Methods for reducing amyloid beta monomer levels in patients with cognitive decline

Abstract

A pharmaceutical composition for reducing amyloid-beta monomer levels is provided. A pharmaceutical composition for reducing amyloid beta monomer levels in a subject, the composition comprising a therapeutically effective amount of a compound of formula: TIFF2026041805000013.tif44123 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient, to be administered to said subject.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 976,325, entitled "Method of Decreasing Amyloid Beta Monomer Levels in Patients with Cognitive Decline," filed February 13, 2020, the entire contents of which are incorporated herein by reference.

[0002] This invention was made with government support under grants R43NS083175 awarded by the National Institute of Neurological Disorders and Stroke and grants R43AG037337, R44AG055247, R01AG051593, R01AG054176, R01AG057780, and R01AG058660 awarded by the National Institute on Aging. The government has certain rights in this invention. Summary of the Invention [Means for solving the problem]

[0003] The present invention is as follows: The present disclosure relates to a method for reducing amyloid beta monomers and a method for treating cognitive decline in a subject, wherein treatment results in an increase in amyloid beta oligomers and a reduction in cognitive decline. The present disclosure relates to treating cognitive decline, wherein target engagement can be measured clinically after treatment. [Brief explanation of the drawings]

[0004] [Figure 1] Figure 1 shows the rate of change in Aβ oligomer levels in patients measured with microimmunoelectrodes. [Figure 2] FIG. 2 shows the percent change in Aβ oligomer levels in the CSF of patients as measured by Western blot. [Figure 3]FIG. 3 illustrates the correlation between Aβ oligomers measured by microimmunoelectrode and Western blot, calculated by Spearman correlation analysis. [Figure 4] FIG. 4 shows CT1812 associated with an increase in Aβ oligomers over time in the patient's CSF, as measured by microimmunoelectrodes. [Figure 5] FIG. 5 shows that CT1812 is associated with an increase in Aβ oligomers over time in patient CSF as measured by Western blot. [Figure 6] FIG. 6 shows the concentrations of CT1812 in the plasma and CSF of patients after treatment. [Figure 7] Figure 7 shows the 3-point difference in Alzheimer's Disease Assessment Scale (ADAS-COG) scores between treated and untreated patients 185 days after administration. [Figure 8] FIG. 8 shows the reduction in Aβ monomer (Aβ1-42) levels in patients receiving a total of 300 mg of CT1812 per day for 185 days. DETAILED DESCRIPTION OF THE INVENTION

[0005] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0006] As used herein, the articles "a" and "an" mean "one or more" or "at least one," unless otherwise indicated. That is, the reference to any element of the invention by the indefinite article "a" or "an" does not exclude the possibility that a plurality of that element is present.

[0007] As used herein, the term "about" means plus or minus 10% of the number with which it is used. Thus, about 50% means in the range of 45% to 55%.

[0008] "Administering," "administration," and the like, when used in connection with a compound of the present disclosure, means providing a compound or pharmaceutical composition according to any of the embodiments described herein to a subject in need of treatment. Preferably, the subject is a mammal, more preferably a human. The present invention includes administering a compound or pharmaceutical composition of the present invention alone or in combination with other therapeutic agents. When administering a compound or pharmaceutical composition of the present invention in combination with other therapeutic agents, the compound or pharmaceutical composition of the present invention and the other therapeutic agents can be administered at the same or different times, and by the same or different routes of administration. The compound can be administered orally, intravenously, intraperitoneally, or by other routes of administration known in the art.

[0009] The term "amyloid-beta level" as used herein includes any measurement of the amount of amyloid-beta measured in a sample taken from a subject. Samples can include, but are not limited to, cerebrospinal fluid, hippocampal interstitial fluid, and plasma. The amount of amyloid-beta can be measured using any method that measures the concentration or amount of protein, including, but not limited to, using microimmunoelectrodes or Western blot.

[0010] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.

[0011] As used herein, "cognitive decline" can refer to any negative change in an animal's cognitive function. For example, cognitive decline can include, but is not limited to, memory loss (e.g., behavioral memory loss), failure to acquire new memories, confusion, impaired judgment, personality changes, disorientation, or any combination thereof. Compounds effective in treating cognitive decline can thus restore the balance of long-term neuronal potentiation (LTP) or long-term neuronal depression (LTD) or synaptic plasticity measured electrophysiologically; inhibit, treat, and / or reduce neurodegeneration; inhibit, treat, and / or reduce general amyloidosis; inhibit, treat, or reduce one or more of amyloidogenesis, amyloid assembly, amyloid aggregation, and amyloid oligomer binding; reduce one or more non-lethal effects of Aβ species on neuronal cells (synaptic loss or dysfunction and and any combination thereof, and further, the compounds may be effective in treating Aβ-related neurodegenerative diseases and disorders, including dementias including, but not limited to, Alzheimer's disease (AD), including mild Alzheimer's disease, Down's syndrome, vascular dementia (cerebral amyloid angiopathy and stroke), dementia with Lewy bodies, HIV dementia, mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-associated cognitive decline (ARCD), preclinical Alzheimer's disease (PCAD), and cognitive impairment without (CIND).

[0012] The phrase "pharmaceutically acceptable" refers to a compound, material, pharmaceutical composition, and / or dosage form that is generally regarded as safe and non-toxic within the scope of sound medical judgment. In particular, pharmaceutically acceptable carriers, diluents, or other excipients used in the pharmaceutical compositions of the present disclosure are physiologically tolerable, compatible with the other ingredients, and do not normally produce an allergic or similar unpleasant reaction (e.g., stomach upset, dizziness, etc.) when administered to a patient. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0013] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines, and alkali or organic acid salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, salvanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfone, methanesulfone, ethanedisulfone, oxalic acid, and isothione. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, the disclosure of which is incorporated herein by reference.

[0014] The terms "subject," "individual," or "patient" are used interchangeably and, as used herein, are intended to include human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals such as non-human primates, sheep, dogs, cats, cows, and horses are preferred. Preferred subjects include human patients. The present method is particularly suitable for treating human patients having a condition, disease, or disorder described herein.

[0015] As used herein, the term "therapeutic" refers to an agent utilized to treat, combat, ameliorate, prevent or ameliorate an undesirable condition or disease in a patient.

[0016] A "therapeutically effective amount" of a compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition according to any embodiment described herein is an amount sufficient to produce a selected effect on at least one symptom or parameter of a particular disease or disorder. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject sees or feels an effect, or the physician observes a change). The effect contemplated herein includes both medical treatment and / or prophylactic treatment, as appropriate. The specific dose of a compound administered in accordance with the present disclosure to achieve a therapeutic and / or prophylactic effect will be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, co-administration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the patient's age, weight, general health, sex, and diet, the time of administration of the specific compound employed, the route of administration, the excretion rate, and the duration of treatment. The therapeutically effective amount to be administered will be determined by the physician, exercising sound medical judgment, in light of the relevant circumstances described above. A therapeutically effective amount of a compound according to any embodiment described herein is typically an amount that is sufficient to achieve an effective systemic concentration or local concentration in a tissue when administered in a physiologically acceptable excipient composition.

[0017] As used herein, the terms "treat," "treated," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to obtain beneficial or desired clinical results, such as protection from (partially or fully) or delay (e.g., attenuating or postponing onset) an undesirable physiological condition, disorder, or disease, or partial or total restoration or inhibition of the decline of a parameter, value, function, or outcome that is or becomes abnormal. For purposes of this disclosure, beneficial or desired clinical results include alleviation of symptoms; reduction in the severity, momentum, or rate of onset of a condition, disorder, or disease; stabilization (i.e., non-worsening) of the condition, disorder, or disease state; delay in onset or slowing of progression of a condition, disorder, or disease state; and immediate relief of actual clinical symptoms, or remission (whether partial or total), regardless of whether it leads to an enhancement or amelioration of the condition, disorder, or disease. Treatment seeks to elicit a clinically significant response without excessive side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment.

[0018] method The present disclosure relates to clinical results in humans, which were surprising and unexpected in light of information available to those skilled in the art. Animal models and preclinical data suggested that CT1812 can selectively displace oligomers and increase their concentrations in cerebrospinal fluid and brain interstitial fluid, but does not affect the concentration of monomers. This is supported by data from human subjects treated with CT1812 for 28 days, which resulted in no change in amyloid beta monomer concentrations in cerebrospinal fluid or interstitial fluid (62 / 976,325 incorporated herein by reference). The results presented herein are surprising and unexpected, as are methods for reducing amyloid beta in human subjects, as are methods for increasing amyloid beta oligomer levels in human subjects, as are methods for increasing amyloid beta oligomer levels in human subjects, as are methods for increasing amyloid beta oligomer levels in human subjects.

[0019] In some embodiments, the present disclosure provides a therapeutically effective amount of a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof to the subject.

[0020] In some embodiments described herein, the subject is a human. In some embodiments described herein, the subject is a subject with cognitive decline. In some embodiments described herein, the subject is a subject with cognitive decline, and the cognitive decline is Alzheimer's disease. In some embodiments described herein, the subject is a subject with Alzheimer's disease.

[0021] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered by a route selected from the group consisting of oral administration, intravenous administration, intramuscular administration, subcutaneous administration, intranasal administration, intradermal administration, and topical administration. In some embodiments, the compound may be formulated as a tablet, a capsule, a powder, a solution, a suspension, and an emulsion.

[0022] In some embodiments, a total daily dose of 10 mg to 2000 mg of compound is administered. The total daily dose of the disclosed compound can be administered to a subject in a single dose or in divided doses. In some embodiments, the dose is 100 mg per day, in some embodiments, the dose is 300 mg per day, and in some embodiments, the dose is 560 mg. In some embodiments, a total dose of 100 mg of compound per day is administered for at least about 6 months. In some embodiments, a total dose of 300 mg of compound per day is administered for at least about 6 months. In some embodiments, a total dose of 560 mg per day is administered for at least about 6 months. In some embodiments, the total daily dose is about 10 mg to about 2000 mg, about 100 mg to about 2000 mg, about 200 mg to about 2000 mg, about 300 mg to about 2000 mg, about 400 mg to about 2000 mg, about 500 mg to about 2000 mg, about 600 mg to about 2000 mg, about 700 mg to about 2000 mg, about 800 mg to about 2000 mg, about 900 mg to about 2000 mg, about 1000 mg to about 2000 mg, about 1200 mg to about 2000 mg, about 1400 mg to about 2000 mg, about 1600 mg to about 2000 mg, about 1800 mg to about 2000 mg, or a value within these ranges. Specific examples include about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, 2000 mg, or a value within a range of any two of these values.

[0023] In some embodiments, CT1812 is administered for at least 6 months. In some embodiments, CT1812 is administered for about 1 day to about 50 years. In some embodiments, CT1812 is administered for about 1 day to about 1 year. In some embodiments, CT1812 is administered for about 1 day to about 6 months, about 3 days to about 6 months, about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 1 month to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 6 months, or any value within these ranges. Specific examples may include about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1 year, or a range between any two of these values.

[0024] In some embodiments, administration of CT1812 results in a change in amyloid beta levels in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, administration of CT1812 results in a decrease in amyloid beta monomer levels. In some embodiments, the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42. In some embodiments, administration of CT1812 results in an increase in amyloid beta oligomers in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, the amyloid beta level after administration of CT1812 is relative to the amyloid beta level before administration of CT1812. In some embodiments, the amyloid beta level is measured using a microimmunoelectrode. In some embodiments, the amyloid beta level is measured using Western blot. In some embodiments, the amyloid beta level is measured using ELISA (enzyme-linked immunosorbent assay).

[0025] In some embodiments, administration of CT1812 results in a reduction in cognitive decline. In some embodiments, administration of CT1812 prevents cognitive decline. In some embodiments, administration of CT1812 results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in maintaining the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in a decrease of at least 3 points in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment.

[0026] In some embodiments, the present disclosure provides a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.

[0027] In some embodiments, the subject is a human. In some embodiments described herein, the subject is a subject with cognitive decline. In some embodiments described herein, the subject is a subject with cognitive decline, wherein the cognitive decline is Alzheimer's disease. In some embodiments described herein, the subject is a subject with Alzheimer's disease.

[0028] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered by a route selected from the group consisting of oral administration, intravenous administration, intramuscular administration, subcutaneous administration, intranasal administration, intradermal administration, and topical administration. In some embodiments, the compound may be formulated as a tablet, a capsule, a powder, a solution, a suspension, and an emulsion.

[0029] In some embodiments, a total daily dose of 10 mg to 2000 mg of the compound in the pharmaceutical composition is administered. The total daily dose of the compound of the present disclosure can be administered to a subject in a single dose or in divided doses. In some embodiments, the dose of the compound in the pharmaceutical composition is 100 mg per day, in some embodiments, the dose of the compound in the pharmaceutical composition is 300 mg per day, and in some embodiments, the dose of the compound in the pharmaceutical composition is 560 mg per day. In some embodiments, a total daily dose of 100 mg of the compound in the pharmaceutical composition is administered for at least about 6 months. In some embodiments, a total daily dose of 300 mg of the compound in the pharmaceutical composition is administered for at least about 6 months. In some embodiments, a total daily dose of about 560 mg of the compound in the pharmaceutical composition is administered for at least about 6 months. In some embodiments, the total daily dose is about 10 mg to about 2000 mg, about 100 mg to about 2000 mg, about 200 mg to about 2000 mg, about 300 mg to about 2000 mg, about 400 mg to about 2000 mg, about 500 mg to about 2000 mg, about 600 mg to about 2000 mg, about 700 mg to about 2000 mg, about 800 mg to about 2000 mg, about 900 mg to about 2000 mg, about 1000 mg to about 2000 mg, about 1200 mg to about 2000 mg, about 1400 mg to about 2000 mg, about 1600 mg to about 2000 mg, about 1800 mg to about 2000 mg, or a value within these ranges. Specific examples include about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, 2000 mg, or a value within a range of any two of these values.

[0030] In some embodiments, the pharmaceutical composition is administered for at least 6 months. In some embodiments, the pharmaceutical composition is administered for about 1 day to about 50 years. In some embodiments, the pharmaceutical composition is administered for about 1 day to about 1 year. In some embodiments, the pharmaceutical composition is administered for about 1 day to about 6 months, about 3 days to about 6 months, about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 1 month to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 6 months, or values ​​within these ranges. Specific examples include about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1 year, or a range between any of these two values.

[0031] In some embodiments, administration of CT1812 results in a change in amyloid beta levels in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, administration of CT1812 results in a decrease in amyloid beta monomer levels. In some embodiments, the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42. In some embodiments, administration of CT1812 results in an increase in amyloid beta oligomers in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, the amyloid beta level after administration of CT1812 is relative to the amyloid beta level before administration of CT1812. In some embodiments, the amyloid beta level is measured using a microimmunoelectrode. In some embodiments, the amyloid beta level is measured using Western blot. In some embodiments, the amyloid beta level is measured using ELISA (enzyme-linked immunosorbent assay).

[0032] In some embodiments, administration of the pharmaceutical composition results in a reduction in cognitive decline. In some embodiments, administration of the pharmaceutical composition prevents cognitive decline. In some embodiments, administration of the pharmaceutical composition results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of the pharmaceutical composition results in a maintenance of the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of the pharmaceutical composition results in a decrease of at least 3 points in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment.

[0033] In some embodiments, the present disclosure provides a therapeutically effective amount of a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof to the subject.

[0034] In some embodiments described herein, the subject is a human. In some embodiments described herein, the subject is a subject with cognitive decline. In some embodiments described herein, the subject is a subject with cognitive decline, and the cognitive decline is Alzheimer's disease. In some embodiments described herein, the subject is a subject with Alzheimer's disease.

[0035] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered by a route selected from the group consisting of oral administration, intravenous administration, intramuscular administration, subcutaneous administration, intranasal administration, intradermal administration, and topical administration. In some embodiments, the compound may be formulated as a tablet, as a capsule, as a powder, as a solution, as a suspension, and as an emulsion.

[0036] In some embodiments, a total daily dose of 10 mg to 2000 mg of compound is administered. The total daily dose of the compound of the present disclosure can be administered to a subject in a single dose or in divided doses. In some embodiments, the dose is 100 mg per day, in some embodiments, the dose is 300 mg per day, and in some embodiments, the dose is about 560 mg per day. In some embodiments, a total daily dose of 100 mg of the compound is administered once. In some embodiments, a total daily dose of 300 mg of the compound is administered once. In some embodiments, a total daily dose of 560 mg of the compound is administered once. In some embodiments, the total daily dose is about 10 mg to about 2000 mg, about 100 mg to about 2000 mg, about 200 mg to about 2000 mg, about 300 mg to about 2000 mg, about 400 mg to about 2000 mg, about 500 mg to about 2000 mg, about 600 mg to about 2000 mg, about 700 mg to about 2000 mg, about 800 mg to about 2000 mg, about 900 mg to about 2000 mg, about 1000 mg to about 2000 mg, about 1200 mg to about 2000 mg, about 1400 mg to about 2000 mg, about 1600 mg to about 2000 mg, about 1800 mg to about 2000 mg, or a value within these ranges. Specific examples include about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, 2000 mg, or a value within a range of any two of these values.

[0037] In some embodiments, CT1812 is administered once. In some embodiments, CT1812 is administered for at least 6 months. In some embodiments, CT1812 is administered for about 1 day to about 50 years. In some embodiments, CT1812 is administered for about 1 day to about 1 year. In some embodiments, CT1812 is administered for about 1 day to about 6 months, about 3 days to about 6 months, about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 1 month to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 6 months, or values ​​within these ranges. Specific examples include about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1 year, or a value within a range of any two of these values.

[0038] In some embodiments, the amyloid beta oligomer level is measured within 24 hours of administration of CT1812. In some embodiments, the amyloid beta oligomer level is measured within 1 week of administration of CT1812. In some embodiments, the amyloid beta oligomer level is measured within 1 month of administration of CT1812. In some embodiments, the amyloid beta oligomer level is measured within 6 months of administration of CT1812. In some embodiments, the amyloid beta oligomer level is measured within about 15 minutes to about 12 months after administration of CT1812, about 15 minutes to about 24 hours after administration of CT1812, about 30 minutes to about 24 hours after administration of CT1812, about 45 minutes to about 24 hours after administration of CT1812, about 1 hour to about 24 hours after administration of CT1812, about 2 hours to about 24 hours after administration of CT1812, or about 3 months after administration of CT1812. about 4 hours to about 24 hours after CT1812 administration, about 6 hours to about 24 hours after CT1812 administration, about 8 hours to about 24 hours after CT1812 administration, about 10 hours to about 24 hours after CT1812 administration, about 12 hours to about 24 hours after CT1812 administration, about 16 hours to about 24 hours after CT1812 administration, about 20 hours to about 24 hours after CT1812 administration, CT1812 Approximately 1 day to 7 days after administration, approximately 2 days to 7 days after administration of CT1812, approximately 1 week to 4 weeks after administration of CT1812, approximately 2 weeks to 4 weeks after administration of CT1812, approximately 3 weeks to 4 weeks after administration of CT1812, approximately 1 month to 12 months after administration of CT1812, approximately 2 months to 12 months after administration of CT1812, approximately 3 months to 12 months after administration of CT1812, approximately 4 months to Measurements are taken at approximately 12 months, approximately 5 to 12 months after administration of CT1812, approximately 6 to 12 months after administration of CT1812, approximately 7 to 12 months after administration of CT1812, approximately 8 to 12 months after administration of CT1812, approximately 9 to 12 months after administration of CT1812, approximately 10 to 12 months after administration of CT1812, and approximately 11 to 12 months after administration of CT1812.

[0039] In some embodiments, the amyloid beta level is indicative of subject involvement after administration of CT1812. In some embodiments, the amyloid beta level increases after administration of CT1812, and the increase in the amyloid beta level is indicative of subject involvement.

[0040] In some embodiments, administration of CT1812 results in a change in amyloid beta levels in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, administration of CT1812 results in a decrease in amyloid beta monomer levels. In some embodiments, the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42. In some embodiments, administration of CT1812 results in an increase in amyloid beta oligomers in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, the amyloid beta level after administration of CT1812 is relative to the amyloid beta level before administration of CT1812. In some embodiments, the amyloid beta level is measured using a microimmunoelectrode. In some embodiments, the amyloid beta level is measured using Western blot. In some embodiments, the amyloid beta level is measured using ELISA (enzyme-linked immunosorbent assay).

[0041] In some embodiments, administration of CT1812 results in a reduction in cognitive decline. In some embodiments, administration of CT1812 prevents cognitive decline. In some embodiments, administration of CT1812 results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in maintaining the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in a decrease of at least 3 points in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment.

[0042] In some embodiments, the present disclosure provides a therapeutically effective amount of a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof to the subject.

[0043] In some embodiments described herein, the subject is a human. In some embodiments described herein, the subject is a subject with cognitive decline. In some embodiments described herein, the subject is a subject with cognitive decline, and the cognitive decline is Alzheimer's disease. In some embodiments described herein, the subject is a subject with Alzheimer's disease.

[0044] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered by a route selected from the group consisting of oral administration, intravenous administration, intramuscular administration, subcutaneous administration, intranasal administration, intradermal administration, and topical administration. In some embodiments, the compound may be formulated as a tablet, a capsule, a powder, a solution, a suspension, and an emulsion.

[0045] In some embodiments, a total daily dose of the compound is administered between 10 mg and 2000 mg. The total daily dose of the compound of the present disclosure may be administered to a subject in a single dose or in divided doses. In some embodiments, the dose is 100 mg per day, in some embodiments, the dose is 300 mg per day, and in some embodiments, the dose is about 560 mg. In some embodiments, a total daily dose of 100 mg of the compound is administered for at least about 6 months. In some embodiments, a total daily dose of 300 mg of the compound is administered for at least about 6 months. In some embodiments, a total daily dose of about 560 mg of the compound is administered for at least about 6 months. In some embodiments, the total daily dose is about 10 mg to about 2000 mg, about 100 mg to about 2000 mg, about 200 mg to about 2000 mg, about 300 mg to about 2000 mg, about 400 mg to about 2000 mg, about 500 mg to about 2000 mg, about 600 mg to about 2000 mg, about 600 mg to about 2000 mg, about 700 mg to about 2000 mg, about 800 mg to about 2000 mg, about 900 mg to about 2000 mg, about 1000 mg to about 2000 mg, about 1200 mg to about 2000 mg, about 1400 mg to about 2000 mg, about 1600 mg to about 2000 mg, about 1800 mg to about 2000 mg, or a value within these ranges. Specific examples include about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, 2000 mg, or a value within a range of any two of these values.

[0046] In some embodiments, CT1812 is administered for at least 6 months. In some embodiments, CT1812 is administered for about 1 day to about 50 years. In some embodiments, CT1812 is administered for about 1 day to about 1 year. In some embodiments, CT1812 is administered for about 1 day to about 6 months, about 3 days to about 6 months, about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 1 month to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 6 months, or any value within these ranges. Specific examples include about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1 year, or a value within a range of any two of these values.

[0047] In some embodiments, administration of CT1812 results in a change in amyloid beta levels in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, administration of CT1812 results in a decrease in amyloid beta monomer levels. In some embodiments, the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42. In some embodiments, administration of CT1812 results in an increase in amyloid beta oligomers in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, the amyloid beta level after administration of CT1812 is relative to the amyloid beta level before administration of CT1812. In some embodiments, the amyloid beta level is measured using a microimmunoelectrode. In some embodiments, the amyloid beta level is measured using Western blot. In some embodiments, the amyloid beta level is measured using ELISA (enzyme-linked immunosorbent assay).

[0048] In some embodiments, administration of CT1812 results in a reduction in cognitive decline. In some embodiments, administration of CT1812 prevents cognitive decline. In some embodiments, administration of CT1812 results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in maintaining the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in a decrease of at least 3 points in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment.

[0049] In some embodiments, the present disclosure provides a therapeutically effective amount of a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof to the subject.

[0050] In some embodiments described herein, the subject is a human. In some embodiments described herein, the subject is a subject with cognitive decline. In some embodiments described herein, the subject is a subject with cognitive decline, and the cognitive decline is Alzheimer's disease. In some embodiments described herein, the subject is a subject with Alzheimer's disease.

[0051] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered by a route selected from the group consisting of oral administration, intravenous administration, intramuscular administration, subcutaneous administration, intranasal administration, intradermal administration, and topical administration. In some embodiments, the compound may be formulated as a tablet, a capsule, a powder, a solution, a suspension, and an emulsion.

[0052] In some embodiments, a total daily dose of the compound is administered between 10 mg and 2000 mg. The total daily dose of the compound of the present disclosure may be administered to a subject in a single dose or in divided doses. In some embodiments, the dose is 100 mg per day, in some embodiments, the dose is 300 mg per day, and in some embodiments, the dose is about 560 mg. In some embodiments, a total daily dose of 100 mg of the compound is administered for at least about 6 months. In some embodiments, a total daily dose of 300 mg of the compound is administered for at least about 6 months. In some embodiments, a total daily dose of 560 mg of the compound is administered for at least about 6 months. In some embodiments, the total daily dose is about 10 mg to about 2000 mg, about 100 mg to about 2000 mg, about 200 mg to about 2000 mg, about 300 mg to about 2000 mg, about 400 mg to about 2000 mg, about 500 mg to about 2000 mg, about 600 mg to about 2000 mg, about 700 mg to about 2000 mg, about 800 mg to about 2000 mg, about 900 mg to about 2000 mg, about 1000 mg to about 2000 mg, about 1200 mg to about 2000 mg, about 1400 mg to about 2000 mg, about 1600 mg to about 2000 mg, about 1800 mg to about 2000 mg, or a value within these ranges. Specific examples include about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, 2000 mg, or a value within a range of any two of these values.

[0053] In some embodiments, CT1812 is administered for at least 6 months. In some embodiments, CT1812 is administered for about 1 day to about 50 years. In some embodiments, CT1812 is administered for about 1 day to about 1 year. In some embodiments, CT1812 is administered for about 1 day to about 6 months, about 3 days to about 6 months, about 1 week to about 6 months, about 2 weeks to about 6 months, about 3 weeks to about 6 months, about 1 month to about 6 months, about 2 months to about 6 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 6 months, or any value within these ranges. Specific examples include about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 1 year, or a value within a range of any two of these values.

[0054] In some embodiments, administration of CT1812 results in a change in amyloid beta levels in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, administration of CT1812 results in a decrease in amyloid beta monomer levels. In some embodiments, the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42. In some embodiments, administration of CT1812 results in an increase in amyloid beta oligomers in cerebrospinal fluid (CSF), hippocampal interstitial fluid, plasma, or a combination thereof. In some embodiments, the amyloid beta level after administration of CT1812 is relative to the amyloid beta level before administration of CT1812. In some embodiments, the amyloid beta level is measured using a microimmunoelectrode. In some embodiments, the amyloid beta level is measured using Western blot. In some embodiments, the amyloid beta level is measured using ELISA (enzyme-linked immunosorbent assay).

[0055] In some embodiments, administration of CT1812 results in a reduction in cognitive decline. In some embodiments, administration of CT1812 prevents cognitive decline. In some embodiments, administration of CT1812 results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in maintaining the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. In some embodiments, administration of CT1812 results in a decrease of at least 3 points in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment. [Example]

[0056] Example 1: Clinical efficacy of CT1812 Methods: We conducted a phase 2 clinical trial (NCT03522129) enrolling patients with mild to moderate Alzheimer's disease (MMSE score 18-26). This randomized, double-blind, placebo-controlled study involved lumbar CSF sampling every 24 hours after a single dose of CT1812. The primary objective of this study was to assess target engagement of CT1812 treatment by measuring the displacement of Aβ oligomers into cerebrospinal fluid (CSF). This measure was quantified by measuring the change from baseline CSF Aβ oligomer concentrations after CT1812 administration compared with placebo. Microimmunoelectrodes coated with the oligomer-specific antibody, A11 (Yuede et al., 2016), were placed in CSF samples from Alzheimer's disease patient samples to detect soluble Aβ after a single dose of CT1812 (560 mg) or placebo.

[0057] Results: Microimmunoelectrode (MIE) measurements of Aβ oligomers in CSF demonstrated a drug-dependent increase in Aβ oligomers over time. After establishing a pre-dose baseline, MIE measurements of oligomer levels showed a clear increase over time in the CSF of patients who received a single dose of CT1812 (vertical dashed line), but not in patients who received placebo (Figure 1). The slopes for patient 1 and patient 3 were significantly different from zero [p<0.001, R 2 =0.7720 (F=91.45) and R 2 = 0.7898 (F = 101.5), whereas the linear slope for the placebo-treated patient (patient 2) was not different from 0 (p = 0.6849, R2 = 0.06891 F = 1.998).

[0058] MIE measurements were confirmed by measuring protein abundance by Western blot. CSF samples from Alzheimer's disease patients (N = 3) were measured by native Western blot probed with the AB-specific antibody 82E1. After a single dose of CT1812 (vertical dashed line), oligomer levels clearly increased over time in the CSF of patients who received a single dose of CT1812, but not in patients who received placebo (Figure 2). The slopes for patients 1 and 3 were significantly different from zero (p < 0.001 for each patient, R 2 =0.9808 (F=41.91) and R 2 = 0.3997 (F = 17.31), respectively). The linear slope for the placebo-treated patient (patient 2) was not different from 0 (p = 0.6849, R 2 = 0.006437F = 0.1684). Spearman correlation analysis showed a significant correlation between MIE and oligomer measurements by Western blot (Figure 3, r - 0.74, p = 3x10 -13 ).

[0059] Interestingly, the drug-induced increase in Aβ oligomers over time was oligomer-specific. The percent change from baseline in Aβ40 and 42 monomers was similar in all three patients (<50% increase). Aβ oligomers increased by more than 200% in two treated patients but not in the placebo-treated patient. CSF Aβ oligomer levels were fit to linear regression, and the significance of the difference in slope from zero was determined for each patient (Figure 4 (measured by microimmunoelectrode) and Figure 5 (measured by Western blot)). A summary of the plasma and CSF data is shown in Table 1 and Figure 6. [Table 1]

[0060] Summary: The results of this study provide early proof of principle that it may be possible to measure target engagement in patients with Alzheimer's disease. The pharmacokinetics of this study suggest an exposure-dependent relationship to elevated oligomers. [Example]

[0061] Example 2: Suppression of cognitive decline by administration of CT1812 Patients treated with CT1812 for at least 6 months (185 days) were compared with those treated with placebo. Patients treated with CT1812 demonstrated a 3-point difference in the Alzheimer's Disease Assessment Score (ADAS-COG) between treated and untreated patients at day 185, suggesting a trend toward improved cognitive function (Figure 7). Patients treated with CT1812 for at least 6 months (185 days) demonstrated a decrease in Aβ protein between the treatment and placebo groups (p=0.017) (Figure 8).

Claims

1. 1. A method for reducing amyloid beta monomer levels in a subject, comprising administering to a subject a therapeutically effective amount of a compound: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof to said subject.

2. The method of claim 1 , wherein the subject is a human.

3. The method of claim 1 , wherein the subject has cognitive decline.

4. The method of claim 3, wherein the cognitive decline is Alzheimer's disease.

5. The method of claim 1 , wherein the subject has Alzheimer's disease.

6. 10. The method of claim 1, wherein the compound is administered for at least six months.

7. 10. The method of claim 1, wherein said therapeutically effective amount administered for at least six months is a total daily dose of about 10 mg to about 2000 mg.

8. 10. The method of claim 1, wherein said therapeutically effective amount administered for at least six months is a total daily dose of about 300 mg.

9. 10. The method of claim 1, wherein said therapeutically effective amount administered for at least six months is a total daily dose of 100 mg.

10. 2. The method of claim 1, wherein the amyloid β monomer is selected from Aβ1-40 and Aβ1-42.

11. The method of claim 1, wherein the method of reducing amyloid beta monomer levels is relative to the amyloid beta monomer levels before administration of the compound.

12. 2. The method of claim 1, wherein the amyloid beta level is measured from cerebrospinal fluid, hippocampal interstitial fluid, plasma, or a combination thereof.

13. 10. The method of claim 1, wherein administering a therapeutically effective amount of the compound results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment.

14. 1. A method for reducing amyloid beta monomer levels in a subject, comprising administering to a subject a compound: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.

15. The method of claim 14 , wherein the subject is a human.

16. 15. The method of claim 14, wherein the subject has cognitive decline.

17. 17. The method of claim 16, wherein the cognitive decline is Alzheimer's disease.

18. 15. The method of claim 14, wherein the subject has Alzheimer's disease.

19. 15. The method of claim 14, wherein the pharmaceutical composition is administered for at least six months.

20. 15. The method of claim 14, wherein said therapeutically effective amount administered for at least six months is a total daily dose of about 10 mg to about 2000 mg.

21. 15. The method of claim 14, wherein the therapeutically effective amount administered for at least six months is a total daily dose of about 300 mg.

22. 15. The method of claim 14, wherein the therapeutically effective amount administered for at least six months is a total daily dose of 100 mg.

23. 15. The method of claim 14, wherein the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42.

24. 15. The method of claim 14, wherein the method of reducing amyloid beta monomer levels is relative to the amyloid beta monomer levels prior to administration of the compound.

25. 15. The method of claim 14, wherein the amyloid beta level is measured from cerebrospinal fluid, hippocampal interstitial fluid, plasma, or a combination thereof.

26. 15. The method of claim 14, wherein administering the therapeutically effective amount of the pharmaceutical composition results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment.

27. 1. A method of increasing amyloid beta oligomer levels in a subject, comprising administering to a subject a therapeutically effective amount of a compound: 【Transformation 3】 or a pharmaceutically acceptable salt thereof to said subject.

28. 28. The method of claim 27, wherein the subject is a human.

29. 28. The method of claim 27, wherein the subject has cognitive decline.

30. 30. The method of claim 29, wherein the cognitive decline is Alzheimer's disease.

31. 28. The method of claim 27, wherein the subject has Alzheimer's disease.

32. 28. The method of claim 27, wherein the compound is administered orally.

33. 28. The method of claim 27, wherein the therapeutically effective amount is a total daily dose of about 10 mg to about 2000 mg.

34. 28. The method of claim 27, wherein the therapeutically effective amount is a total daily dose of about 560 mg.

35. 28. The method of claim 27, wherein the therapeutically effective amount is a total daily dose of about 300 mg.

36. 28. The method of claim 27, wherein the therapeutically effective amount is a total daily dose of 100 mg.

37. 28. The method of claim 27, wherein the method of increasing amyloid beta oligomer levels is relative to the amyloid beta oligomer levels before administration of the compound.

38. 28. The method of claim 27, wherein the amyloid beta level is measured from cerebrospinal fluid, hippocampal interstitial fluid, plasma, or a combination thereof.

39. 28. The method of claim 27, wherein the amyloid beta level is measured within 24 hours after administration of CT1812.

40. 1. A method of treating cognitive decline in a subject, comprising administering to a subject a therapeutically effective amount of a compound: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof to said subject.

41. 41. The method of claim 40, wherein the subject is a human.

42. 41. The method of claim 40, wherein the cognitive decline is Alzheimer's disease.

43. 41. The method of claim 40, wherein the compound is administered for at least six months.

44. 41. The method of claim 40, wherein said therapeutically effective amount administered for at least six months is a total daily dose of about 10 mg to about 2000 mg.

45. 41. The method of claim 40, wherein the therapeutically effective amount administered for at least six months is a total daily dose of about 300 mg.

46. 41. The method of claim 40, wherein the therapeutically effective amount administered for at least six months is a total daily dose of 100 mg.

47. 41. The method of claim 40, wherein administering the therapeutically effective amount of the compound results in an alteration in the level of amyloid beta in the subject.

48. 48. The method of claim 47, wherein the level of amyloid beta is relative to the level of amyloid beta monomer before administration of the compound.

49. 48. The method of claim 47, wherein the change in the level of amyloid beta is selected from a decrease in amyloid beta monomers, an increase in amyloid beta oligomers, or both.

50. 48. The method of claim 47, wherein the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42.

51. 48. The method of claim 47, wherein the amyloid beta level is measured from cerebrospinal fluid, hippocampal interstitial fluid, plasma, or a combination thereof.

52. 41. The method of claim 40, wherein administering the therapeutically effective amount of the compound results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to the subject's ADAS-COG score before treatment.

53. 41. The method of claim 40, wherein administering the therapeutically effective amount of the compound results in a decrease in the subject's Alzheimer's Disease Assessment Score (ADAS-COG) score of at least 3 points.

54. 1. A method of treating Alzheimer's disease in a subject, comprising administering to a subject a therapeutically effective amount of a compound: 【Transformation 5】 or a pharmaceutically acceptable salt thereof to said subject.

55. 55. The method of claim 54, wherein the subject is a human.

56. 55. The method of claim 54, wherein the compound is administered for at least six months.

57. 55. The method of claim 54, wherein said therapeutically effective amount administered for at least six months is a total daily dose of about 10 mg to about 2000 mg.

58. 55. The method of claim 54, wherein the therapeutically effective amount administered for at least six months is a total daily dose of about 300 mg.

59. 55. The method of claim 54, wherein the therapeutically effective amount administered for at least six months is a total daily dose of 100 mg.

60. 55. The method of claim 54, wherein administering the therapeutically effective amount of the compound results in an alteration in the level of amyloid beta in the subject.

61. 61. The method of claim 60, wherein the level of amyloid beta is relative to the level of amyloid beta monomer before administration of the compound.

62. 61. The method of claim 60, wherein the change in the level of amyloid beta is selected from a decrease in amyloid beta monomers, an increase in amyloid beta oligomers, or both.

63. 61. The method of claim 60, wherein the amyloid beta monomer is selected from Aβ1-40 and Aβ1-42.

64. 61. The method of claim 60, wherein the amyloid beta level is measured from cerebrospinal fluid, hippocampal interstitial fluid, plasma, or a combination thereof.

65. 55. The method of claim 54, wherein administering said therapeutically effective amount of the compound results in a decrease in said subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to said subject's ADAS-COG score before treatment.

66. 55. The method of claim 54, wherein administering said therapeutically effective amount of the compound results in at least a 3 point decrease in said subject's Alzheimer's Disease Assessment Score (ADAS-COG) score compared to said subject's ADAS-COG score before treatment.

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