gene. 99. The method according to embodiment 98, wherein the mutation in the presenilin-2 amino acid sequence comprises a mutation at asparagine 141 or methionine 239 described in SEQ ID NO: 3. 100. The method according to Embodiment 99, wherein asparagine 141 is mutated to isoleucine and methionine 239 is mutated to valine. 101. A method for improving the cognition of a subject in need of cognitive improvement, comprising: (a) obtaining the results of a genetic test of the subject for at least one mutation associated with sporadic Alzheimer's disease; and (b) administering to the subject a composition comprising ETP69 if the genetic test indicates that the subject has at least one mutation associated with sporadic Alzheimer's disease. 102. The method according to Embodiment 101, wherein the at least one mutation associated with sporadic Alzheimer's disease comprises a mutation in the apolipoprotein (APOE)e4 gene. 103. The method according to Embodiment 102, wherein the mutation in the APOE e4 gene encodes a mutation in the apolipoprotein e4 amino acid sequence expressed from the APOE e4 gene. 104. The method according to Embodiment 101, wherein the genetic risk factors associated with sporadic Alzheimer's disease include gene mutations. 105. The method according to Embodiment 103, wherein the gene comprises ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C. 106. The method according to any of the above embodiments, wherein the administration results in an increase in synaptic integrity in the subject compared to the synaptic integrity measured before the administration of the composition. 107. The method according to any of the above embodiments, wherein the administration results in an increase in dendritic spine density compared to the dendritic spine density measured before administration of the composition. [Examples]

[0126] The following examples are provided to illustrate various embodiments of the present invention and are not intended to limit the invention in any way. The examples of the present invention, together with the methods described herein, represent preferred embodiments herein and are illustrative and not intended to limit the scope of the invention. Modifications and other uses that fall within the scope of the gist of the invention as defined by the claims will come to mind for those skilled in the art.

[0127] The examples described herein include results from five different cohorts that received a single intraperitoneal injection (S), additional intraperitoneal injection (B), or repeated intraperitoneal injection (R) of DMSO or ETP69 (10 mg / kg) in DMSO at 18 months (four cohorts) and 14 months (one cohort). In addition, a sixth cohort was orally administered OraB solution or ETP69 (50 mg / kg) in OraB.

[0128] Example 1: Treatment of a mouse model of Alzheimer's disease ETP69 was tested for its cognitive and visual rescue activity in a preclinical model of early-onset Alzheimer's disease (ADtg mice). Overall, a full set of spontaneous motor behavior, cognitive behavior, and visual behavior tests were performed in ADtg mice after a single or double injection of ETP69. The histological and biochemical effects of ETP69 on Alzheimer's disease were also determined. Effects on neuropathology associated with Alzheimer's disease, as well as on synaptic and neuronal structural integrity, were observed. Data on spontaneous motor function, cognitive function, and visual function in aged and young wild-type mice, as well as aged and young ADtg mice, are presented herein.

[0129] Such ADtg mice, being a transgenic model, can mimic early-onset human carriers of Alzheimer's disease mutations among human patients. For example, ADtg mice can mimic the effects of Alzheimer's disease on the brain or retina, and / or cognitive impairment, behavioral impairment, or visual impairment associated with human Alzheimer's disease. ADtg mice are a double transgenic mouse model of early-onset Alzheimer's disease. ADtg mice are 2xTg AD or APP. SWE / PS1 ΔE9 These mice can also be referred to as mice [Tg(APPswe,PSEN1dE9)85Dbo]. These well-established double transgenic mouse models of AD possess a mouse / human chimeric amyloid precursor protein (a human amyloid-beta (A4) precursor protein 695 (APP(Mo / HuAPP695swe))) which overexpresses a humanized version of the Swedish mutation (K670N, M671L) of familial Alzheimer's disease (FAD)), and a mutant human presenilin 1 (PS1-ΔE9; with exon 9 deletion), both of which are directed to CNS neurons under the control of a prion (Prn) protein promoter. These mice produce and secrete high levels of amyloidogenic human Aβ peptide. 1-42 The level is Aβ 1-40 It is more dominant, and both are found to dramatically aggregate into cerebral plaques and vascular deposits after 4-5 months of age. Amyloid-beta plaques accumulate in brain regions such as the cortex and hippocampus. By 5-6 months of age, ADtg mice also show synaptic loss and neuroinflammation (reactive astrocytes and activated microglia surrounding these plaques), and by 10 months of age, the mice begin to show signs of learning and memory impairment. Thus, 2XTg AD mice reproduce the major features of amyloid pathology in Alzheimer's disease, including amyloid plaque formation and soluble Aβ, which lead to neurodegeneration. 1-42 This could be a useful model for oligomers, vascular amyloidosis, enhanced phosphorylation of microtubule-associated protein tau, and neuroinflammation.

[0130] In these experiments, designed to partially test the therapeutic capacity of ETP69 in aged mice and Alzheimer's disease mouse models, the first objective was to test the improvement or retention of memory and spine formation, as well as the increase in BDNF, by ETP69 in aged WT mice. The second objective was to investigate the therapeutic capacity of ETP69 in preventing cognitive decline and synaptic loss in aged ADtg mice.

[0131] To test the cognitive-improving effect of ETP69 in a mouse model of Alzheimer's disease, wild-type and ADtg mice (18 months old, male and female) were administered either ETP69 or a vehicle (DMSO / saline). On day 1, mice were treated with an injection of 10 mg / kg of ETP69 or the vehicle. Subsequently, starting on day 2, mice were tested in a variety of behavioral tests, including a Y-maze, visual alternating behavior, open-field Barnes maze, and / or fear conditioning. On either day 4 or day 19, mice were sacrificed, and tissue was analyzed for histone trimethylation levels, Aβ levels, immunohistochemistry (GFAP, IGF1), spine number (Golgi-Cox staining), neurotrophic support, and synaptic markers. The experimental design is summarized in Figures 2A-2D.

[0132] The results of the Y-maze test indicate hippocampus-dependent spatial memory. In this test, ADtg mice treated with ETP69 showed improved spontaneous alternation behavior rates compared to mice treated with the vehicle (Figures 3A-3B).

[0133] The results of Koronyo's Visual X-Maze (Color) demonstrate visual cognitive memory and visual cognitive learning. In this test, ADtg mice treated with ETP69 showed improved rates of spontaneous alternation and bidirectional movement between colors compared to mice treated with the vehicle (Figures 4A-4J).

[0134] The results of the open-field Barnes maze test demonstrate hippocampus-dependent spatial learning and memory. In this test, ADtg mice treated with ETP69 showed improved memory retention, a reduced number of wrong entries, and reduced latency compared to mice treated with the vehicle (Figures 5A-5C).

[0135] The results of the fear conditioning test demonstrate spatial memory. In this test, ADtg mice treated with ETP69 showed memory protection and increased freezing time (Figures 6A-6B).

[0136] Golgi-Cox staining of brain tissue sections reveals the integrity of neuronal spines and neural structures. The Golgi-Cox method is a reliable and widely used method for studying brain cellular structure, revealing neuronal morphology and dendritic branching with low background. Chromium salts that bind to neuronal proteins are randomly formed during impregnation and then converted into black mercury sulfide deposits upon alkali treatment (Ramon-Moliner, 1970; Spacek, 1989; Rosoklija et al., 2014). The structure of the impregnated neuron, including the cell body, axon, dendrites, and spine, can be easily visualized. Qualitative observations of the brains of ADtg mice treated with ETP69 using these methods are expected to show a higher spine density compared to the brains of control ADtg mice injected with DMSO. Figures 7A–7D include Golgi-Cox stained images of whole neurons and their dendritic projections.

[0137] The novelty of this study lies in its investigation of the therapeutic effects of ETP69 in ADtg mice and aged wild-type mice. This point allows the results of these studies to be linked to early-onset Alzheimer's disease, whereas previous studies may not have been useful in this regard. The goal of these studies was to test the potential preservation and protection of visual and cognitive function by ETP69 using ADtg mice. A series of behavioral data show a significant protective effect. Further studies using ETP69, a specific inhibitor of SUV39H1, would evaluate additional parameters related to Alzheimer's disease pathology, neurotrophic secretion, histone methylation, and synaptic / neuronal integrity. Overall, these experiments provide evidence that ETP69 can preserve neural network integrity as well as cognitive and visual function. The preservation of cognitive and visual function in response to ETP69 treatment is relevant to the fields of neuroscience and neuro-ophthalmology (e.g., neurology, neurosurgery, and ophthalmology), and healthcare professionals in these fields may benefit from this data.

[0138] Additional experiments will analyze synaptic integrity and brain cell structure after administration of ETP69 to a mouse model of familial Alzheimer's disease. Histological and biochemical methods will be used to evaluate amyloid-beta-related Alzheimer's disease-associated pathology, to further confirm molecular mechanisms, and to further assess synaptic and neuronal retention and regeneration.

[0139] These results are also applicable to methods of administering histone methyltransferase inhibitors to treat and rescue cognitive and / or visual impairment in early-onset, late-onset, familial, or other types of Alzheimer's disease.

[0140] Example 2: Treatment of Alzheimer's disease The effects of single and repeated injections of ETP69 were tested in mice. The experimental timeline is shown in Figure 8. Three parallel injection conditions were tested, as shown in Table 2: single injection, additional injection, and repeated injection. Single-injection mice received one injection of ETP69 or DMSO on day 0. Additional injection mice received one injection of ETP69 or DMSO on day 0 and one injection on day 9. Repeated injection mice received 11 injections of ETP69 or DMSO on day 0 or day 9. Both wild-type and AD model (APP / PS1 transgenic) mice were tested.

[0141] [Table 2]

[0142] The effects of ETP69 on cognitive and visual function protection were tested using the Y-maze test. Both wild-type and AD+ mice treated with ETP69 showed a decrease in total entry counts (Figure 9A). This indicates a decrease in spontaneous motility. Looking at the alternation rate, a surrogate indicator of cognition, AD+ mice administered with DMSO showed a significant decrease compared to wild-type mice administered with DMSO. However, when AD+ mice were treated with ETP69, the alternation rate significantly increased (Figure 9B).

[0143] Figures 10A to 10D show the results for mice in the color mode of the visual stimulus X-maze test. Looking at the alternating behavior rate, a surrogate measure of cognition, AD+ mice administered with DMSO showed a significant decrease compared to wild-type mice administered with DMSO. However, when AD+ mice were treated with ETP69, the alternating behavior rate and bidirectional movement rate increased significantly (Figures 10A to 10D). Figures 10E to 10F show the results for the contrast mode of the visual stimulus X-maze test. Looking at the alternating behavior rate, AD+ mice administered with DMSO showed a significant decrease compared to wild-type mice administered with DMSO. However, when AD+ mice were treated with ETP69, the alternating behavior rate increased significantly.

[0144] The results of the open-field Barnes maze test demonstrate hippocampus-dependent spatial memory and learning. AD+ mice treated with ETP69 showed improved memory retention compared to AD+ mice treated with DMSO (Figures 11A-11C). A comparison of the results for single injection (S), replenishment injection (B), and repeated injection (R) is shown in Figures 11D-11H.

[0145] The results of the fear conditioning test demonstrate spatial memory. AD+ mice treated with ETP69 showed an increase in freezing time, which suggests memory protection (Figure 12).

[0146] To detect the cellular structure and morphology of nerve cells, the right hemisphere of 18-month-old mice was stained using the Golgi-Cox method. Figure 13A shows a representative image of the cingulate cortex of mice administered with DMSO or ETP69, and Figure 13B shows a representative image of the hippocampal region of mice treated with ETP69. Quantification of dendritic spines and elongated spines in the cingulate cortex and hippocampus showed an increase in dendritic spines and elongated (immature) spines in mice treated with ETP69 (Figures 13C-13D). Furthermore, AD+ mice treated with ETP69 showed a significant increase in the ratio of elongated spines to all spines compared to AD+ mice administered with DMSO alone (Figures 13E-13F). Spine retention by ETP69 was associated with a reduction in errors in the Barnes maze test (Figure 13G).

[0147] Brains of 18-month-old AD+ mice were stained for H3K9me3 and DAPI in neurons. Figure 14A is a representative image of H3K9me3 signaling across the cortical layer. Figure 14B is a representative image comparing brains treated with ETP69 and DMSO control. Quantification of H2K9me3 staining showed a significant decrease in TEP69-treated mice compared to wild-type mice in both the cortex and hippocampus (Figure 14C). Figure 14D shows immunohistochemistry of 6E10+ amyloid-β plaques and GFAP+ astrogliosis in coronal sections of AD+ mice treated with ETP69 or DMSO. Quantification shows a 42% decrease in the amount of 6E10 amyloid plaques detected in the brains of ETP69-treated mice (Figure 14E). AD+ mice showed a 6.8-fold increase in GFAP+ astrogliosis compared to wild-type mice. Treatment of AD+ mice with ETP69 resulted in a 58% reduction in GFAP luminescence (Figure 14F). Quantitative Western blot analysis and immunohistochemical analysis showed similar effects on GFAP levels in the hippocampus (Figure 14G).

[0148] These results are applicable to methods of treating Alzheimer's disease by administering histone methyltransferase inhibitors such as ETP69 to subjects, and provide evidence that the compositions disclosed herein are useful in treating cognitive and biochemical impairments associated with Alzheimer's disease, including familial Alzheimer's disease, early-onset Alzheimer's disease, and mid-to-late-stage Alzheimer's disease.

[0149] Example 3: Neuroprotective effect of ETP69 The effects of ETP69 injection were tested in 14-month-old mice. Wild-type mice were divided into two treatment groups: mice injected with ETP69 (n=10) and mice injected with DMSO (N=10). AD+ mice were also divided into two treatment groups: mice injected with ETP69 (n=8) and mice injected with DMSO (N=7). The experimental protocol is shown in Figure 15.

[0150] Mice were tested for visual cognitive memory and visual cognitive learning using a visual X-maze. ADP+ mice treated with ETP69 showed improved alternating behavior compared to untreated mice (Figures 16A-16D).

[0151] Fear conditioning tests were used to assess spatial memory. AD+ mice treated with ETP69 showed increased freezing time, suggesting memory protection (Figures 17A-17B).

[0152] Brain sections were stained for H3K9me3, 6E10, and GFAP. Representative images are shown in Figure 18A. Quantitative immunohistochemistry showed that AD+ mice treated with ET69 showed reduced levels of H3K9me3, 6E10, GFAP, and Iba1 compared to untreated AD+ mice (Figures 18B-18E).

[0153] Additional experiments demonstrated dramatic effects of ETP69 on brain macrophages, microglia, and astrocytes, beyond the range of neurons (Figures 21A–21L). These phagocytic inflammatory cells may be involved in immune activation and the removal of toxic Aβ. The restoration of the juvenile phenotype may explain the reduction of neuroinflammation and Aβ plaques in AD+ mice treated with ET69.

[0154] These results are applicable to methods for preventing or delaying the onset of Alzheimer's disease by administering histone methyltransferase inhibitors such as ETP69 to subjects, and provide evidence that the compositions disclosed herein are useful in preventing or delaying the onset of cognitive and biochemical impairments associated with Alzheimer's disease, including familial Alzheimer's disease, early-onset Alzheimer's disease, and mid-to-late-stage Alzheimer's disease.

[0155] Overall, experiments in these examples using multiple cohorts of 14 and 18-month-old AD mouse models (AD+ mice) and age / sex-matched control mice provide support for the possibility that the chromatin state of a subject can be altered by inhibiting the H3K9me3-modulating enzyme SUV39H1 with the compound ETP69 (also known as NT1721), thereby restoring memory and synaptic plasticity in the aging brain and AD brain. The therapeutic utility of ETP69 was demonstrated in experiments in both aged WT mice and established transgenic mouse models of AD (APPSWE / PS1ΔE9, AD+ mice) after a single intraperitoneal injection (S), an additional intraperitoneal injection (B), or weekly intraperitoneal repeated injections (R) of ETP69, as described in these examples. The data show that a significant reduction in brain H3K9m3 was achieved along with a reduction in AD-related pathologies (amyloidosis and neuroinflammation), restoration of synaptic integrity as spine density, and preservation of various aspects of cognitive function. In addition, mass spectrometry studies of the whole proteome profile identified several mechanisms of action of ETP69 in aged WT and AD+ mice. Among the proteins most upregulated after ETP69 administration were VGF and HP / HPX, which may be involved in the BDNF / TrkB signaling pathway and the antioxidant stress / anti-inflammatory pathway, respectively. Experiments with ETP69 have shown that it is generally safe and tolerable in humans. Therefore, ETP69 and related compounds may be useful in treating age-related neurological disorders, reversing the biological clock, preserving the integrity of neural networks, or restoring cognitive or visual function.

[0156] Example 4: Mass spectrometry analysis of pathway activation by ETP69 Figures 19A, 19B, and 20 include comprehensive proteome data obtained by mass spectrometry analysis. Figure 19A shows a comparison of upregulated proteins in ETP69-treated AD+ mice compared to untreated AD+ mice. Proteins such as VAV3, CORO2A, and HPX were upregulated in the brains of untreated AD+ mice. Some of these proteins, such as HPX, may be involved in antioxidant stress pathways or anti-inflammatory pathways. The analysis shows that the BDNF pathway is activated by ETP69 (Figure 19B, Z-score: 2.359, p<0.0001). Ingenuity analysis shows that ETP69 results in activation of proteins related to learning and cognition, as well as inhibition of proteins related to conditioning, anxiety, and other behaviors (Figure 20).

[0157] The expression of VGF, BDNF, and NCAM in 18-month-old AD+ mice after a single ETP69 injection was analyzed. Representative images are shown in Figure 22. A significant increase in BDNF and VGF expression was observed in the dentate gyrus and other hippocampal regions of 18-month-old AD-Tg mice after ETP69 treatment.

[0158] Example 5: Effect of oral ETP69 in 18-month-old mice 18-month-old wild-type and AD+ mice were administered an oral dose of 50 mg / kg of ETP69 or oraB once daily for 4 weeks. The experimental protocol is shown in Figure 23.

[0159] As shown in Figure 24A, mice were tested in an open field test on day 1. Standing behavior and total spontaneous kinetic energy were measured in mice administered oraB and ETP69 (Figures 24B-24G). On day 2, mice were tested in a color-mode visual stimulus X-maze. The results showed the beneficial effect of the oral formulation of ETP69 in reversing cognitive impairment in aged mice (Figures 25A-25E). On day 3, mice were tested in a contrast-mode visual stimulus X-maze. The results are shown in Figures 26A-26E.

[0160] On days 4–7, mice were tested in the training phase of the Barnes maze (Figure 27A). On day 10, mice were tested in the retention phase. On days 11–12, mice were tested in the reversal phase. The results are shown in Figures 27B–27E. A significant reversal of cognitive deficits was observed in aged AD model mice after oral administration of ETP69.

[0161] Preferred embodiments of the present invention have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided for illustrative purposes only. Those skilled in the art will readily come up with numerous modifications, changes, and alternatives that do not depart from the present invention. It should be understood that various alternative forms of the embodiments described herein can be used. The following claims define the scope of the present invention, and methods and configurations within the scope of these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

1. A composition comprising ETP69 for use in a method for treating, preventing, or delaying the onset of Alzheimer's disease in a subject who needs to be treated, prevented, or delayed the onset thereof, wherein the method comprises administering the composition to the subject, wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease, and the subject is at risk of developing early-onset Alzheimer's disease.

2. The composition according to claim 1, wherein the at least one mutation associated with familial Alzheimer's disease comprises a mutation in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene.

3. The composition according to claim 1, wherein the genetic risk factor associated with sporadic Alzheimer's disease includes the subject being a carrier of apolipoprotein (APOE) e4 allele.

4. The composition according to claim 1, wherein the genetic risk factors associated with sporadic Alzheimer's disease include mutations in genes comprising ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C.

5. The composition according to claim 1, wherein the subject does not have symptoms of Alzheimer's disease.

6. The composition according to claim 1, wherein delaying the onset of Alzheimer's disease includes delaying the onset of at least one symptom of Alzheimer's disease.

7. The composition according to claim 6, wherein the delay in the onset of at least one symptom is at least six months.

8. The composition according to claim 6, wherein the symptoms include memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech impairment, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality.

9. The composition according to claim 1, wherein the treatment results in improvement in mental state tests and / or neuroimaging tests.

10. A composition comprising ETP69 for use in a method to improve the cognition of a subject at risk of developing Alzheimer's disease, wherein the method comprises administering the composition to the subject, wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease, or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease, and the subject is at risk of developing early-onset Alzheimer's disease.

11. The composition according to claim 10, wherein the at least one mutation associated with familial Alzheimer's disease comprises a mutation in the amyloid precursor protein (APP) gene, the presenilin-1 (PSEN1) gene, or the presenilin-2 (PSEN2) gene.

12. The composition according to claim 10, wherein the genetic risk factor associated with sporadic Alzheimer's disease is that the subject is a carrier of apolipoprotein (APOE) e4 allele.

13. The composition according to claim 10, wherein the genetic risk factors associated with sporadic Alzheimer's disease include mutations in genes comprising ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5 / DRB1, INPP5D, MEF2C, MS4A6A / MS4A4E, PICALM, PLD3, ACE, PTK2B, SORL1, TREM2, or UNC5C.

14. The composition according to claim 10, wherein the subject does not have symptoms of Alzheimer's disease.

15. The composition according to claim 10, wherein the method improves the subject's memory impairment, difficulty concentrating, difficulty completing familiar tasks, confusion about time or place, difficulty understanding visual images and spatial relationships, speech impairment, misplacing objects, impaired or poor judgment, withdrawal, and / or changes in mood or personality, the improvement comprising a score improved compared to a score obtained before administration of the composition.

16. The composition according to claim 15, wherein the treatment results in improvement in mental state tests and / or neuroimaging tests.

17. The composition according to claim 16, wherein the mental state test is a short-duration mental state test (MMSE), a Mini-Cog test, a Cantab Mobile test, a Cognigram test, a Cognivue test, or a Cognition test and an automated neuropsychological assessment measurement (ANAM) test.

18. The composition according to claim 1 or 10, wherein the improvement includes a reduction in β-amyloid deposition compared to the amount of β-amyloid deposition measured before administration of the composition.

19. The composition according to claim 1 or 10, wherein administration results in an increase in synaptic integrity in the subject compared to synaptic integrity measured before administration of the composition.

20. The composition according to claim 1 or 10, wherein administration results in an increase in dendritic spine density compared to the dendritic spine density measured before administration of the composition.

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