Methods of treating neurological disorders with Anti-abeta antibodies

Abstract

Methods of treating amyloidogenic disorders in a human subject including monitoring regimes for detection and management of Amyloid Related Imaging Abnormality (ARIA) are provided.

Description

METHODS OF TREATING NEUROLOGICAL DISORDERS WITH ANTI-ABETA ANTIBODIES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 676,246, filed July 26, 2024, U.S. Provisional Application No.63 / 676,249, filed July 26, 2024, and U.S. Provisional Application No.63 / 676,253, filed July 26, 2024, each of which is incorporated herein by reference in its entirety. SEQUENCE LISTING

[0002] A computer readable form of the Sequence Listing is filed with this application by electronic submission and is incorporated into this application by reference in its entirety. The Sequence Listing is contained in the file created on July 22, 2025, having the file name “20- 1030-WO5_SEQLIST” and is 22 kb in size. FIELD

[0003] The present disclosure relates to anti-Amyloid beta (A ) antibodies as well ascompositions and methods of their use. BACKGROUND

[0004] Alzheimer's disease (AD) is a progressive disease resulting in senile dementia. The disease is generally categorized as late onset, which occurs in old age (65+years) and early onset, which develops well before the senile period, i.e., between 35 and 60 years. Disease pathology appears to be the same for both types of disease, but abnormalities tend to be more severe and widespread in cases beginning at an earlier age. The disease is characterized by at least two types of lesions in the brain, neurofibrillary tangles and senile plaques. Neurofibrillary tangles are intracellular deposits of microtubule associated tau protein consisting of two filaments twisted about each other in pairs. Senile plaques (i.e., amyloid plaques) are areas of disorganized neuropil up to 150 m across with extracellular amyloid deposits at the center which are visible by microscopic analysis of sections of brain tissue.

[0005] The principal constituent of the plaques is a peptide termed amyloid beta (A orAbeta) or -amyloid peptide. A peptide is a 4-kDa internal fragment of 39-43 amino acidsof a larger transmembrane glycoprotein termed amyloid precursor protein (APP). As a resultof proteolytic processing of APP by different secretase enzymes, A is primarily found inboth a short form, 40 amino acids in length, and a long form, ranging from 42-43 amino acids in length. Part of the hydrophobic transmembrane domain of APP is found at the carboxy endof A , and may account for the ability of A to aggregate into plaques, particularly in thecase of the long form. Accumulation of amyloid plaques in the brain eventually leads to neuronal cell death. The physical symptoms associated with this type of neural deterioration characterize Alzheimer's disease.

[0006] Monoclonal antibodies (mAbs) targeting amyloid beta have been demonstrated clinically to reduce amyloid plaque burden in patients. The FDA has granted accelerated approval for the anti-amyloid antibodies aducanumab and lecanemab. The FDA approvals of these antibodies were based on the antibodies demonstrating a reduction of amyloid beta on PET imaging, a surrogate endpoint that was determined to be reasonably likely to predict clinical benefit. Indeed, clinical trials of anti-amyloid antibodies, including aducanumab and lecanemab, showed that reduction in plaque burden was associated with slowing of cognitive decline in Alzheimer’s disease. However, these treatments suffer from limited efficacy and / or treatment-related side effects. Further, these antibodies require intravenous administration and / or frequent high-dose subcutaneous administration, leading to a burden on patients and caregivers. Therefore, there remains a need for efficacious and safe anti-amyloid antibodies for the treatment Alzheimer’s disease, particularly those that are efficacious when subcutaneously administered as part of a relatively infrequent dosing regimen. SUMMARY

[0007] The present disclosure relates to methods of treating Alzheimer’s disease in a subject, that, in addition to administering to the subject an anti-amyloid antibody or an antigen-binding fragment thereof, provides that the subject receives magnetic resonance imaging (MRI) of the brain before the first administration of the anti-amyloid antibody or an antigen-binding fragment thereof, and receives at least one additional brain MRI before one or more subsequent administrations of the antibody or antigen-binding fragment thereof. The disclosure provides methods that provide for monitoring the formation, presence or status of amyloid related imaging abnormalities (ARIA), including ARIA-edema (ARIA-E), and / or ARIA-hemosiderin deposition (ARIA-H). The disclosure also relates to certainantibodies (and antibody fragments) that specifically bind to A , methods of producing suchantibodies and antibody fragments and associated nucleic acids, pharmaceutical formulationsand compositions of antibodies that show high affinity binding to A for prophylactic and / ortherapeutic use to, for example, treat, reduce the risk of or delay the outset of amyloidogenic disease, prevent, reduce or inhibit markers of amyloidogenic disease, e.g., amyloid plaques, and improve cognition. The present disclosure further relates to methods of detecting amyloid plaques and measuring the efficacy of treatment in patients being treated for amyloidogenic disease. The disclosure is based, at least in part, on the identification andcharacterization of monoclonal antibodies that specifically bind to A peptide and areeffective at reducing plaque burden and neutralizing soluble A species associated withamyloidogenic disorders.

[0008] In one aspect, the disclosure provides a method of treating Alzheimer’s disease in a subject, including administering to the subject an anti-amyloid antibody or an antigen- binding fragment thereof, wherein (i) the subject receives magnetic resonance imaging (MRI) of the brain before the first administration of the anti-amyloid antibody or an antigen- binding fragment thereof, and (ii) the subject receives at least one additional brain MRI before at least one subsequent administration of the anti-amyloid antibody or an antigen- binding fragment thereof.

[0009] In some embodiments, an MRI is administered to a subject prior to (i) a first administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) one or more consecutive doses of an anti-amyloid antibody or an antigen-binding fragment. In other embodiments, the methods provide an MRI administered to a subject (is obtained from the subject) prior to (i) the administration of a first administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) one or more non-consecutive doses of an anti-amyloid antibody or an antigen-binding fragment. In yet other embodiments, the disclosure provides methods in which an MRI is administered to a subject (is obtained from the subject) prior to (i) the administration of a first administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) one or more consecutive doses and at least one non-consecutive dose of an anti-amyloid antibody or an antigen-binding fragment, thereof wherein (a) the MRIs prior to the consecutive doses precede the MRIs prior to the non-consecutive doses, or (b) the MRIs prior to the non-consecutive doses precede the MRIs prior to the consecutive dose.

[0010] In some embodiments, the disclosure provides methods in which 2, 3, 4, 5, 6, or 7 MRI are administered. In further embodiments, the disclosure provides methods wherein 2 MRI are administered, selected from the group consisting of: prior to the first and third doses, prior to the first and fourth doses, prior to the first and fifth doses, prior to the first and sixth doses, and prior to the first and seventh doses. In a related embodiment, the 2 MRI areadministered prior to the first and fourth doses. In further embodiments, the disclosure provides methods wherein 3 MRI are administered, selected from the group consisting of: prior to the first, third, and sixth doses, prior to the first, third, and seventh doses, prior to the first, fourth, and sixth doses, and prior to the first, fourth, and seventh doses, In a further related embodiment, the disclosure provides methods in which the 3 MRI are administered prior to the first, third, and seventh doses, and prior to the first, fourth, and seventh doses. In further embodiments, the disclosure provides methods, wherein 4 MRI are administered, selected from the group consisting of: prior to the first, third, fifth, and seventh does, and prior to the first, fifth, seventh, and fourteenth doses.

[0011] In some embodiments, the disclosure provides methods in which 3, 4, 5, or 6 MRI are administered. In further embodiments, 3 MRI are administered, selected from the group consisting of: prior to the first, second, and fourth doses, prior to the first, second and fifth doses, prior to the first, second and sixth doses, and prior to the first, second and seventh doses. In a further related embodiment, the MRI are administered prior to the first, second and seventh doses. In another further related embodiment, 4 MRI are administered, selected from the group consisting of: prior to the first, second, fourth, and seventh doses, prior to the first, second, fifth, and seventh doses, prior to the first, second, seventh and thirteenth doses, prior to the first, third, fourth, and seventh doses, prior to the first, third, fourth, and eighth doses, and prior to the first, second, third, and seventh doses. In other further embodiments, 5 MRI are administered, selected from the group consisting of: prior to the first, third, fourth, seventh, and tenth doses, prior to the first, second, fifth, and seventh doses, prior to the first, second, seventh, and thirteenth doses, prior to the first, third, fourth, and seventh doses, prior to the first, third, fourth, and eighth doses, prior to the first, second, third, seventh, and ninth doses, prior to the first, second, third, and seventh, and thirteenth doses, and prior to the first, second, third, fourth, and seventh doses. In another further embodiment, 6 MRI are administered, prior to the first, second, third, seventh, ninth, and thirteenth doses.

[0012] In some embodiments, the disclosure provides methods in which at least one MRI is administered after a final dose of anti-amyloid antibody or an antigen binding fragment thereof is administered. In further embodiments, one MRI is administered after a final dose of anti-amyloid antibody or an antigen binding fragment thereof is administered. In a related embodiment, the MRI is administered between about two weeks and one year after a final dose of anti-amyloid antibody or an antigen binding fragment thereof is administered. In a further related embodiment, the MRI is administered about one month after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered. In anotherfurther embodiment, two MRIs are administered after a final dose of anti-amyloid antibody or an antigen binding fragment thereof is administered. In another further related embodiment, one MRI is administered between about two weeks and two months after a final dose of anti-amyloid antibody or an antigen binding fragment thereof is administered, and a second MRI is administered between about two months and twelve months after a final dose of anti-amyloid antibody or an antigen binding fragment thereof is administered.

[0013] In some embodiments, the disclosure provides methods in which the subject receives the brain MRI in order to evaluate for or determine the presence of amyloid related imaging abnormalities (ARIA), ARIA-edema (ARIA-E), and / or ARIA-hemosiderin deposition (ARIA-H), which, in some embodiments, can help determine treatment decisions. For instance, in some embodiments, when (i) ARIA-E is present at a severity of Mild or Mild+ with an ARIA-E clinical severity of Moderate or Severe, or (ii) ARIA-E is present at a severity of Moderate, Moderate+ or Severe, or (iii) ARIA-H is present at a severity of Mild with an ARIA-H clinical severity of symptomatic, or (iv) ARIA-H is present at a severity of Moderate or Severe, the subject receives additional brain MRIs every 4 to 6 weeks until (a)resolution of ARIA E or stabilization of ARIA H or (b) for a period of up to 26 weeks.

[0014] In some embodiments, when (i) ARIA-E is present at a severity of Mild or Mild+ with an ARIA-E clinical severity of Moderate or Severe, or (ii) ARIA-E is present at a severity of Moderate, Moderate+ or Severe, or (iii) ARIA-H is present at a severity of Mild with an ARIA-H clinical severity of symptomatic, or (iv) ARIA-H is present at a severity of Moderate or Severe, administration of the anti-amyloid antibody or an antigen-bindingfragment is suspended until resolution of ARIA E or stabilization of ARIA H.

[0015] In some embodiments, the methods of treating Alzheimer’s disease include administering to a subject about 45 mg to about 200mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In a further embodiment, brain amyloid plaque is reduced in the subject administered about 45 mg to about 200 mg of an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks. In another further embodiment, the subject administered about 45 mg to about 200 mg or an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks is converted from amyloid positive to amyloid negative. In a related embodiment, the method includes administering to the subject about 100 mg to about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In another related embodiment, the method includes administering to the subject about 150 mg to about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In further related embodiment, the methodincludes administering to the subject about 100 mg of the anti-amyloid antibody or antigen- binding fragment thereof. In another further related embodiment, the method includes administering to the subject about 150 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In some related embodiment, the method includes administering to the subject about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

[0016] In some embodiments, the methods of treating Alzheimer’s disease include administering to a subject about 205 mg to about 400 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In a further embodiment, brain amyloid plaque is reduced in the subject administered about 205 mg to about 400 mg or an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks. In another further embodiment, the subject administered about 205 mg to about 400 mg of an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks is converted from amyloid positive to amyloid negative. In a related embodiment, the method includes administering to the subject about 300 mg to about 400 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In another related embodiment, the method includes administering to the subject about 350 mg to about 400 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In further related embodiment, the method includes administering to the subject about 300 mg of the anti-amyloid antibody or antigen- binding fragment thereof. In another further related embodiment, the method includes administering to the subject about 350 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In some related embodiment, the method includes administering to the subject about 400 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

[0017] In some embodiments, the methods of treating Alzheimer’s disease include administering to a subject about 405 mg to about 700 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In a further embodiment, brain amyloid plaque is reduced in the subject administered about 405 mg to about 700 mg or an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks. In another further embodiment, the subject administered about 405 mg to about 700 mg of an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks is converted from amyloid positive to amyloid negative. In a related embodiment, the method includes administering to the subject about 500 mg to about 700 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In another related embodiment, the method includes administering to the subject about 600 mg to about 700 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In further related embodiment, the methodincludes administering to the subject about 500 mg of the anti-amyloid antibody or antigen- binding fragment thereof. In another further related embodiment, the method includes administering to the subject about 600 mg of the anti-amyloid antibody or antigen-binding fragment thereof. In some related embodiment, the method includes administering to the subject about 700 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

[0018] In a related embodiment of the foregoing, the anti-amyloid antibody is administered once every 4 weeks.

[0019] In some embodiments, the methods of treating Alzheimer’s disease in a subject includes administering about 35 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks. In a further embodiment, brain amyloid beta plaque is reduced in a subject administered about 35 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In another further embodiment, the subject administered about 35 mg to about 100 mg of an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks is converted from amyloid positive to amyloid negative. In a related embodiment, the methods includes administering about 50 mg to about 100 mg of the anti- amyloid antibody or antigen-binding fragment thereof. In other related embodiments, the method includes administering about 100 mg of the anti-amyloid antibody or antigen- binding fragment thereof.

[0020] In some embodiments, the methods of treating Alzheimer’s disease in a subject includes administering about 100 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks. In a further embodiment, brain amyloid beta plaque is reduced in a subject administered about 100 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In another further embodiment, the subject administered about 100 mg to about 200 mg of an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks is converted from amyloid positive to amyloid negative. In a related embodiment, the methods includes administering about 150 mg to about 200 mg of the anti- amyloid antibody or antigen-binding fragment thereof. In other related embodiments, the method includes administering about 200 mg of the anti-amyloid antibody or antigen- binding fragment thereof.

[0021] In some embodiments, the methods of treating Alzheimer’s disease in a subject includes administering about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks. In a furtherembodiment, brain amyloid beta plaque is reduced in a subject administered about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In another further embodiment, the subject administered about 250 mg to about 350 mg of an anti-amyloid antibody or antigen-binding fragment thereof once about every 3-5 weeks is converted from amyloid positive to amyloid negative. In a related embodiment, the methods includes administering about 300 mg to about 350 mg of the anti- amyloid antibody or antigen-binding fragment thereof. In other related embodiments, the method includes administering about 350 mg of the anti-amyloid antibody or antigen- binding fragment thereof.

[0022] In a related embodiment of the foregoing, the anti-amyloid antibody or antigen- binding fragment thereof is administered once about every 2 weeks.

[0023] In some embodiments, the anti-amyloid antibody or an antigen-bindingfragment thereof binds to an epitope located within the N-terminus of an A peptide, and theepitope includes at least one amino acid selected from amino acids 1-10 of the A peptide. Insome embodiments, the anti-amyloid antibody or an antigen-binding fragment thereof bindsto an epitope comprising at least one amino acid selected from amino acids 1-7 of the Apeptide. In some embodiments, the anti-amyloid antibody or an antigen-binding fragment thereof binds to amyloid 1-42 protofibrils with an apparent KD of about 5 nM or less. In some embodiments, the anti-amyloid antibody or an antigen-binding fragment thereof binds to amyloid1-42protofibrils with an apparent KD of about 1 nM or less. In some embodiments, the anti-amyloid antibody or an antigen-binding fragment thereof binds to amyloid1-28monomers with an apparent KD of about 10 nM or less.

[0024] In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof is administered as a pharmaceutical composition comprising the anti-amyloid antibody or antigen-binding fragment thereof and a pharmaceutically acceptable diluent. In some embodiments, the administration is intravenous or subcutaneous. In some embodiments, the administration is subcutaneous.

[0025] In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 and a light chain variable region comprising light chain CDR1, CDR2, and CDR3, wherein heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 3, heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 4, heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 5,light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 6, light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 7, and light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0026] In some embodiments, the heavy chain variable region, excluding the CDRs, is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region, excluding the CDRs, is at least 95% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the heavy chain variable region, excluding the CDRs, is at least 98% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region, excluding the CDRs, is at least 98% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the heavy chain variable region consists of SEQ ID NO: 1, and wherein the light chain variable region consists of the amino acid sequence of SEQ ID NO: 2.

[0027] In some embodiments, the anti-amyloid antibody is a humanized IgG1. In some embodiments, the anti-amyloid antibody is a full antibody, a chimeric antibody, a CDR- grafted antibody, or a recombinant antibody.

[0028] In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 9 and / or a light chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 10. In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO: 9 and / or a light chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO: 10. In some embodiments, the anti-amyloid antibody comprises a heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 9, with or without the C-terminal lysine, and a light chain constant region comprising an amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid antibody comprises a heavy chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 9, with or without the C-terminal lysine, and a light chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 10.

[0029] In some embodiments, the anti-amyloid antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain comprising an amino acid sequence of SEQ ID NO: 12. In someembodiments, the anti-amyloid antibody comprises a heavy chain consisting essentially of an amino acid sequence of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain consisting essentially of an amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-amyloid antibody comprises a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the anti-amyloid antibody is h2731.

[0030] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 100 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 150 mg of an anti-amyloid antibody once about every 4 weeks; the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 200 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0031] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 50 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methods include subcutaneously administering to the subject about 75 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methods include subcutaneously administering to the subject about 100mg of an anti- amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methods include subcutaneously administering to the subject about 150 mg of an anti-amyloid antibody once about every 4 weeks; the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methodsinclude subcutaneously administering to the subject about 200 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0032] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 50mg of an anti-amyloid antibody once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0033] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 75 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In another embodiment, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 100 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In some other embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 200 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In another further embodiment, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 100 mg of an anti-amyloid antibody once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject.

[0034] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 300 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methods include subcutaneously administering to the subject about 350 mg of an anti-amyloid antibody once about every 4weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methods include subcutaneously administering to the subject about 400 mg of an anti- amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0035] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 100 mg of an anti-amyloid antibody once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0036] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 150 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In another embodiment, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 200 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In some other embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 400 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In another further embodiment, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 200 mg of an anti-amyloid antibody once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject.

[0037] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 500 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibodycomprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methods include subcutaneously administering to the subject about 600 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the methods include subcutaneously administering to the subject about 700mg of an anti- amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0038] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject about 350 mg of an anti-amyloid antibody once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0039] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 500 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In another embodiment, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 600 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In some other embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 700 mg of an anti-amyloid antibody once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject. In another further embodiment, the disclosure provides that the methods of treating Alzheimer’s disease in a subject includes subcutaneously administering to the subject about 350 mg of an anti-amyloid antibody once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain SEQ ID NO: 12, wherein amyloid plaque is reduced in the subject.

[0040] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include subcutaneously administering to the subject a doseof an anti-A antibody sufficient to achieve a Cave value of about 20 μg / mL to about 40μg / mL, the anti-A antibody comprising a heavy chain of SEQ ID NO: 11, with or withoutthe C-terminal lysine, and a light chain of SEQ ID NO: 12. In some of such embodiments, thedisclosure also provides for subcutaneously administering to the subject a dose of an anti-Aantibody sufficient to achieve an AUC0-tauvalue of about 15,000 hr*ug / mL to about 30,000hr*ug / mL, the anti-A antibody comprising a heavy chain of SEQ ID NO: 11, with orwithout the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0041] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include that a maximum concentration over a dosing interval (Cmax) of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 30 μg / mL to about 60 μg / mL. In some embodiments, a Cmax value of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 50 μg / mL to about 60 μg / mL. In some embodiments, a Cmax value of the anti-amyloid antibody or antigen binding fragment thereof in the subject does not exceed about 60 μg / mL. In some embodiments, the Cmax value is a serum Cmax value. In some embodiments, the Cmax value is a plasma Cmax value.

[0042] In some embodiments, an average concentration over the dosing interval (Cavevalue) of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 20 μg / mL to about 40 μg / mL. In some embodiments, a Cavevalue of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 30 μg / mL to about 40 μg / mL. In some embodiments, a Cavevalue of the anti-amyloid antibody or antigen binding fragment thereof in the subject does not exceed about 40 μg / mL. In some embodiments, the Cave value is a serum Cave value. In some embodiments, the Cave value is a plasma Cave value.

[0043] In some embodiments, wherein the area under the concentration-time curve for dosing interval (AUC0-tau value) of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 15,000 hr*ug / mL to about 30,000 hr*ug / mL. In some embodiments, the AUC0-tau value of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 20,000 hr*ug / mL to about 30,000 hr*ug / mL. In some embodiments, the AUC0-tau value of the anti-amyloid antibody or antigen binding fragment thereof in the subject is does not exceed about 30,000 hr*ug / mL. In some embodiments, theAUC0-tau value is a serum AUC0-tau value. In some embodiments, the AUC0-tau value is a plasma AUC0-tau value.

[0044] In some embodiments, brain amyloid beta plaque in the subject is reduced. In some embodiments, the reduction of brain amyloid beta plaque comprises a reduction of at least about 30 centiloids to about 70 centiloids. In some embodiments, the reduction of brain amyloid beta plaque comprises a reduction of from about 45 centiloids to about 80 centiloids. In some embodiments, the reduction of brain amyloid beta plaque comprises a reduction of about 50 centiloids to about 85 centiloids. In some embodiments, the reduction of brain amyloid beta plaque comprises a reduction of at least about 40% to about 90%. In some embodiments, the reduction of brain amyloid beta plaque comprises a reduction of from about 60% to about 100%. In other embodiments, the reduction of brain amyloid beta plaque comprises a reduction of about 65% to about 100%.

[0045] In some embodiments, the reduction of brain amyloid beta plaque is a reduction compared to baseline (the value prior to beginning treatment using a method of the present disclosure). In some embodiments, the reduction of brain amyloid beta plaque is a reduction compared to the subject prior to the administration of the anti-amyloid antibody.

[0046] In some embodiments, the reduction of brain amyloid beta plaque is achieved after 6 months of treatment. In some embodiments, the reduction of brain amyloid beta plaque is achieved after about 12 months of treatment. In some embodiments, the reduction of brain amyloid beta plaque is achieved after about 18 months of treatment. In some embodiments, the reduction of brain amyloid beta plaque is assessed by Positron Emission Tomography (PET).

[0047] In some embodiments, the subject is converted from amyloid positive to amyloid negative.

[0048] In some embodiments, treating comprises increasing a probability of converting the subject from amyloid positive to amyloid negative. In some embodiments, treating comprises a probability of converting the subject from amyloid positive to amyloid negative by about 10% to about 40%. In some embodiments, treating comprises a probability of converting the subject from amyloid positive to amyloid negative by about 30% to about 60%. In some embodiments, treating comprises a probability of converting the subject from amyloid positive to amyloid negative by about 40% to about 80%. In some embodiments, the probability of converting the subject from amyloid positive to amyloid negative is a probability after about 6 months of treatment. In some embodiments, the probability of converting the subject from amyloid positive to amyloid negative is a probability after about12 months of treatment. In some embodiments, the probability of converting the subject from amyloid positive to amyloid negative is a probability after about 18 months of treatment.

[0049] In some embodiments, treating comprises slowing, halting, or reversing decline in cognitive function. In some embodiments, treating comprises slowing decline in cognitive function. In some embodiments, cognitive function is measured by at least one of the following CRD-SB, ADAS-Cog14, ADCOMS, and ADCS MCI-ADL. In some embodiments, cognitive function is measured by ADCOMS.

[0050] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include modulating a biomarker in a subject, comprising administering to the subject from about 45 mg to about 200 mg of an anti-amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include modulating a biomarker in a subject, comprising administering to the subject from about 205 mg to about 400 mg of an anti-amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include modulating a biomarker in a subject, comprising administering to the subject from about 405 mg to about 700 mg of an anti-amyloid antibody once about every 3-5 weeks, the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12.

[0051] In some embodiments, the disclosure provides that the methods of treatingAlzheimer’s disease in a subject include increasing a ratio of A 42 / 40 in a subject,comprising administering to the subject about 45 mg to about 200 mg of an anti-amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’sdisease in a subject include increasing a ratio of A 42 / 40 in a subject, comprisingadministering to the subject about 205 mg to about 400 mg of an anti-amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’s diseasein a subject include increasing a ratio of A 42 / 40 in a subject, comprising administering tothe subject about 405 mg to about 700 mg of an anti-amyloid antibody once about every 3- 5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0052] In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include decreasing an amount of phospho-tau in a subject, comprising administering to the subject about 45 mg to about 200 mg of an anti-amyloid antibody or antigen binding fragment thereof once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include decreasing an amount of phospho-tau in a subject, comprising administering to the subject about 205 mg to about 400 mg of an anti-amyloid antibody or antigen binding fragment thereof once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the disclosure provides that the methods of treating Alzheimer’s disease in a subject include decreasing an amount of phospho-tau in a subject, comprising administering to the subject about 405 mg to about 700 mg of an anti-amyloid antibody or antigen binding fragment thereof once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some of such embodiments, the disclosure also provides for decreasing an amount of phospho-tau in a subject, comprising administering to the subject about 35 mg to about 100 mg of an anti-amyloid antibody or antigen binding fragment thereof twice about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some of such embodiments, the disclosure also provides for decreasing an amount of phospho-tau in a subject, comprising administering to the subject about 100 mg to about 200 mg of an anti- amyloid antibody or antigen binding fragment thereof twice about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12. In some of such embodiments, the disclosure also provides for decreasing an amount of phospho-tau in a subject, comprising administering to the subject about 250 mg to about 350 mg of an anti-amyloid antibody or antigen binding fragment thereof twice about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0053] In some embodiments, the administration comprises a single subcutaneous injection. In some embodiments, a biomarker in the subject is modulated. In some embodiments, the biomarker in the subject is modulated compared to baseline. In some embodiments, the method further comprises detecting a biomarker in a sample collected from the subject. In some embodiments, the method further comprises quantifying a biomarker in a sample collected from the subject.

[0054] In some embodiments, the biomarker comprises the ratio of A 42 / 40 in thesubject. In some embodiments, the ratio of A 42 / 40 in the subject increases at least 25%. Insome embodiments, the ratio of A 42 / 40 in the subject increases at least 50%. In someembodiments, the ratio of A 42 / 40 in the subject increases about 25% to about 100%. Insome embodiments, the ratio of A 42 / 40 in the subject increases about 50% to about 100%.

[0055] In some embodiments, the biomarker comprises a phospho-tau value. In some embodiments, the phospho-tau value comprises at least one of the following: a p181-tau value, a p212-tau value, p217-tau value, a p231-tau value, and a p235-tau value. In some embodiments, the phospho-tau value comprises a p181-tau value. In some embodiments, the phospho-tau value comprises a p212-tau value. In some embodiments, the phospho-tau value comprises a p217-tau value. In some embodiments, the phospho-tau value comprises a p231- tau value. In some embodiments, the phospho-tau value comprises a p235-tau value. In some embodiments, the phospho-tau value decreases. In some embodiments, the phospho-tau value decreases at least about 10%. In some embodiments, the phospho-tau value decreases about 10% to about 30%. In some embodiments, the phospho-tau value decreases about 20% to about 30%.

[0056] In some embodiments, the sample comprises blood or a portion thereof collected from the subject. In some embodiments, the sample comprises plasma collected from the subject. In some embodiments, the sample comprises serum collected from the subject. In some embodiments, the sample comprises cerebral spinal fluid (“CSF”) collected from the subject.

[0057] In some embodiments, the method comprises a risk of ARIA-E that is less than about 45%. In some embodiments, the method comprises a risk of ARIA-E from about 25% to about 45%. In some embodiments, the method comprises a risk of ARIA-E of less than about 75%. In some embodiments, the method comprises a risk of ARIA-E of about 50% to about 75%. In some embodiments, the method comprises a risk of symptomatic ARIA-E that is less than about 15%. In some embodiments, the method comprises a risk of symptomaticARIA-E that is less than about 30%. In some embodiments, the risk of ARIA-E is a risk of severe ARIA-E.

[0058] In some embodiments, the risk of ARIA-E is the risk after about 6 months of treatment. In some embodiments, the risk of ARIA-E is the risk after about 12 months of treatment. In some embodiments, the risk of ARIA-E is the risk after about 18 months of treatment. In some embodiments, the subject does not experience symptomatic ARIA-E during treatment.

[0059] In some embodiments, the method comprises a risk of ARIA-H that is less than about 35%. In some embodiments, the method comprises a risk of ARIA-H from about 10% to about 35%. In other embodiments, the risk of ARIA-H is a risk of severe ARIA-H. In some embodiments, the risk of ARIA-H is the risk after about 6 months of treatment. In some embodiments, the subject does not experience symptomatic ARIA-H during treatment.

[0060] In some embodiments, the subject is an APOE4 homozygous subject. In some embodiments, the subject is an APOE4 heterozygous subject or an APOE4 noncarrier. In some embodiments, the method further comprises determining the APOE4 status of the subject prior to administration.

[0061] In some embodiments, the duration of the treatment and MRI monitoring is at least 6 months. In some embodiments, the duration of the treatment and MRI monitoring is at least 12 months. In some embodiments, the duration of the treatment and MRI monitoring is at least 18 months.

[0062] In some embodiments, the administration is performed using a syringe. In some embodiments, the administration is performed using an autoinjector.

[0063] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. DESCRIPTION

[0064] Monoclonal antibodies (mAbs) targeting the N-terminus of amyloid beta (A )have been demonstrated clinically to reduce amyloid plaque burden and at least two such antibodies, aducanumab and lecanemab, showed that significant reduction in plaque burden was associated with slowing of cognitive decline in Alzheimer’s disease (AD). Preclinical studies have also indicated that monoclonal antibodies (mAbs) targeting N-terminal epitopesof A elicit an antibody-dependent microglial-mediated A -plaque clearance andneutralization of soluble toxic A oligomers both in vitro and in vivo. It is hypothesized thatadministration of N-terminal A targeting mAbs slows disease progression via clearance ofA plaques and neutralization of soluble A aggregates in patients with AD. The presentdisclosure provides methods of treating Alzheimer’s disease and / or reducing amyloid plaqueby intravenous or subcutaneous administration of N-terminal A targeting mAbs.

[0065] Before describing particular aspects of the disclosure in more detail, a number of terms are defined. Definitions

[0066] The term “antibody” includes intact antibodies and binding fragments thereof. Typically, fragments compete with the intact antibody from which they were derived for specific binding to the target. Fragments include separate heavy chains, light chains Fab,Fab , F(ab )2, F(ab)c, Fv and single domain antibodies. Single (variable)domain antibodies include VH regions separated from their VL partners (or vice versa) in conventional antibodies (Ward et al., 1989, Nature 341: 544-546) as well as VH regions (sometimes known as VHH) from species such as Camelidae or cartilaginous fish (e.g., a nurse shark) in which VH regions are not associated with VL regions (see, e.g., WO 9404678). Single domain antibodies in which one chain is separated from its natural partners are sometimes known as Dabs and single domain antibodies from Camelidae or cartilaginous fish are sometimes known as nanobodies. Constant regions or parts of constant regions may or may not be present in single domain antibodies. For example, natural single variable region antibodies from Camelidae include a VHH variable region, and CH2 and CH3 constant regions. Single domain antibodies can be subject of humanization by analogous approaches to conventional antibodies. The Dabs type of antibodies are usually obtained from antibodies of human origin. NANOBODY types of antibody are of Camelidae or shark origin and can be subject to humanization. Fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins. The term “antibody” also includes a bispecific antibody. A bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy / light chain pairs and two different binding sites (see, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol., 79:315-321 (1990); Kostelny et al., J. Immunol., 148:1547-53 (1992)).

[0067] An immunoglobulin light or heavy chain variable region (also sometimes referred to herein as a “light chain variable domain” (“VL domain”) or “heavy chain variable domain” (“VH domain”), respectively) consists of a “framework” region interrupted by three “complementarity determining regions” or “CDRs.” The framework regions serve to align the CDRs for specific binding to an epitope of an antigen. The CDRs include the amino acid residues of an antibody that are primarily responsible for antigen binding. From amino-terminus to carboxyl-terminus, both VL and VH domains comprise the following framework (FR) and CDR regions: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDRs 1, 2, and 3 of a VL domain are also sometimes referred to herein, respectively, as CDR-L1, CDR-L2, and CDR-L3; CDRs 1, 2, and 3 of a VH domain are also sometimes referred to herein, respectively, as CDR-H1, CDR-H2, and CDR-H3. When the application discloses a VL sequence with R as the C-terminal residue, the R can alternatively be considered as being the N-terminal residue of the light chain constant region. Thus, the application should also be understood as disclosing the VL sequence without the C-terminal R.

[0068] The assignment of amino acids to each VL and VH domain is in accordance with any conventional definition of CDRs. Conventional definitions include, the Kabat definition (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991), the Chothia definition (Chothia & Lesk, J. Mol. Biol. 196:901-917, 1987; Chothia et al., Nature 342:878-883, 1989); a composite of Chothia Kabat CDR in which CDR-H1 is a composite of Chothia and Kabat CDRs; the AbM definition used by Oxford Molecular’s antibody modelling software; and, the contact definition of Martin et al (bioinfo.org.uk / abs) (see Table A). Kabat provides a widely used numbering convention (Kabat numbering) in which corresponding residues between different heavy chains or between different light chains are assigned the same number. When an antibody is said to comprise CDRs by a certain definition of CDRs (e.g., Kabat) that definition specifies the minimum number of CDR residues present in the antibody (i.e., the Kabat CDRs). It does not exclude that other residues falling within another conventional CDR definition but outside the specified definition are also present. For example, an antibody comprising CDRs defined by Kabat includes among other possibilities, an antibody in which the CDRs contain Kabat CDR residues and no other CDR residues, and an antibody in which CDR H1 is a composite Chothia-Kabat CDR H1 and other CDRs contain Kabat CDR residues and no additional CDR residues based on other definitions. Table AConventional Definitions of CDRs Using Kabat Numbering*CDR-H1 by Chothia can end at H32, H33, or H34 (depending on the length of the loop). This is because the Kabat numbering scheme places insertions of extra residues at 35A and 35B, whereas Chothia numbering places them at 31A and 31B. If neither H35A nor H35B (Kabat numbering) is present, the Chothia CDR-H1 loop ends at H32. If only H35A is present, it ends at H33. If both H35A and H35B are present, it ends at H34.

[0069] In some embodiments, the CDRs of the humanized antibodies of the present invention are of a definition selected from the group of Kabat, Chothia, Kabat / Chothia Composite, AbM and Contact.

[0070] One or several amino acids at the amino or carboxy terminus of the light and / or heavy chain, such as a C-terminal lysine of the heavy chain, may be missing or derivatized in a portion or all of the molecules. Substitutions can be made in the constant regions to reduce or increase effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No.5,624,821; Tso et al., US Patent No.5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem.279:6213, 2004). Exemplary substitutions include a Gln at position 250 and / or a Leu at position 428 (EU numbering is used in this paragraph for the constant region) for increasing the half-life of an antibody. Substitution at any or all ofpositions 234, 235, 236 and / or 237 reduce affinity for Fc receptors, particularly Fc RIreceptor (see, e.g., US 6,624,821). An alanine substitution at positions 234, 235, and 237 of human IgG1 can be used for reducing effector functions. Some antibodies have alaninesubstitution at positions 234, 235 and 237 of human IgG1 for reducing effector functions. Optionally, positions 234, 236 and / or 237 in human IgG2 are substituted with alanine and position 235 with glutamine (see, e.g., US 5,624,821). In some antibodies, a mutation at one or more of positions 241, 264, 265, 270, 296, 297, 322, 329, and 331 by EU numbering of human IgG1 is used. In some antibodies, a mutation at one or more of positions 318, 320, and 322 by EU numbering of human IgG1 is used. In some antibodies, positions 234 and / or 235 are substituted with alanine and / or position 329 is substituted with glycine. In some antibodies, positions 234 and 235 are substituted with alanine. In some antibodies, the isotype is human IgG2 or IgG4. As an example, the C-terminal lysine on SEQ ID NO:11 (heavy chain) or SEQ ID NO:9 (heavy chain constant region) is optional such that SEQ ID NO:11 and SEQ ID NO:9 may be considered with or without the C-terminal lysine.

[0071] The term "humanized immunoglobulin" or "humanized antibody" refers to an immunoglobulin or antibody that includes at least one humanized immunoglobulin or antibody chain (i.e., at least one humanized light or heavy chain). The term "humanized immunoglobulin chain" or "humanized antibody chain" (i.e., a "humanized immunoglobulin light chain" or "humanized immunoglobulin heavy chain") refers to an immunoglobulin or antibody chain (i.e., a light or heavy chain, respectively) having a variable region that includes a variable framework region substantially from a human immunoglobulin or antibody and complementarity determining regions (CDRs) (e.g., at least one CDR, preferably two CDRs, more preferably three CDRs) substantially from a non-human immunoglobulin or antibody, and further includes constant regions (e.g., at least one constant region or portion thereof, in the case of a light chain, and preferably three constant regions in the case of a heavy chain). The term "humanized variable region" (e.g., "humanized light chain variable region" or "humanized heavy chain variable region") refers to a variable region that includes a variable framework region substantially from a human immunoglobulin or antibody and complementarity determining regions (CDRs) substantially from a non-human immunoglobulin or antibody. “Excluding the CDRs” as used herein means the portions of the antibody that do not include the amino acids of the CDRS, for example the framework regions and antibody constant regions.

[0072] Accordingly, regions or residues of a humanized immunoglobulin or antibody, or of a humanized immunoglobulin or antibody chain, except possibly the CDRs, are substantially identical to the corresponding regions or residues of one or more native human immunoglobulin sequences. The term "corresponding region" or "corresponding residue" refers to a region or residue on a second amino acid or nucleotide sequence which occupiesthe same (i.e., equivalent) position as a region or residue on a first amino acid or nucleotide sequence, when the first and second sequences are optimally aligned for comparison purposes.

[0073] The term “epitope” or "antigenic determinant" refers to a site on an antigen to which an antibody binds. An epitope can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of one or more proteins. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8- 10 amino acids in a unique spatial conformation. When an epitope is said to be within a rangeof amino acid residues in a protein (e.g., within residues 1 to 6 of A ), the range is inclusiveof the residues defining its borders. Certain residues within the range contribute to the epitope, whereas others may not. The residues that form the epitope may or may not be contiguous with one another. Similarly, when an antibody binds to an epitope found within a particular range of amino acids, the antibody need not contact all the amino acids residues within the range, and the residues of the epitope that are contacted by the antibody may or may not be contiguous with one another. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols, in Methods in Molecular Biology, Vol.66, Glenn E. Morris, Ed. (1996).

[0074] Antibodies that recognize the same epitope can be identified in a simple immunoassay showing the ability of one antibody to block or compete with the binding of another antibody to a target antigen, i.e., a competitive binding assay. Competitive binding is determined in an assay in which the immunoglobulin under test inhibits specific binding of areference antibody to a common antigen, such as A . Numerous types of competitive bindingassays are known, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see Stahli et al., Methods in Enzymology 9:242 (1983)); solid phase direct biotin-avidin EIA (see Kirkland et al., J. Immunol.137:3614 (1986)); solid phase direct labeled assay, solid phase direct labeled sandwich assay (see Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988)); solid phase direct label RIA using I-125 label (see Morel et al., Mol. Immunol.25(1):7 (1988)); solid phase direct biotin-avidin EIA (Cheung et al., Virology 176:546 (1990)); and direct labeled RIA. (Moldenhauer et al., Scand. J. Immunol.32:77 (1990)). Typically, such an assay involves the use of purified antigen bound to a solid surfaceor cells bearing either of these, an unlabeled test immunoglobulin and a labeled reference immunoglobulin. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin. Usually the test immunoglobulin is present in excess. Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, or more.

[0075] Competition between antibodies is determined by an assay in which an antibody under test inhibits specific binding of a reference antibody (e.g.3D6, aducanumab, bapineuzumab) to a common antigen (see, e.g., Junghans et al., Cancer Res.50:1495, 1990). A test antibody competes with a reference antibody if an excess of a test antibody (e.g., at least 2×, 5×, 10×, 20× or 100×) inhibits binding of the reference antibody by at least 50% but preferably 75%, 90% or 99% as measured in a competitive binding assay. Antibodies identified by competition assay (competing antibodies) include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur.

[0076] The epitope of an antibody can also be defined by X-ray crystallography of the antibody bound to its antigen to identify contact residues. Alternatively, two antibodies have the same epitope if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

[0077] An epitope is also recognized by immunologic cells, for example, B cells and / or T cells. Cellular recognition of an epitope can be determined by in vitro assays that measure antigen-dependent proliferation, as determined by3H-thymidine incorporation, by cytokine secretion, by antibody secretion, or by antigen-dependent killing (cytotoxic T lymphocyte assay).

[0078] Exemplary epitopes or antigenic determinants can be found within the humanamyloid precursor protein (APP) but are preferably found within the A peptide of APP.Multiple isoforms of APP exist, for example APP695, APP751, and APP770. Amino acids within APP are assigned numbers according to the sequence of the APP770isoform (see e.g., GenBank Accession No. P05067, also set forth as SEQ ID NO: 85).

[0079] A (also referred to herein as beta amyloid peptide and A-beta) peptide is a about4-kDa internal fragment of 39-43 amino acids of APP (A 39, A 40, A 41, A 42, and A 43).A 40, for example, consists of residues 672-711 of APP and A 42 consists of residues 673-713 of APP. As a result of proteolytic processing of APP by different secretase enzymes invivo or in situ, A is found in both a "short form", 40 amino acids in length, and a "longform", ranging from 42-43 amino acids in length. Preferred epitopes or antigenicdeterminants, as described herein, are located within the N-terminus of the A peptide andinclude residues within amino acids 1-10 of A , preferably from residues 1-3, 1-4, 1-5, 1-6,1-7, or 3-7 of A 42. Additional referred epitopes or antigenic determinants include residues2-4, 5, 6, 7, or 8 of A , residues 3-5, 6, 7, 8, or 9 of A , or residues 4-7, 8, 9, or 10 of A 42.

[0080] "Soluble" or "dissociated" A refers to A species that are either monomeric,aggregated, oligomeric, associated or not with other proteins and lipids, which remain insolution (supernatant) after centrifugation at 100,000 × g. "Insoluble" A refers to aggregatedA species, amyloid (beta-sheet) or not, that do not remain in solution after 100,000 x gcentrifugation, for example, A held together by noncovalent bonds. A (e.g., A 42) isbelieved to aggregate, at least in part, due to the presence of hydrophobic residues at the C- terminus of the peptide (part of the transmembrane domain of APP). One method to preparesoluble A is to dissolve lyophilized peptide in neat DMSO with sonication. The resultingsolution is centrifuged to remove any insoluble particulates.

[0081] "Specific binding" of an antibody mean that the antibody exhibits appreciable affinity for antigen or a preferred epitope and, preferably, does not exhibit significant cross reactivity. "Appreciable" or preferred binding include binding with an affinity of at least 106, 107, 108, 109M-1, or 1010M-1. Affinities greater 107M-1, preferably greater than 108M-1are more preferred. Values intermediate of those set forth herein are also intended to be within the scope of the present disclosure and a preferred binding affinity can be indicated as a range of affinities, for example, 106to 1010M-1, preferably 107to 1010M-1, more preferably 108to 1010M-1. An antibody that "does not exhibit significant cross reactivity" is one that will not appreciably bind to an undesirable entity (e.g., an undesirable proteinaceous entity). Forexample, an antibody that specifically binds to A will appreciably bind A but will notsignificantly react with non-A proteins or peptides (e.g., non-A proteins or peptidesincluded in plaques). An antibody specific for a preferred epitope will, for example, not significantly cross-react with remote epitopes on the same protein or peptide. Specific binding can be determined according to any art-recognized means for determining such binding. Preferably, specific binding is determined according to Scatchard analysis and / or competitive binding assays.

[0082] Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins. Binding fragments include Fab, Fab', F(ab')2, Fabc, Fv, single chains, and single-chain antibodies.

[0083] The term “peripheral administration” as used herein includes, e.g., intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, intranasal, intra-ocular / vitreal, rectal, or vaginal administration. While all these forms of administration are clearly contemplated as being within the scope of the disclosure, an example of a form for administration would be a solution for injection, in particular for subcutaneous, intravenous or intraarterial injection or drip. A suitable pharmaceutical composition for injection can comprise a buffer, a surfactant, optionally a stabilizer agent, etc. Preparations for peripheral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Preservatives and other additives can also be present such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like.

[0084] The term “patient” includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment. In some embodiments, the term “individual” is used interchangeably with “patient.”

[0085] The term “subject” includes human and other subjects that receive either prophylactic or therapeutic treatment, and includes, but is not limited to “patients” described herein.

[0086] The term "effective dose" or "effective dosage" is defined as an amount sufficient to achieve or at least partially achieve the desired effect. The term "therapeutically effective dose" is defined as an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Amounts effective for this use will depend upon the severity of the infection and the general state of the patient's own immune system.

[0087] The term "treatment" as used herein, is defined as the application or administration of a therapeutic agent to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient, who has a disease, a symptom of disease or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease, the symptoms of disease or the predisposition toward disease.

[0088] The term "amyloidogenic disease" includes any disease associated with (or caused by) the formation or deposition of insoluble amyloid fibrils or amyloid plaques. Exemplary amyloidogenic diseases include, but are not limited to systemic amyloidosis, Alzheimer'sdisease, mature onset diabetes, Parkinson's disease, Huntington's disease, fronto-temporal dementia, Down’s syndrome, mild cognitive impairment, prion-related transmissible spongiform encephalopathies (kuru and Creutzfeldt-Jacob disease in humans and scrapie and BSE in sheep and cattle, respectively), and the like. Different amyloidogenic diseases are defined or characterized by the nature of the polypeptide component of the fibrils deposited. For example, in subjects or patients having Alzheimer's disease, -amyloid protein (e.g., wild-type, variant, or truncated -amyloid protein) is the characterizing polypeptide component of the amyloid deposit. Accordingly, Alzheimer's disease is an example of a"disease characterized by deposits of A " or a "disease associated with deposits of A ", e.g.,in the brain of a subject or patient. The terms " -amyloid protein", " -amyloid peptide", " -amyloid", "A " and "A peptide" are used interchangeably herein.

[0089] An individual is at increased risk of a disease if the subject has at least one known risk-factor (e.g., genetic, biochemical, family history, situational exposure) placing individuals with that risk factor at a statistically significant greater risk of developing the disease than individuals without the risk factor.

[0090] The term “symptom” refers to a subjective evidence of a disease, such as altered gait, as perceived by the patient. A “sign” refers to objective evidence of a disease as observed by a physician.

[0091] Statistical significance means p<0.05.

[0092] “Half-life (t1 / 2)” refers to the time required for the concentration of the antigen binding polypeptide to reach half of its original value. The serum half-life of proteins can be measured by pharmacokinetic studies according to the method described by Kim et al. (Eur. J. of Immuno.24: 542, 1994). According to this method, radiolabeled protein is injected intravenously into mice and its plasma concentration is periodically measured as a function of time, for example, at about 3 minutes to about 72 hours after the injection. Other methods for pharmacokinetic analysis and determination of the half-life of a molecule will be familiar to those skilled in the art. Details may be found in Kenneth, A et al: Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists and in Peters et al, Pharmacokinetic analysis: A Practical Approach (1996).

[0093] “Clearance (CL)” refers to the volume of plasma irreversibly cleared of a protein per unit time. Clearance is calculated as the Dose / AUC (AUC : is the Area Under Curve or Area under the plasma drug concentration time curve). Clearance can also be calculated by the rate of drug elimination divided by the plasma concentration of the drug (rate of elimination = CL*concentration).

[0094] “Mean Residence Time (MRT)” is the average time that the antigen binding polypeptides reside in the body before being irreversibly eliminated. Calculated as MRT= AUMC / AUC.

[0095] “Steady state concentration” (Css) is the concentration reached when the drug elimination rate becomes equal to drug administration rate as a result of continued drug administration. Css fluctuates between peak and trough levels and is measured in microgram / ml.

[0096] “Baseline” as used herein is the value of a parameter before or at the time of administration of the pharmaceutical composition of the present invention, including, for example, the value of a given biomarker or a subject’s status prior to the first administration of an antibody of the present disclosure.

[0097] “Amyloid negative” means the subject does not possess brain amyloid beta plaque that is observable using positron emission tomography (“PET”) and includes, but is not limited to, subjects having a centiloid value of zero.

[0098] “Amyloid positive” means the subject possesses brain amyloid beta plaque that is observable using PET.

[0099] “ARIA risk” or “risk of ARIA” as used herein refers to the probability that a subject will develop an Amyloid Related Imaging Abnormality that is observable by magnetic resonance imaging (“MRI”). A total ARIA risk includes the risk of developing observable ARIA-E and / or observable ARIA-H. In contrast, “a risk of ARIA-E” refers only to the probability that a subject will develop ARIA-E observable by MRI, irrespective of whether the subject develops observable ARIA-H, and “a risk of ARIA-H” refers only to the probability that a subject will develop ARIA-H observable by MRI, irrespective of whether the subject develops observable ARIA-E. ARIA risk may be assessed at baseline (prior to the administration of an anti-amyloid antibody of the present disclosure) or, alternatively, during or after treatment. Treatment Regimes

[0100] Prophylactic applications: pharmaceutical compositions or medicaments are administered to a patient susceptible to, or otherwise at risk of, Alzheimer's disease or other amyloidogenic disease in an amount sufficient to eliminate or reduce the risk, lessen the severity, or delay the outset of the disease, including biochemical, histologic and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. Patient susceptibility or risk fordeveloping an amyloidogenic disease can be determined, for example, from a genetic marker, a biochemical marker, unspecified hereditary risk or other means. In therapeutic applications, compositions or medicaments are administered to a patient suspected of, or already suffering from such a disease in an amount sufficient to cure, or at least partially arrest, the symptoms of the disease (biochemical, histologic and / or behavioral), including its complications and intermediate pathological phenotypes in development of the disease.

[0101] In some embodiments, administration of agent reduces or eliminates cognitive impairment in patients that have not yet developed characteristic Alzheimer's, or other amyloidogenic disease cognitive pathology. An amount adequate to accomplish therapeutic or prophylactic treatment is defined as a therapeutically- or prophylactically-effective dose. In both prophylactic and therapeutic regimes, agents are usually administered in several dosages until a sufficient immune response has been achieved, where "immune response" or "immunological response" includes the development of a humoral (antibody mediated) and / or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against an antigen in a recipient subject. Such a response can be an active response, i.e., induced by administration of immunogen, or a passive response, i.e., induced by administration of immunoglobulin or antibody or primed T-cells.

[0102] In some embodiments, antibody is administered on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. In some embodiments, a single dosage may be administered about once or twice every week, about once or twice every two weeks, about once or twice every three weeks, about once or twice every four weeks, about once or twice every five weeks, or about once or twice every six weeks. In one particular embodiment, antibody is administered once about every four weeks intravenously or subcutaneously. In another embodiment, antibody is administered once about every two weeks intravenously or subcutaneously.

[0103] Intervals can also be irregular as indicated by measuring blood levels of antibodyto A in the patient. In some methods, dosage is adjusted to achieve a plasma antibodyconcentration of 1-1000 g / ml and in some methods 25-300 g / ml. Alternatively, antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies.

[0104] In some embodiments, a patient with Alzheimer’s disease administered apharmaceutically effective amount of an anti-A antibody (or antigen-binding fragmentthereof) as described herein is treated by reduction in amyloid plaque burden, measured by PET imaging.

[0105] In another embodiment, an anti-A antibody (or antigen-binding fragmentthereof) as described herein can be administered in a fixed amount at each administration. For example, a fixed amount of about 20 mg, about 25 mg, about 45 mg, about 70 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 205 mg, about 250, about 300 mg, about 350 mg, about 400 mg, about 405 mg, about 450, about 500 mg, about 600 mg, or about 700 mg can be administered at one time to an individual. In one particular embodiment, about 20 mg, about 25 mg, about 45 mg, about 70 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 205 mg, about 250, about 300 mg, about 350 mg, about 400 mg, about 405 mg, about 450, about 500 mg, about 600 mg, or about 700 mg of antibody is administered once about every four weeks subcutaneously to an individual.

[0106] In one particular embodiment, about 100 mg, about 200 mg, or about 350 mg of antibody is administered twice about every four weeks subcutaneously. In one particular embodiment, about 100 mg, about 200 mg, or about 350 mg of antibody is administered once about every two weeks subcutaneously.

[0107] In another particular embodiment, about 45 mg, about 70 mg, about 100 mg, about 125 mg, about 150 mg, about 175 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, or about 700 mg of h2731 is administered once about every four weeks subcutaneously. In another particular embodiment, about 100 mg, about 200 mg, or about 350 mg of h2731 is administered twice about every four weeks subcutaneously. In another particular embodiment, about 100 mg, about 200 mg, or about 350 mg of h2731 is administered once about every two weeks subcutaneously.

[0108] The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, compositions containing the present antibodies or a cocktail thereof are administered to a patient not already in the disease state to enhance the patient's resistance. Such an amount is defined to be a "prophylactic effective dose." In this use, the precise amounts again depend upon the patient's state of health and general immunity. A relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives.

[0109] In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and in some aspects, until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patent can be administered a prophylactic regime.

[0110] Administration: therapeutic agents can be administered by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intracranial, intraperitoneal, intranasal, intraocular or intramuscular means for prophylactic and / or therapeutic treatment. Intramuscular injection is most typically performed in the arm or leg muscles. In some methods, agents are injected directly into a particular tissue where deposits have accumulated, for example intracranial injection. Intramuscular injection or intravenous infusion are preferred for administration of antibody. In some methods, particular therapeutic antibodies are injected directly into the cranium. In some methods, antibodies are administered as a sustained release composition or device. In some embodiments, antibodies are administered subcutaneously using an autoinjector device. Dosing Regimens

[0111] The present disclosure provides methods of treating neurological disorders (e.g., Alzheimer’s Disease), the method comprising administering a composition comprising an anti-amyloid antibody. For example, in some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject about 20 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. For example, in some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject about 205 mg to about 400 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. For example, in some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject about 405 mg to about 700 mg of an anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0112] The present disclosure also provides methods of reducing amyloid plaque in a subject. For example, in some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 20 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. For example, in some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subjectabout 205 mg to about 400 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. For example, in some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 405 mg to about 700 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0113] The present disclosure further provides methods of converting a subject from amyloid positive to amyloid negative. For example, in some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject about 20 mg to about 200 mg of an anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. For example, in some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject about 205 mg to about 400 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. For example, in some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject about 405 mg to about 700 mg of an anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0114] In some embodiments, the method comprises administering to the subject about 20 mg to about 200 mg (e.g., about 45 mg to about 200 mg, about 70 mg to about 200 mg, about 100 mg to about 200 mg, about 125 mg to about 200 mg, or about 150 mg to about 200 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject about 205 mg to about 400 mg (e.g., about 250 mg to about 400 mg, about 300 mg to about 400 mg, or about 350 mg to about 400 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject about 405 mg to about 700 mg (e.g., about 450 mg to about 700 mg, about 500 mg to about 700 mg, or about 600 mg to about 700 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject about 20 mg to about 200 mg (e.g., about 45 mg to about 200 mg, about 70 mg to about 200 mg, about 100 mg to about 200 mg, about 125 mg to about 200 mg, or about 150 mg to about 200 mg) of the anti- amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In some embodiments, the method comprises administering to the subject about 205 mg to about 400 mg (e.g., about 250 mg to about 400 mg, about 300 mg to about 400 mg, or about 350mg to about 400 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In some embodiments, the method comprises administering to the subject about 405 mg to about 700 mg (e.g., about 450 mg to about 700 mg, about 500 mg to about 700 mg, or about 600 mg to about 700 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks.

[0115] In example embodiments, the method comprises administering to the subject about 40 mg to about 50 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 65 mg to about 75 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 95 mg to about 105 mg of the anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 145 mg to about 155 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 195 mg to about 205 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 295 mg to about 305 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 345 mg to about 355 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 375 mg to about 400 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 445 mg to about 455 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 495 mg to about 505 mg of the anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 545 mg to about 555 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 595 mg to about 605 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 645 mg to about 655 mg of the anti-amyloidantibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 695 mg to about 705 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0116] In some embodiments, the method comprises administering to the subject about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg, or about 700 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 400 mg, 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks (e.g., once about every 4 weeks).

[0117] In example embodiments, the method comprises administering to the subject about 45 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 70 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 150 mg of the anti-amyloid antibody or an antigen- binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 200 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 300 mg of the anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 400 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 450 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 500 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 550 mg of the anti-amyloid antibody or an antigen- binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 600 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 650 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 700 mg of the anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0118] In example embodiments, the method comprises administering to the subject about 45 mg of the anti-amyloid antibody or an antigen-binding fragment thereof onceabout every 4 weeks. In example embodiments, the method comprises administering to the subject about 70 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 150 mg of the anti-amyloid antibody or an antigen- binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 200 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 300 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 350 mg of the anti- amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 400 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 450 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 500 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 550 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 600 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 650 mg of the anti-amyloid antibody or an antigen- binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject about 700 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks.

[0119] In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen- binding fragment thereof once about a month. In some embodiments, the method comprisesadministering the anti-amyloid antibody or an antigen-binding fragment thereof once about every 28 days.

[0120] In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration (e.g., a single subcutaneous injection) once about every 3-5 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration once about every 4 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration once every 4 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration once about a month. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration once about every 28 days.

[0121] In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject about 10 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject about 100 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 205 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject about 50 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject about 150 mg to about 200 mg of an anti- amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks).

[0122] In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 10 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 50 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 100 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 150 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 205 mg to about 350 mg of an anti- amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks).

[0123] In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject about 10 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject about 50 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject about 150 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subjectabout 205 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks).

[0124] In some embodiments, the method comprises administering to the subject about 10 mg to about 100 mg (e.g., about 25 mg to about 100 mg, about 35 mg to about 100 mg, about 50 mg to about 100 mg, or about 75 mg to about 100 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the method comprises administering to the subject about 100 mg to about 200 mg (e.g., about 125 mg to about 200 mg, about 150 mg to about 200 mg, or about 175 mg to about 200 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In some embodiments, the method comprises administering to the subject about 225 mg to about 350 mg (e.g., about 250 mg to about 350 mg, about 275 mg to about 350 mg, or about 300 mg to about 350 mg) of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks).

[0125] In example embodiments, the method comprises administering to the subject about 5 mg to about 15 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 45 mg to about 55 mg, about 70 mg to about 80 mg, about 95 mg to about 105 mg, about 100 mg to about 105 mg, about 120 mg to about 130 mg, about 145 mg to about 155 mg, about 170 mg to about 180 mg, about 195 mg to about 205 mg, about 220 mg to about 230 mg, about 245 mg to about 255 mg, about 260 mg to about 280 mg, about 295 mg to about 305 mg, about 320 mg to about 330 mg, or about 345 mg to about 355 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks).

[0126] In some embodiments, the method comprises administering to the subject about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg,about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once every 2 weeks).

[0127] In example embodiments, the method comprises administering to the subject about 35 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 35 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0128] In example embodiments, the method comprises administering to the subject about 50 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 50 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0129] In example embodiments, the method comprises administering to the subject about 75 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 75 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0130] In example embodiments, the method comprises administering to the subject about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0131] In example embodiments, the method comprises administering to the subject about 150 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 150 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0132] In example embodiments, the method comprises administering to the subject about 200 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twiceabout every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 200 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0133] In example embodiments, the method comprises administering to the subject about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0134] In example embodiments, the method comprises administering to the subject about 300 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 300 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0135] In example embodiments, the method comprises administering to the subject about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0136] In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 4 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen- binding fragment thereof twice about a month. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 28 days.

[0137] In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration (e.g., a single subcutaneous injection) once about every 1-3 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration once about every 2 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration once every 2 weeks. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a single administration once about every 14 days.

[0138] In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as an injection. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a parenteral injection. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof via intravenous injection or subcutaneous injection. In example embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof as a subcutaneous injection. In some embodiments, the method comprises administering the anti-amyloid antibody or an antigen-binding fragment thereof via an autoinjector.Anti-A Antibodies

[0139] The present disclosure provides methods of using an antibody or fragment thereofthat that specifically binds to A peptide. In some aspects, the present disclosure utilizesanti-amyloid antibodies or fragments thereof that achieve therapeutic efficacy using monthly subcutaneous dosing. The present disclosure further describes selecting and designing anti-amyloid antibodies or fragments thereof suitable for monthly subcutaneous dosing.

[0140] In some embodiments, monoclonal antibodies for use in the disclosure bind to anepitope within residues 1-6 of A (with the first N terminal residue of natural A designated1). Some monoclonal antibodies bind to an epitope within amino acids 1-6, some to an epitope within 1-5, and some to an epitope within 1-4. Some antibodies bind to epitopes within amino acids 1-3, 2-5, 3-5, 2-4, 2-5, 2-6, 3-5, or 3-6. When an antibody is said to bindto an epitope within specified residues, such as A 1-6 for example, what is meant is that theantibody specifically binds to a polypeptide containing at least one of the specified residues(i.e., at least one amino acid from A 1-6 in this an example); such antibody does notnecessarily contact every residue within A 1-6. In some embodiments, the antibody binds toan epitope including at least one amino acid from acid selected from amino acids 1-10 of theA peptide. In another aspect, the antibody binds to an epitope including at least one aminoacid from acid selected from amino acids 1-7 of the A peptide. Additional amino acids ofthe epitope may be outside the region of amino acids 1-10 or amino acids 1-7.

[0141] The antibodies used in such methods can be humanized, human or fragments thereof (e.g., antigen binding fragments) and can be monoclonal or polyclonal, as described herein. In yet another aspect, the disclosure features administering antibodies prepared from ahuman immunized with A peptide, which human can be the patient to be treated withantibody.

[0142] In some embodiments, the anti-amyloid antibody or fragment includes a heavy chain variable region having a heavy chain CDR1, CDR2 and CDR3 and a light chain variable region comprising a light chain CDR1, CDR2 and CDR3 from the constructs show in Table 1. Table 1

[0143] In some embodiments, the anti-amyloid antibody or fragment of the disclosure includes a heavy chain variable region (VH) as shown for one of the constructs in Table 1. In some embodiments, the anti-amyloid antibody or fragment also includes light chain variable region (VL) as shown for one of the constructs in Table 1.

[0144] In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 and a light chain variable region comprising light chain CDR1, CDR2, and CDR3, wherein heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 3, heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 4, heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 5, light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 6, light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 7, and light chain CDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0145] In some embodiments, for example, the anti-amyloid antibody or fragment thereof for use in methods of the present disclosure include a heavy chain variable region that is at least 90% (e.g., at least 95%, at least 98%, or 100%) identical to SEQ ID NO: 1 and thelight chain variable region, excluding the CDRs, that is at least 90% (e.g., at least 95%, at least 98%, or 100%) identical to SEQ ID NO: 2.

[0146] In some embodiments, the heavy chain variable region, excluding the CDRs, is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region, excluding the CDRs, is at least 95% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the heavy chain variable region, excluding the CDRs, is at least 98% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region, excluding the CDRs, is at least 98% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the heavy chain variable region consists of SEQ ID NO: 1, and wherein the light chain variable region consists of the amino acid sequence of SEQ ID NO: 2.

[0147] In some embodiments, the anti-amyloid antibody is a full antibody, a chimeric antibody, a CDR-grafted antibody, or a recombinant antibody. In some embodiments, the anti-amyloid antibody is a humanized IgG. In some embodiments, the anti-amyloid antibody is a humanized IgG1.

[0148] In some embodiments, the anti-amyloid antibody or fragment thereof for use in methods of the present disclosure also include a heavy chain constant region that is at least 75% identical to SEQ ID NO: 9. For example, the heavy chain constant region may be 75% identical, 80%, identical, 85% identical, 90% identical, 95% identical, 96% identical, 97% identical, 98% identical, 99% identical, of 100% identical to SEQ ID NO: 9.

[0149] In some embodiments, the anti-amyloid antibody or fragment thereof for use in methods of the present disclosure also include a light chain constant region that is at least 75% identical to SEQ ID NO: 10. For example, the light chain constant region may be 75% identical, 80%, identical, 85% identical, 90% identical, 95% identical, 96% identical, 97% identical, 98% identical, 99% identical, of 100% identical to SEQ ID NO: 10.

[0150] In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 9 and / or a light chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 10. In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO: 9 and / or a light chain constant region comprising an amino acid sequence at least 98% identicalto SEQ ID NO: 10. In some embodiments, the anti-amyloid antibody comprises a heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 9, with or without the C-terminal lysine, and a light chain constant region comprising an amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-amyloid antibody comprises a heavy chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 9, with or without the C-terminal lysine, and a light chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 10.

[0151] In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 11 and / or a light chain comprising an amino acid sequence at least 95% identical to SEQ ID NO: 12. In some embodiments, the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain comprising an amino acid sequence at least 98% identical to SEQ ID NO: 11 and / or a light chain comprising an amino acid sequence at least 98% identical to SEQ ID NO: 12. In example embodiments, the anti- amyloid antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain comprising an amino acid sequence of SEQ ID NO: 12. In example embodiments, the anti-amyloid antibody comprises a heavy chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 12. In example embodiments, the anti-amyloid antibody comprises a heavy chain constant region consisting of an amino acid sequence of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain constant region consisting of an amino acid sequence of SEQ ID NO: 12. In example embodiments, the anti-amyloid antibody is h2731.

[0152] A variant antibodies or fragments that are less than 100% identical to thesequences described in Table 1A (plus any constant region) can differ from an anti-Aantibody of Table 1 by as few as 1 to 15 amino acid residues, as few as 1 to 10 amino acid residues, such as 6-10, as few as 5, as few as 4, 3, 2, or even 1 amino acid residue. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Families of amino acid residues having side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine,leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity (e.g.,the ability to bind an A polypeptide).

[0153] For example, it is possible to introduce mutations only in a framework region(s) of the antibody molecules (i.e., in a region(s) excluding the CDRs) . Introduced mutations can be silent or neutral missense mutations, i.e., have no, or little, effect on an antibody's ability to bind antigen. These types of mutations can be useful to optimize codon usage, or improve a hybridoma's antibody production. Alternatively, non-neutral missense mutations can alter an antibody's ability to bind antigen. One of skill in the art would be able to design and test mutant molecules with desired properties such as no alteration in antigen binding activity or alteration in binding activity (e.g., improvements in antigen binding activity or change in antibody specificity). Following mutagenesis, the encoded protein can routinely be expressed and the functional and / or biological activity of the encoded protein, (e.g., ability toimmunospecifically bind at least one epitope of an A polypeptide) can be determined usingtechniques described herein or by routinely modifying techniques known in the art.

[0154] In each of the foregoing embodiments, the antibody or fragment of the disclosure may be a humanized antibody as described herein. For example, the antibody may be a human IgG1 antibody. In addition, the antibody may a full antibody, a chimeric antibody, a CDR-grafted antibody, or a recombinant antibody. Fragments of the antibody may be a Fab,Fab , F(ab )2, Fabc, or Fv. Fragments are produced by recombinant DNA techniques, or byenzymatic or chemical separation of intact immunoglobulins.

[0155] The antibody h2731 possesses several physicochemical properties that make it suitable for use in methods of the present disclosure, including, for example, properties described in Tables 2 and 3. Additional properties, including pharmacokinetic parameters, are discussed herein. Table 2

[0156] Table 2 provides IC50 and / or EC50 values data for h2731 binding various amyloid species, including A 1-42 fibrils, A 1-42 aggregates and A pE3-42 fibrils. See, e.g., U.S. PatentNo.11,440,953.

[0157] An assay based on the competition (inhibition) of binding of a labeled antibody to an antigen-coated plate was used to determine IC50for h2731. The IC50was then divided by the IC50for bapineuzumab (hBP) to yield a half maximal inhibitory concentration (IC50) ratio, shown in Column 1 of Table 2. The ratio of 0.61 demonstrates that h2731 exhibits betterperformance than hBP in binding A 1-42 fibrils. Using a similar competition assay, it wasdemonstrated that h2731 exhibits an IC50value of 5.024 μg / mL (Column 2 of Table 2), which several fold lower than the IC50value observed for hBP.

[0158] The direct binding of h2731 to A 1-42 and A pE3-42 fibrils was also assessed byELISA (Columns 3 and 4 of Table 2), providing an EC50 value of 36.71 ng / mL for h2731against A 1-42 fibrils. h2731 demonstrated strong affinity to fibrils and significantly greateravidity than aducanumab. Further, a 3-fold increase in assay signal (OD490) and a 15 to 20- fold lower estimated EC50 indicated increased overall binding and relative avidity of h2731 tofibrillar A relative to aducanumab.

[0159] However, while h2731 binds with high apparent affinity to the N-terminus of fulllength A , it does not specifically bind to pyroglutamate-modified A (A pE3-42). h2731bound with a half-maximal effective concentration (EC50) of 8.1 ng / mL (54 pM) to fibrillarA species with an unmodified N-terminus (A 1-42). h2731 demonstrated no detectablebinding to A pE3-42 up to 100ng / ml.Table 3Abeta: amyloid beta, A ; ka: association rate constant; kd: dissociation rate constant;KD: apparent equilibrium dissociation constant; mAb: monoclonal antibody; Rmax: maximum response; SPR: surface plasmon resonance.

[0160] Table 3 provides additional amyloid binding data for h2731, including data onbinding dynamics of h2731 to recombinant A 1-42 fibrils and Aß1-28 monomer. As shown inColumn 2 of Table 3, h2731 binds A 1-42 fibrils and Aß1-28 monomer with associationconstants of 3.72 x 105 M 1 s 1 and 1.19 x 105 M 1 s 1 respectively. Although aducanumabbinds A fibrils at a faster association rate (ka), the much slower dissociation rate (kd) ofh2731 of the disclosure resulted in greater measured avidity (i.e., lower KD*) than aducanumab.

[0161] Off-rate data (kd) are for h2731 shown in Column 3 of Table 3, providing kdvalues of 2.62 x 10-5 s-1 and 5.95 x 10-4 s-1 for h2731 against A 1-42 fibrils and Aß1-28monomer, respectively. The enhanced relative avidity of h2731 of the disclosure for fibrillarA observed by ELISA was confirmed by SPR equilibrium binding kinetics (Column 4 ofTable 3), which indicated a 5- to 11-fold greater avidity (apparent KD) than aducanumab, including 4-7 nM binding affinity for Aß1-28monomer.

[0162] In additional embodiments, the methods of the present disclosure may utilize one or more of several different anti-amyloid antibodies or fragments thereof. In particular, antibodies suitable for use in methods of the present disclosure possess physiochemical and pharmacological properties, discussed herein, that allow for therapeutically effective dosing using once monthly subcutaneous administration and / or twice monthly subcutaneous administration. Additional exemplary anti-amyloid antibodies suitable for use in methods of the present disclosure include those in U.S. Patent No.11,440,953, which is incorporated by reference herein in its entirety.

[0163] In some embodiments, the anti-amyloid antibody or binding fragments, variant,or derivative binds to A (or a fragment or variant thereof) with an off rate (k(off)) of lessthan or equal to 5×10 2 sec 1, 10 2 sec 1, 5×10 3 sec 1 or 10 3 sec 1. In certain embodiments,the anti-amyloid antibody or binding fragments, variant, or derivative binds to A (or afragment or variant thereof) with an off rate (k(off)) of less than or equal to 5×104 sec 1, 10 4sec 1, 5×10 5 sec 1, or 10 5 sec 1, 5×10 6 sec 1, 10 6 sec 1, 5×10 7 sec 1 or 10 7 sec 1.

[0164] In some embodiments, the anti-amyloid antibody or binding fragments, variant,or derivative binds to A (or a fragment or variant thereof) with an on rate (k(on)) of greaterthan or equal to 103 M 1 sec 1, 5×103 M 1 sec 1, 104 M 1 sec 1 or 5×104 M 1 sec 1. Incertain embodiments, the anti-amyloid antibody or binding fragments, variant, or derivativebinds to A (or a fragment or variant thereof) with an on rate (k(on)) greater than or equal to105 M 1 sec 1, 5×105 M 1 sec 1, 106 M 1 sec 1, or 5×106 M 1 sec 1 or 107 M 1 sec 1.

[0165] Anti-A antibodies or antigen-binding fragments, variants or derivatives thereof,as described herein can also be described or specified in terms of their binding affinity A .Binding affinities can include those with a dissociation constant or Kd less than 5×10 2 M,10 2 M, 5×10 3 M, 10 3 M, 5×10 4 M, 10 4 M, 5×10 5 M, 10 5 M, 5×10 6 M, 10 6 M,5×10 7 M, 10 7 M, 5×10 8 M, 10 8 M, 5×10 9 M, 10 9 M, 5×10 10 M, 10 10 M, 5×10 11 M,10 11 M, 5×10 12 M, 10 12 M, 5×10 13 M, 10 13 M, 5×10 14 M, 10 14 M, 5×10 15 M, or 10 15 M.

[0166] The present disclosure will be more fully described by the following non-limiting examples.

[0167] SEQ ID NO: 1 h2731_VH (Variable Heavy) Amino Acid Sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMSWVRQAPGKGLEWVASIRSGSGRTYYSDNVKGRF TISRDNSKNTLYLQMNSLRAEDTAVYYCVRYDHYSGSSDYWGQGTLVTVSS

[0168] SEQ ID NO: 2 h2731_VL (Variable Light) Amino Acid Sequence DVVMTQSPLSLPVTLGEPASISCKSSQSLLDYDGKTYLNWLLQKPGQSPQRLIYRVTNRDTGVPDRFS GSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPRSFGQGTKVEIK

[0169] SEQ ID NO: 3: VH CDR1 GFTFSNYGMS

[0170] SEQ ID NO: 4: VH CDR2 SIRSGSGRTYYSDNVKG

[0171] SEQ ID NO: 5: VH CDR3 YDHYSGSSDY

[0172] SEQ ID NO: 6: VL CDR1 KSSQSLLDYDGKTYLN

[0173] SEQ ID NO: 7: VL CDR2 RVTNRDT

[0174] SEQ ID NO: 8: VL CDR3 WQGTHFPRS

[0175] SEQ ID NO: 9: huIgG1 Constant Amino Acid Sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK

[0176] SEQ ID NO: 10: huKappa Constant Amino Acid SequenceRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0177] SEQ ID NO: 11: h2731 Complete Heavy Chain Amino Acid Sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMSWVRQAPGKGLEWVASIRSGSGRTYY SDNVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRYDHYSGSSDYWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0178] SEQ ID NO: 12: h2731 Complete Light Chain Amino Acid Sequence DVVMTQSPLSLPVTLGEPASISCKSSQSLLDYDGKTYLNWLLQKPGQSPQRLIYRVTNRD TGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPRSFGQGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0179] SEQ ID NO: 13: h2731_VH (Variable Heavy) Nucleotide Sequence GAAGTGCAGCTTCTGGAGAGCGGGGGCGGCCTGGTGCAGCCGGGCGGATCCCTGAGACTGTC CTGTGCCGCGTCCGGTTTTACCTTCTCCAACTACGGAATGTCATGGGTCCGCCAAGCACCCG GAAAGGGATTGGAATGGGTGGCTTCGATCCGGTCCGGCTCGGGACGGACCTACTACTCCGAT AACGTCAAGGGCAGATTCACTATTAGCCGGGACAACAGCAAGAATACCCTGTACCTCCAAAT GAACTCCCTGAGGGCCGAGGACACCGCCGTGTATTACTGCGTGCGCTACGACCACTACTCGG GTTCCTCTGATTACTGGGGACAGGGGACCCTCGTGACTGTGTCAAGC

[0180] SEQ ID NO: 14: h2731_VL (Variable Light) Nucleotide Sequence GATGTCGTGATGACTCAGTCACCTCTGTCCCTGCCTGTGACCCTTGGGGAACCCGCCTCGAT CTCGTGCAAGAGCTCCCAGAGCCTGCTCGACTATGATGGAAAGACCTACCTGAACTGGTTGC TCCAAAAGCCGGGCCAGAGCCCCCAGAGGCTGATCTACCGCGTGACCAACCGCGACACCGGG GTGCCGGACCGGTTCTCCGGATCCGGCAGCGGCACTGACTTCACCCTGAAAATTTCCAGAGT GGAAGCCGAGGACGTGGGAGTGTACTACTGTTGGCAGGGTACTCACTTTCCACGGTCCTTCG GTCAAGGAACCAAGGTCGAGATCAAG

[0181] SEQ ID NO: 15: huIgG1 Constant Nucleotide Sequence GCCAGCACTAAGGGGCCTAGCGTCTTTCCGCTGGCCCCGTCCTCCAAGTCCACTTCGGGTGG AACCGCGGCACTGGGGTGCCTCGTGAAGGACTACTTCCCCGAGCCGGTCACCGTGTCCTGGA ACTCGGGAGCCCTGACCTCCGGAGTGCATACTTTCCCTGCGGTGCTGCAGTCCTCCGGGCTC TACTCGCTGTCAAGCGTGGTCACCGTCCCGAGCTCATCCCTGGGTACTCAGACCTACATTTG CAACGTGAACCACAAACCTTCCAACACCAAGGTCGACAAGAAAGTGGAGCCTAAGAGCTGCG ACAAGACCCACACCTGTCCCCCGTGTCCCGCCCCTGAGCTGCTGGGCGGCCCCAGCGTGTTC CTCTTCCCGCCTAAGCCGAAGGACACTCTGATGATCTCGAGAACCCCTGAAGTGACCTGTGT GGTGGTGGATGTGTCCCACGAGGATCCGGAAGTGAAGTTCAATTGGTACGTGGACGGAGTGG AAGTCCATAACGCCAAGACCAAGCCCCGCGAGGAACAGTACAACTCAACTTACCGGGTGGTG TCAGTGCTGACCGTGCTGCACCAAGATTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTCTC CAACAAGGCGCTGCCGGCCCCCATTGAAAAGACCATCAGCAAGGCTAAGGGCCAGCCCCGGG AACCACAGGTCTACACCTTGCCCCCTTCCCGGGAGGAAATGACCAAGAACCAAGTGTCGCTG ACGTGCCTGGTCAAGGGCTTTTATCCATCTGACATCGCCGTGGAGTGGGAAAGCAACGGCCA GCCGGAAAACAACTACAAGACTACCCCGCCTGTGCTGGACTCCGACGGCTCGTTCTTCCTGT ATTCCAAGCTCACCGTGGATAAGTCCAGATGGCAGCAGGGCAATGTGTTCAGCTGCAGCGTG ATGCATGAGGCCCTGCACAACCACTACACTCAGAAATCACTGTCCCTTTCCCCCGGAAAGTA A

[0182] SEQ ID NO: 16: huKappa Constant Nucleotide Sequence CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGA AGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAG GACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAA AGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA GGGGAGAGTGTTAA

[0183] SEQ ID NO: 17: h2731 Complete Heavy Chain Nucleotide Sequence GAGGTGCAGCTCTTGGAGTCTGGGGGAGGCTTGGTGCAGCCAGGGGGGTCCCTAAGACTCTCCTGTGC AGCCTCTGGATTCACCTTCTCCAACTATGGCATGTCCTGGGTCCGCCAGGCTCCAGGGAAGGGACTGG AGTGGGTCGCTTCTATTCGCTCCGGTAGTGGTAGGACATACTACTCAGATAACGTGAAGGGCCGGTTC ACAATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGATAC GGCCGTTTATTACTGTGTGCGCTACGACCATTACTCTGGATCCTCTGACTACTGGGGCCAAGGCACCC TTGTCACAGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCTTCCAAGAGC ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTTGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCT ACTCCCTCAGCAGCGTGGTGACTGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG AATCACAAGCCCAGCAACACCAAGGTGGATAAGAAGGTTGAGCCCAAATCTTGTGACAAAACTCACAC ATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTGTTCCCCCCAAAACCCA AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGAC CCAGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGAGAGA GGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATG GCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCTCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTCGAGTGGGAGAGCA ATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TATTCCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCA TGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCCGGGAAA

[0184] SEQ ID NO: 18: h2731 Complete Light Chain Nucleotide Sequence GATGTTGTGATGACCCAGTCCCCACTCTCTTTGCCCGTTACCCTTGGAGAACCTGCCTCCATCTCTTG CAAGTCAAGTCAGAGCCTCTTAGATTACGATGGAAAGACATATTTGAATTGGTTGCTGCAGAAGCCAG GCCAGTCTCCACAGCGCCTAATCTATCGGGTGACCAACCGGGACACTGGAGTCCCTGACAGGTTCAGT GGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTGGGAGTTTA TTATTGCTGGCAAGGCACACATTTTCCGCGCTCTTTCGGACAGGGGACCAAGGTGGAAATAAAACGAA CTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGCTTAAGTCCGGAACTGCTAGC GTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCT CCAATCGGGAAACTCCCAGGAGAGCGTCACAGAGCAGGACAGCAAAGACAGCACCTACAGCCTCAGCA GCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAG GGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT Pharmaceutical Compositions

[0185] In some embodiments, the anti-A antibody or fragment thereof is administered aspart of a pharmaceutical composition. Several methods of preparing pharmaceuticalcompositions comprising anti-A antibodies, or antigen-binding fragments, variants, orderivatives thereof to a subject in need thereof are known. In some embodiments, the anti-Aantibodies or antigen-binding fragments thereof are formulated for parenteral administration.In example embodiments, the anti-A antibodies or antigen-binding fragments thereof areformulated for subcutaneous injection.

[0186] For the purposes of the disclosure, a pharmaceutically effective amount of an anti-A antibody, or antigen-binding fragment thereof, variant, or derivative thereof, means anamount sufficient to achieve effective binding to a target and to achieve a benefit, e.g., reduce brain amyloid plaques without affecting vascular amyloid, or minimizes the occurrence ofmicrohemorrhage during chronic dosing of the anti-A antibody or antigen-binding fragmentthereof. In some embodiments, an anti-A antibody or antigen-binding fragment thereof,variant, or derivative thereof crosses the blood-brain barrier in an effective amount to reduce brain amyloid plaques.

[0187] The amount of an anti-A antibody, or fragment, variant, or derivative thereof, tobe combined with the carrier materials to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. Dosage regimens also can be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response).

[0188] The present disclosure provides several pharmaceutically effective amounts ofanti-A antibodies or antigen-binding fragment thereof (e.g., about 20 mg to about 200 mg,about 205 mg to about 400 mg, or about 405 mg to about 700 mg, and additional amounts and / or ranges disclosed herein elsewhere). The present disclosure therefore provides the use of pharmaceutical compositions comprising these amounts in the methods disclosed herein. Such pharmaceutically effective amounts can be administered as a single dose, multiple doses or over an established period of time in an infusion. In example embodiments, these pharmaceutical compositions are administered as a single dose. In example embodiments, these pharmaceutical compositions are administered as a single subcutaneous injection. In some embodiments, the administration comprises two subcutaneous injections. In some embodiments, the administration comprises two or more (e.g., 2, 3, or 4) subcutaneous injections. In some embodiments, a biomarker in the subject is modulated. In some embodiments, the biomarker in the subject is modulated compared to baseline. In some embodiments, the method further comprises detecting a biomarker in a sample collected from the subject. In some embodiments, the method further comprises quantifying a biomarker in a sample collected from the subject.

[0189] For example, in some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject a pharmaceutical composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 to about 700 mg of an anti-amyloid antibody or an antigen- binding fragment thereof once about every 3-5 weeks.

[0190] In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject a pharmaceuticalcomposition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0191] In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject a pharmaceutical composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to 700 mg of an anti-amyloid antibody or an antigen- binding fragment thereof once about every 3-5 weeks (e.g., once about every 4 weeks).

[0192] For example, in some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject a pharmaceutical composition comprising from about 10 mg to about 100 mg, about 100 mg to about 200 mg, or about 205 mg to about 350 mg of an anti-amyloid antibody or an antigen- binding fragment thereof twice about every 3-5 weeks. In some aspects, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject a pharmaceutical composition comprising from about 50 mg to about 100 mg, about 150 mg to about 200 mg, or about 250 mg to 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks.

[0193] For example, in some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject a pharmaceutical composition comprising from about 10 mg to about 100 mg, about 100 mg to about 200 mg, or about 205 mg to about 350 mg of an anti-amyloid antibody or an antigen- binding fragment thereof once about every 2 weeks. In some aspects, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising administering to the subject a pharmaceutical composition comprising from about 50 mg to about 100 mg, about 150 mg to about 200 mg, or about 250 mg to 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0194] In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject a pharmaceutical composition comprising from about 10 mg to about 100 mg, about 100 mg to about 200 mg, or about 205 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In some embodiments, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising administering to the subject a pharmaceutical composition comprising from about 50 mg to about 100 mg, about150 mg to about 200 mg, or about 250 mg to 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks.

[0195] In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject a pharmaceutical composition comprising from about 10 mg to about 100 mg, about 100 mg to about 200 mg, or about 205 mg to about 350 mg of an anti-amyloid antibody or an antigen- binding fragment thereof twice about every 3-5 weeks. In some embodiments, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising administering to the subject a pharmaceutical composition comprising from about 50 mg to about 100 mg, about 150 mg to about 200 mg, or about 250 mg to 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks.

[0196] In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 15 mg to about 25 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 35 mg to about 45 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 65 mg to about 75 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 95 mg to about 105 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 145 mg to about 155 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 195 mg to about 205 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 200 mg to about 210 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 245 mg to aboutevery 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 295 mg to about 305 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 345 mg to about 355 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 395 mg to about 405 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 445 mg to about 455 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 495 mg to about 505 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 545 mg to about 555 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 595 mg to about 605 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 645 mg to about 655 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 695 mg to about 705 mg of the anti- amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0197] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 5 mg to about 15 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 20 mg to about 30 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 30 mg to about 40 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprisesadministering to the subject a pharmaceutical composition comprising about 45 mg to about 55 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 70 mg to about 80 mg of the anti- amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 95 mg to about 105 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 120 mg to about 130 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 145 mg to about 155 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 170 mg to about 180 mg of the anti- amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 195 mg to about 205 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 220 mg to about 230 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 245 mg to about 255 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 270 mg to about 280 mg of the anti- amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 295 mg to about 305 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 320 mg to about 330 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 345 mg to about355 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks.

[0198] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 20 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 45 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 70 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 150 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 200 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, these pharmaceutical compositions are administered as a single subcutaneous injection once about every 3-5 weeks (e.g., once about every 4 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 205 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 300 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 400 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, these pharmaceutical compositions are administered as a single subcutaneous injection onceabout every 3-5 weeks (e.g., once about every 4 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 450 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 500 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 550 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 600 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 650 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 700 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks. In example embodiments, these pharmaceutical compositions are administered as a single subcutaneous injection once about every 3-5 weeks (e.g., once about every 4 weeks).

[0199] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 20 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 45 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 70 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 150 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 200 mg of the anti-amyloid antibody or an antigen-bindingfragment thereof once about every 4 weeks. In example embodiments, these pharmaceutical compositions are administered as a single subcutaneous injection once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 205 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 300 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 400 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, these pharmaceutical compositions are administered as a single subcutaneous injection once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 450 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 500 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 550 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 600 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 650 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 700 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 4 weeks. In example embodiments, these pharmaceutical compositions are administered as a single subcutaneous injection once about every 4 weeks.

[0200] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 35 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 35 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0201] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 50 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 50 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0202] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 75 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 75 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0203] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 100 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0204] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 150 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 150 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0205] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 200 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject apharmaceutical composition comprising about 200 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0206] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 250 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0207] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 300 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 300 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0208] In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks). In example embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 350 mg of the anti-amyloid antibody or an antigen-binding fragment thereof once about every 2 weeks.

[0209] In another aspect, the present disclosure features administering an antibody with a pharmaceutical carrier as a pharmaceutical composition. Alternatively, the antibody can be administered to a patient by administering a polynucleotide encoding at least one antibody chain. The polynucleotide is expressed to produce the antibody chain in the patient. Optionally, the polynucleotide encodes heavy and light chains of the antibody. The polynucleotide is expressed to produce the heavy and light chains in the patient. In exemplary embodiments, the patient is monitored for level of administered antibody in the blood of the patient.

[0210] In some embodiments, the pharmaceutical composition comprises apharmaceutically effective amount of an anti-A antibody or fragment thereof and apharmaceutically acceptable diluent. As discussed herein, anti-A antibodies, or antigen-binding fragments, variants, or derivatives thereof can be formulated so as to facilitate administration and promote stability of the active agent. In certain embodiments, pharmaceutical compositions in accordance with the present disclosure comprise apharmaceutically acceptable, non-toxic, sterile carrier such as physiological saline, non-toxic buffers, preservatives and the like.

[0211] The pharmaceutical compositions used in this disclosure comprise pharmaceutically acceptable carriers, including, e.g., ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0212] Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. In many cases, isotonic agents can be included, for example, sugars, polyalcohols or salts in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0213] Preparations for parenteral administration (e.g., intravenous or subcutaneous injection) include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Furthermore, the pharmaceutical composition of the disclosure can comprise further agents such as dopamine or psychopharmacologic drugs, depending on the intended use of the pharmaceutical composition.

[0214] Therapeutic compositions for use in methods of the present disclosure are typically substantially pure from undesired contaminants. This means that the agent is typically at least 50% w / w pure of interfering proteins and other contaminants arising from its production or purification but does not exclude the possibility that the agent is combined withan excess of pharmaceutical acceptable carrier(s) or other vehicle intended to facilitate its use. Sometimes monoclonal antibodies (or other therapeutic agents) are at least 60%, 70%, 80%, 90%, 95% or 99% w / w pure of interfering proteins and contaminants from production or purification. Pharmacokinetic Endpoints

[0215] The present disclosure provides dosing regimens for anti-amyloid antibodies that are designed to achieve drug exposure profiles in subjects that are suitable for the clearance of amyloid plaque and / or treatment of neurodegenerative diseases (e.g., Alzheimer’s disease). To this end, the present disclosure provides methods of administering anti-amyloid antibodies to achieve particular pharmacokinetic endpoints in subjects, including, for example, values of the following parameters that are suitable for plaque clearance and / or treatment of the disease: average concentration over the dosing interval (Cave), steady state concentration over the dosing interval (Css), maximum concentration over the dosing interval (Cmax), area under the concentration-time curve from time zero to infinity AUC0- , and the area under the concentration-time curve for dosing interval (AUC0-tau). In various embodiments, these pharmacokinetic endpoints can be assessed in a number of bodily fluids collected from the subject, including, for example, whole blood, blood serum, blood plasma, and / or CSF. Maximum Drug Concentration (Cmax)

[0216] Thus, in another aspect, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising subcutaneously administering to the subject adose of an anti-A antibody sufficient to achieve a Cmax value (steady state Cmax value) ofabout 30 μg / mL to about 60 μg / mL. In another aspect, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising subcutaneously administering tothe subject a dose of an anti-A antibody sufficient to achieve a Cmax value of about 30μg / mL to about 60 μg / mL. In another aspect, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising subcutaneouslyadministering to the subject a dose of an anti-A antibody sufficient to achieve a Cmax valueof about 30 μg / mL to about 60 μg / mL. In example embodiments, the anti-A antibodycomprises a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0217] In some embodiments, treating comprises achieving a Cmax of the anti-amyloid antibody or antigen binding fragment thereof in the subject of about 30 μg / mL to about 60μg / mL (e.g., about 35 μg / mL to about 60 μg / mL, about 40 μg / mL to about 60 μg / mL, about 45 μg / mL to about 60 μg / mL, about 30 μg / mL to about 55 μg / mL, about 35 μg / mL to about 55 μg / mL, about 30 μg / mL to about 50 μg / mL, or about 35 μg / mL to about 50 μg / mL). In some embodiments, the Cmaxvalue is a steady state serum Cmaxvalue. In some embodiments, the Cmaxvalue is a steady state plasma Cmaxvalue. Average Drug Concentration (Cave)

[0218] In another aspect, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising subcutaneously administering to the subject adose of an anti-A antibody sufficient to achieve a serum Cave value of about 20 μg / mL toabout 40 μg / mL In another aspect, the present disclosure provides a method of reducing amyloid plaque in a subject, comprising subcutaneously administering to the subject a dose ofan anti-A antibody sufficient to achieve a serum Cave value of about 20 μg / mL to about 40μg / mL. In another aspect, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising subcutaneously administering to thesubject a dose of an anti-A antibody sufficient to achieve a serum Cave value of about 20μg / mL to about 40 μg / mL In example embodiments, the anti-A antibody comprises a heavychain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, treating comprises achieving a Cmaxof the anti-amyloid antibody or antigen binding fragment thereof in the subject of about 20 μg / mL to about 40 μg / mL (e.g., about 23 μg / mL to about 40 μg / mL, about 25 μg / mL to about 40 μg / mL, about 28 μg / mL to about 40 μg / mL, about 30 μg / mL to about 40 μg / mL, about 35 μg / mL to about 40 μg / mL, about 20 μg / mL to about 38 μg / mL, about 23 μg / mL to about 38 μg / mL, about 25 μg / mL to about 38 μg / mL, about 28 μg / mL to about 38 μg / mL, about 20 μg / mL to about 35 μg / mL, about 20 μg / mL to about 30 μg / mL, or about 25 μg / mL to about 30 μg / mL). In some embodiments, the Cave value is a steady state serum Cave value. In some embodiments, the Cave value is a steady state plasma Cave value. Area Under the Concentration-Time Curve for the Dosing Interval (AUC0-tau)

[0219] In another aspect, the present disclosure provides a method of treating Alzheimer’s disease in a subject, comprising subcutaneously administering to the subject adose of an anti-A antibody sufficient to achieve an area under the concentration-time curvefor the dosing interval (AUC0-tau) value of about 15,000 hr*ug / mL to about 30,000 hr*ug / mL. In another aspect, the present disclosure provides a method of reducing amyloid plaque in asubject, comprising subcutaneously administering to the subject a dose of an anti-Aantibody sufficient to achieve a AUC0-tau value of about 15,000 hr*ug / mL to about 30,000 hr*ug / mL. In another aspect, the present disclosure provides a method of converting a subject from amyloid positive to amyloid negative, comprising subcutaneously administering to thesubject a dose of an anti-A antibody sufficient to achieve a AUC0-tau value of about 15,000hr*ug / mL to about 30,000 hr*ug / mL. In example embodiments, the anti-A antibodycomprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0220] In some embodiments, treating comprises achieving an AUC0-tauvalue (steady state AUC0-tauvalue) of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 15,000 hr*ug / mL to about 30,000 hr*ug / mL (e.g., 16,000 hr*ug / mL to about 30,000 hr*ug / mL, 18,000 hr*ug / mL to about 30,000 hr*ug / mL, 20,000 hr*ug / mL to about 30,000 hr*ug / mL, 22,000 hr*ug / mL to about 30,000 hr*ug / mL, or 25,000 hr*ug / mL to about 30,000 hr*ug / mL). In some embodiments, treating comprises achieving an AUC0-tau value (steady state AUC0-tau value) of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 15,000 hr*ug / mL to about 25,000 hr*ug / mL (e.g., 16,000 hr*ug / mL to about 25,000 hr*ug / mL, 18,000 hr*ug / mL to about 25,000 hr*ug / mL, 20,000 hr*ug / mL to about 25,000 hr*ug / mL, or 22,000 hr*ug / mL to about 25,000 hr*ug / mL). In some embodiments, the AUC0-tau value is a steady state serum AUC0-tau value. In some embodiments, the AUC0-tauvalue is a steady state plasma AUC0-tauvalue. Amyloid Plaque Clearance

[0221] The present disclosure further provides the use of anti-amyloid antibodies to reduce amyloid plaque in a subject. Amyloid plaque reduction has been shown to correlate with slowing of cognitive decline during treatment with anti-amyloid antibodies. See, e.g.,M. Shi, et al., Impact of Anti-amyloid- Monoclonal Antibodies on the Pathology andClinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab.14 FRONT. AGING NEUROSCI.1 (2022); C.H. van Dyck, et al., Lecanemab in Early Alzheimer’s Disease 388 N. ENGL. J. MED.9 (2023). Indeed, the FDA granted accelerated approval to both aducanumab and lecanemab based on plaque reduction data from clinical trials.

[0222] Thus, in another embodiment, the methods of treating Alzheimer’s disease in a subject having amyloid plaque include: (a) administering to the subject a composition comprising from about 20 mg to about 200 mg (e.g., about 20 mg, 45 mg, 70 mg, 100 mg, 150 mg, or 200 mg), about 205 mg to about 400 mg (e.g., 205 mg, 250 mg, 300 mg, 350 mg, or 400 mg), or about 405 mgto about 700 mg (e.g., about 405 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg) of an anti-amyloid antibody once about every 4 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; and (b) reducing the amyloid plaque in the subject.

[0223] Thus, in another embodiment, the methods of treating Alzheimer’s disease in a subject having amyloid plaque include: (a) administering to the subject a composition comprising from about 10 mg to about 100 mg (e.g., about 25 mg, about 35 mg, about 50 mg, about 75 mg, or about 100 mg), about 100 mg to about 200 mg (e.g., about 105 mg, about 110 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg), or about 205 mg to about 350 mg (e.g., about 205 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, or about 350 mg) of an anti-amyloid antibody once about every 2 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; and (b) reducing the amyloid plaque in the subject.

[0224] Detection of brain amyloid plaques is conducted by methods known to one of skill in the art. In some embodiments, the method further comprises assessing the amyloid by Positron Emission Tomography (PET) imaging. In some embodiments, the amyloid reduction is determined by PET. PET imaging agents are known to one of skill in the art and include 18F-florbetapir, florbetaben F18, and flutemetamol F18. In some embodiments, amyloid plaque, as measured by PET, is quantified by a composite standard uptake value ratio (SUVR). In some embodiments, amyloid plaque, as measured by PET, is calculated using the Centiloid scale. In some embodiments, change in amyloid plaque burden is measured by change in SUVR over time. In some embodiments, change in amyloid plaque burden is measured by change in Centiloid over time. See, Navitsky M, Joshi AD, Kennedy I, et al., Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale, Alzheimer’s Dement 201814:1565-71 and Oshi AD, Pontecorvo MJ, Lu M, et al., A Semiautomated Method for Quantification of F 18 Florbetapir PET Images, J Nucl Med.2015; 56(11):1736-41.

[0225] Thus, in another embodiment, the present methods include reducing amyloid plaque in a subject, the method comprising:(a) administering to the subject a composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti- amyloid antibody once about every 4 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; and (b) reducing the amyloid plaque in the subject, as determined by PET.

[0226] In another embodiment, the present methods include treating Alzheimer’s disease in a subject, comprising: (a) observing a first amyloid plaque value obtained from a first PET scan of the subject; (b) subcutaneously administering to the subject a composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti-amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; or (c) observing a second amyloid plaque value obtained from a second PET scan of the subject; and (d) comparing the first amyloid plaque value to the second amyloid plaque value, thereby observing a reduction in amyloid plaque in the subject.

[0227] In another embodiment, the present methods include treating Alzheimer’s disease in a subject having amyloid plaque, the method comprising: (a) performing a first PET scan on the subject, thereby observing a first amyloid plaque value; (b) administering to the subject a composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti- amyloid antibody once about every 3-5 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; (c) performing a second PET scan on the subject, thereby observing a second amyloid plaque value; and (d) comparing the first amyloid plaque value to the second amyloid plaque value, thereby observing a reduction in amyloid plaque in the subject.

[0228] In another embodiment, the present methods include reducing amyloid plaque in a subject, comprising: (a) observing a first amyloid plaque value obtained from a first PET scan of the subject;(b) subcutaneously administering to the subject a composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti-amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; or (c) observing a second amyloid plaque value obtained from a second PET scan of the subject; and (d) comparing the first amyloid plaque value to the second amyloid plaque value, thereby observing a reduction in amyloid plaque in the subject.

[0229] In another embodiment, the present methods include reducing amyloid plaque in a subject having amyloid plaque, the method comprising: (a) performing a first PET scan on the subject, thereby observing a first amyloid plaque value; (b) administering to the subject a composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti- amyloid antibody once about every 3-5 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; (c) performing a second PET scan on the subject, thereby observing a second amyloid plaque value; and (d) comparing the first amyloid plaque value to the second amyloid plaque value, thereby observing a reduction in amyloid plaque in the subject.

[0230] In another embodiment, the present methods include reducing amyloid plaque in a subject having amyloid plaque, the method comprising: (a) performing a first PET scan on the subject, thereby observing a first amyloid plaque value; (b) administering to the subject a composition comprising from about 10 to about 100 mg, about 100 mg to 200 mg, or about 205 mg to about 350 mg of an anti-amyloid antibody once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; (c) performing a second PET scan on the subject, thereby observing a second amyloid plaque value; and(d) comparing the first amyloid plaque value to the second amyloid plaque value, thereby observing a reduction in amyloid plaque in the subject.

[0231] In some embodiments, treating comprises a reduction in amyloid beta plaque (i.e., brain amyloid beta plaque) in the subject. In some embodiments, the treatment results in the subject achieving a reduction of amyloid beta plaque. In some embodiments, the subject achieves a reduction of amyloid beta plaque as assessed by PET.

[0232] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 10 centiloids (e.g., at least about 15 centiloids, at least about 20 centiloids, at least about 25 centiloids, or at least about 30 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 30 centiloids after 6 months of treatment (e.g., at least about 35 centiloids, at least about 40 centiloids, at least about 45 centiloids, at least about 50 centiloids, at least about 55 centiloids, or at least about 60 centiloids). In some embodiments, the reduction of amyloid beta plaque is achieved after about 6 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 12 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 18 months of treatment.

[0233] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 10 centiloids to about 90 centiloids (e.g., about 20 centiloids to about 90 centiloids, about 30 centiloids to about 90 centiloids, about 40 centiloids to about 90 centiloids, or about 50 centiloids to about 90 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 10 centiloids to about 80 centiloids (e.g., about 20 centiloids to about 80 centiloids, about 30 centiloids to about 80 centiloids, about 40 centiloids to about 80 centiloids, or about 50 centiloids to about 80 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 10 centiloids to about 70 centiloids (e.g., about 20 centiloids to about 70 centiloids, about 30 centiloids to about 70 centiloids, about 40 centiloids to about 70 centiloids, or about 50 centiloids to about 70 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 10 centiloids to about 60 centiloids (e.g., about 20 centiloids to about 60 centiloids, about 30 centiloids to about 60 centiloids, about 40 centiloids to about 60 centiloids, or about 50 centiloids to about 60 centiloids). In some embodiments, the reduction of amyloid beta plaque is achieved after about 6 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 12 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 18 months of treatment.

[0234] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 10 centiloids after about 6 months of treatment (e.g., at least about 15 centiloids, at least about 20 centiloids, at least about 25 centiloids, or at least about 30 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 30 centiloids after about 6 months of treatment (e.g., at least about 35 centiloids, at least about 40 centiloids, at least about 45 centiloids, or at least about 50 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 10 centiloids, about 15 centiloids, about 20 centiloids, about 25 centiloids, about 30 centiloids, about 35 centiloids, about 40 centiloids, about 45 centiloids, about 50 centiloids, about 55 centiloids, about 60 centiloids, about 65 centiloids, about 70 centiloids, about 75 centiloids, about 80 centiloids, about 85 centiloids, about 90 centiloids or about 95 centiloids. In some embodiments, the reduction of amyloid beta plaque is achieved after about 6 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 12 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 18 months of treatment.

[0235] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 10 centiloids to about 80 centiloids after about 6 months of treatment (e.g., about 20 centiloids to about 80 centiloids, about 30 centiloids to about 80 centiloids, about 10 centiloids to about 60 centiloids, or about 10 centiloids to about 50 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 30 centiloids to about 70 centiloids after about 6 months of treatment (e.g., about 40 centiloids to about 70 centiloids, about 50 centiloids to about 70 centiloids, about 30 centiloids to about 60 centiloids, or about 30 centiloids to about 50 centiloids).

[0236] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 25 centiloids after about 12 months of treatment (e.g., at least about 35 centiloids, at least about 40 centiloids, at least about 45 centiloids, or at least about 50 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 40 centiloids after about 12 months of treatment (e.g., at least about 45 centiloids, at least about 50 centiloids, at least about 55 centiloids, or at least about 60 centiloids).

[0237] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 20 centiloids to about 90 centiloids after about 12 months of treatment (e.g., about 30 centiloids to about 90 centiloids, about 40 centiloids to about 90 centiloids, about 20 centiloids to about 80 centiloids, or about 20 centiloids to about 70 centiloids). In someembodiments, the reduction of amyloid beta plaque comprises a reduction by about 45 centiloids to about 80 centiloids after about 12 months of treatment (e.g., about 50 centiloids to about 80 centiloids, about 55 centiloids to about 80 centiloids, about 45 centiloids to about 75 centiloids, or about 45 centiloids to about 70 centiloids).

[0238] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 35 centiloids after about 18 months of treatment (e.g., at least about 40 centiloids, at least about 45 centiloids, at least about 50 centiloids, or at least about 55 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least about 50 centiloids after about 18 months of treatment (e.g., at least about 55 centiloids, at least about 60 centiloids, at least about 65 centiloids, or at least about 70 centiloids).

[0239] In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 30 centiloids to about 100 centiloids after about 18 months of treatment (e.g., about 40 centiloids to about 100 centiloids, about 50 centiloids to about 100 centiloids, about 30 centiloids to about 95 centiloids, or about 30 centiloids to about 90 centiloids). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by about 50 centiloids to about 85 centiloids after about 18 months of treatment (e.g., about 65 centiloids to about 85 centiloids, about 70 centiloids to about 85 centiloids, about 50 centiloids to about 80 centiloids, or about 50 centiloids to about 75 centiloids).

[0240] In some embodiments, the reduction in amyloid beta plaque comprises a reduction of at least about 30% (e.g., at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%). In some embodiments, the reduction of amyloid beta plaque comprises a reduction of about 30% to about 100% (e.g., about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, or about 70% to about 100%). In some embodiments, reduction of amyloid beta plaque in the subject comprises a reduction of about 30% to about 90% (e.g., about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, or about 70% to about 90%,). In some embodiments, the reduction of amyloid beta plaque comprises a reduction of about 30% to about 80% (e.g., about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%). In some embodiments, the reduction of amyloid beta plaque comprises a reduction of about 30% to about 70% (e.g., about 40% to about 70%, or about 50% to about 70%). In some embodiments, the reduction of amyloid beta plaque comprises a reduction of about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, orabout 100%. In some embodiments, the reduction of amyloid beta plaque is achieved after about 6 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 12 months of treatment. In some embodiments, the reduction of amyloid beta plaque is achieved after about 18 months of treatment.

[0241] In some embodiments, the reduction in amyloid beta plaque comprises a reduction of at least about 20% after about 6 months of treatment (e.g., at least 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%). In some embodiments, the reduction of amyloid beta plaque comprises a reduction of about 20% to about 90% after about 6 months of treatment (e.g., about 30% to about 90%, about 40% to about 90%, or about 50% to about 90%). In some embodiments, reduction of amyloid beta plaque in the subject comprises a reduction of about 30% to about 70% after about 6 months of treatment (e.g., about 35% to about 70%, about 40% to about 70%, about 30% to about 65%, or about 30% to about 60%).

[0242] In some embodiments, the reduction in amyloid beta plaque comprises a reduction of at least about 30% after about 12 months of treatment (e.g., at least 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60%). In some embodiments, the reduction of amyloid beta plaque comprises a reduction of about 30% to about 100% after about 12 months of treatment (e.g., about 40% to about 100%, about 50% to about 100%, or about 50% to about 90%). In some embodiments, reduction of amyloid beta plaque in the subject comprises a reduction of about 60% to about 100% after about 12 months of treatment (e.g., about 65% to about 100%, about 70% to about 100%, about 65% to about 95%, or about 65% to about 90%).

[0243] In some embodiments, the reduction in amyloid beta plaque comprises a reduction of at least about 40% after about 18 months of treatment (e.g., at least 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%). In some embodiments, the reduction of amyloid beta plaque comprises a reduction of about 40% to about 100% after about 18 months of treatment (e.g., about 50% to about 100%, about 60% to about 100%, or about 50% to about 90%). In some embodiments, reduction of amyloid beta plaque in the subject comprises a reduction of about 65% to about 100% after about 18 months of treatment (e.g., about 70% to about 100%, about 75% to about 100%, about 65% to about 95%, or about 65% to about 90%).

[0244] In some embodiments, the reduction in amyloid beta plaque comprises a reduction of amyloid beta plaque in the subject comprises a reduction by at least 0.05 PET Standard Update Value Ratio (“SUVr”) units (e.g., at least 0.10 PET SUVr units, at least 0.15 PETSUVr units, at least 0.20 PET SUVr units, or at least 0.25 PET SUVr unit). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least 0.25 PET SUVr units (e.g., at least 0.30 PET SUVr units, at least 0.35 PET SUVr units, or at least 0.40 PET SUVr units, or at least 0.45 PET SUVr). In some embodiments, the reduction of amyloid beta plaque comprises a reduction by at least 0.50 PET SUVr units (e.g., at least 0.55 PET SUVr units, at least 0.60 PET SUVr units, or at least 0.65 PET SUVr units, or at least 0.70 PET SUVr).

[0245] In some embodiments, the reduction of amyloid beta plaque occurs after about 6 months (e.g., after about 24 weeks) of treatment. In some embodiments, the reduction of amyloid beta plaque occurs after about 12 months (e.g., after about 48 weeks) of treatment. In some embodiments, the reduction of amyloid beta plaque occurs after about 18 months (e.g., after about 72 weeks) of treatment. In some embodiments, the reduction of amyloid beta plaque is compared to baseline (amyloid plaque values prior to beginning treatment).

[0246] In some embodiments, the treatment results in the subject achieving amyloid negative status. In some embodiments, the subject is converted from amyloid positive status to amyloid negative status.

[0247] In another embodiment, the present methods include converting a subject from amyloid positive to amyloid negative, the method comprising: (a) administering to the subject a composition comprising from about 20 mg to about 200 mg (e.g., about 45 mg, about 70 mg, about 100 mg, about 150 mg, or about 200 mg), about 205 mg to about 400 mg (e.g., about 205 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg), about 405 mg to 700 mg (e.g., about 405 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, 650 mg, or about 700 mg) of an anti-amyloid antibody once about every 4 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; and (b) reducing the amyloid plaque in the subject, such that the subject is amyloid negative, as determined by PET.

[0248] In another embodiment, the present methods include converting a subject from amyloid positive to amyloid negative, the method comprising: (a) administering to the subject a composition comprising from about 10 mg to about 100 mg (e.g., about 25 mg, about 35 mg, about 50 mg, about 75 mg, or about 100 mg), about 100 mg to about 200 mg (e.g., about 105 mg, about 110 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg), or about 205 mg to about 350 mg(e.g., about 205 mg, about 225 mg, about 250 mg, 2 about 75 mg, about 300 mg, about 325 mg, or about 350 mg) of an anti-amyloid antibody once about every 2 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; and (b) reducing the amyloid plaque in the subject, such that the subject is amyloid negative, as determined by PET.

[0249] In some embodiments, treating comprises at least about 10% (e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 45%, or at least about 50%) of subjects being converted from amyloid positive status to amyloid negative status. In some embodiments, treating comprises about 10% to about 90% (e.g., about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 10% to about 80%, about 10% to about 70%, or about 10% to about 60%) of subjects being converted from amyloid positive status to amyloid negative status. In some embodiments, treating comprises about 30% to about 80% (e.g., about 40% to about 80%, about 50% to about 80%, about 30% to about 70%, or about 30% to about 60%) of subjects being converted from amyloid positive status to amyloid negative status. In some embodiments, the achievement of amyloid negative status occurs after about 6 months of treatment. In some embodiments, the achievement of amyloid negative status occurs after about 12 months of treatment. In some embodiments, the achievement of amyloid negative status occurs after about 18 months of treatment.

[0250] In some embodiments, treating comprises at least about 5% (e.g., at least about 10%, at least about 15%, at least about 20%, or at least about 25%) of subjects being converted from amyloid positive status to amyloid negative status after about 6 months. In some embodiments, treating comprises about 5% to about 50% (e.g., about 10% to about 50%, about 20% to about 50%, about 10% to about 45%, or about 10% to about 40%) of subjects being converted from amyloid positive status to amyloid negative status after about 6 months. In some embodiments, treating comprises about 10% to about 40% (e.g., about 15% to about 40%, about 20% to about 40%, about 10% to about 35%, or about 10% to about 30%) of subjects being converted from amyloid positive status to amyloid negative status after about 6 months.

[0251] In some embodiments, treating comprises at least about 15% (e.g., at least about 20%, at least about 25%, at least about 30%, or at least about 35%) of subjects being converted from amyloid positive status to amyloid negative status after about 12 months. In some embodiments, treating comprises about 15% to about 80% (e.g., about 20% to about80%, about 30% to about 80%, about 15% to about 75%, or about 15% to about 70%) of subjects being converted from amyloid positive status to amyloid negative status after about 12 months. In some embodiments, treating comprises about 30% to about 60% (e.g., about 35% to about 60%, about 40% to about 60%, about 30% to about 55%, or about 30% to about 50%) of subjects being converted from amyloid positive status to amyloid negative status after about 12 months.

[0252] In some embodiments, treating comprises at least about 25% (e.g., at least about 30%, at least about 35%, at least about 40%, or at least about 45%) of subjects being converted from amyloid positive status to amyloid negative status after about 18 months. In some embodiments, treating comprises about 25% to about 100% (e.g., about 30% to about 100%, about 40% to about 100%, about 25% to about 95%, or about 25% to about 90%) of subjects being converted from amyloid positive status to amyloid negative status after about 18 months. In some embodiments, treating comprises about 40% to about 80% (e.g., about 45% to about 80%, about 50% to about 80%, about 40% to about 75%, or about 40% to about 70%) of subjects being converted from amyloid positive status to amyloid negative status after about 18 months.

[0253] In some embodiments, amyloid beta plaque in a subject is measured about 3 months, 6 months, 12 months, and / or 18 months after treatment is initiated. In some embodiments, amyloid beta plaque in a subject is measured, about once a month, about once every 3 months, about once every 6 months, or about once every year after treatment is initiated. Cognitive Decline

[0254] Cognitive decline is a feature of neurodegenerative diseases, including Alzheimer’s disease. Initial stages of cognitive decline in Alzheimer’s disease may manifest as forgetfulness. However, as the disease progresses, the effects of cognitive decline more broadly affect the patient’s life and behavior, affecting executive function, language skills, and visuospatial processing. This, in turn, may lead to issues with decision-making, problem- solving, and independent living. Finally, Alzheimer's disease culminates in significant cognitive decline and dementia, leading to impairments in basic memory retention affected and simple daily activities.

[0255] Recent evidence has demonstrated a link between reduction in brain amyloid load and slowing of cognitive decline in Alzheimer’s patients. See, e.g., Y. Zhang, et al., Amyloid -based therapy for Alzheimer’s disease: challenges, successes and future, 8 SIGNALTRANSDUCTION AND TARGETED THERAPY 248 (2023). For example, a phase 2 clinical trial of donanemab showed both a reduction in brain amyloid load and a slowing of cognitive decline. More recently, a phase 3 clinical trial of lecanemab also reported both a reduction in brain amyloid plaque and a slowing of cognitive decline. In light of this recent clinical evidence, a causal link is emerging between clearing amyloid plaque and slowing cognitive decline in patients.

[0256] In some embodiments, treating Alzheimer’s disease may include the slowing, halting, and / or reversing of cognitive decline in subjects. In some embodiments, treating comprises slowing, halting, and / or reversing a decline in cognitive function. In another embodiment, treating comprises a reduction (e.g., slowing or halting) in a decline in cognitive function. In another embodiment, treating comprises slowing a decline in cognitive function. In another embodiment, treating comprises halting a decline in cognitive function. In another embodiment, treating comprises reversing a decline in cognitive function.

[0257] Various cognitive assessment tools are available and can be used in conjunction with methods of the present disclosure, including, for example, Mini-Mental State Exam (MMSE), Alzheimer’s Disease Composite Score (ADCOMS), Alzheimer's Disease Assessment Scale - Cognitive (ADAS-COG) (including, for example a 14-item Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog14)), Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL-MCI), Clinician Interview-Based Impression (CIBI), Neurological Test Battery (NTB), Disability Assessment for Dementia (DAD), Clinical Dementia Rating-sum of boxes (CDR-SB), Neuropsychiatric Inventory (NPI). In some embodiments, treating comprises slowing, halting and / or reversing of cognitive decline as assessed using one of these cognitive assessment tools. In another embodiment, methods of the present disclose further comprise monitoring the subject by at least one of these cognitive assessment tools.

[0258] In some embodiments, cognitive function is measured by at least one of the following CRD-SB, ADAS-Cog14, ADCOMS, and ADCS MCI-ADL. In some embodiments, cognitive function is measured using CRD-SB. In some embodiments, cognitive function in measured using ADAS-Cog14. In some embodiments, cognitive function is measured using ADCOMS. In some embodiments, cognitive function is measured using ADCS MCI-ADL.

[0259] In some embodiments, cognitive function is measured on multiple occasions, such as before administering the dosage and at week 4, week 16, 6 months, and / or 1 year after administering the dosage. In some embodiments, cognitive function is measured about 3months, 6 months, 12 months, and / or 18 months after treatment is initiated. In some embodiments, cognitive function is measured, about once a month, about once every 3 months, about once every 6 months, or about once every year after treatment is initiated. Biomarker Modulation

[0260] In another embodiment, the present methods include modulating a biomarker in a subject, comprising administering to the subject a composition comprising from about 20 mg to about 200 mg (e.g., about 45 mg, about 70 mg, about 100 mg, about 150 mg, or about 200 mg), about 205 mg to about 400 mg (e.g., about 205 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg), or about 405 mg to about 700 mg (e.g., about 405 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg) of an anti- amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In another embodiment, the present disclosure provides a method of modulating a biomarker in a subject, comprising administering to the subject a composition comprising from about 10 mg to about 100 mg (e.g., about 25 mg, about 35 mg, about 50 mg, about 75 mg, or about 100 mg), about 100 mg to about 200 mg (e.g., about 105 mg, about 110 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg), or about 250 mg to about 350 mg (e.g., about 250 mg, about 275 mg, about 300 mg, about 325 mg, or about 350 mg) of an anti-amyloid antibody twice about every 3-5 weeks (e.g., once about every 2 weeks), the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. Amyloid Beta Ratio

[0261] In some embodiments, the biomarker comprises the ratio of A 42 / 40 in thesubject. The A 42 / A 40 ratio (e.g., the ratio of amyloid 42 to amyloid 40 in CSF and / orblood) has been demonstrated to be associated with well-established indicators of AD,including amyloid PET and CSF biomarkers, with lower A 42 / A 40 ratios (e.g., an A 42 / 40ratio <0.150) corresponding to higher amyloid plaque burden. See, e.g., C. Delaby, et al., TheA 1–42 / A 1–40 ratio in CSF is more strongly associated to tau markers and clinicalprogression than A 1–42 alone, 14 ALZHEIMER’S RESEARCH & THERAPY 20 (2022); X.Chang, et al., A Review of Application of A 42 / 40 Ratio in Diagnosis and Prognosis ofAlzheimer’s Disease.90 J. ALZHEIMER’S DISEASE 495 (2002). For example, total plasmaA 42 / A 40 ratio has demonstrated value in the identification of individuals suffering frommild cognitive impairment (MCI), in the prediction of progression to dementia, and in thedetection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSFbiomarkers. See, e.g., V. Perez-Grijalba, et al., Plasma A 42 / 40 Ratio Detects Early Stages ofAlzheimer’s Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255Study. 6 J. PREVENTION OF ALZHEIMER’S DISEASE 34, (2019). Thus, changes in A 42 / A 40ratio may be useful in following individuals throughout the course of treatment, e.g., with anincrease in the A 42 / A 40 ratio signaling a reduction in amyloid plaque burden duringtreatment.

[0262] Further, an emerging trend in the treatment of Alzheimer disease (AD) is the shift of the therapeutic target population from people with dementia or MCI to cognitively healthy people at risk of AD. This population of at-risk people is difficult to identify if -amyloid(A ) positivity is the primary criterion for eligibility in clinical trials. Using this metric, thescreening rate of failure (SRF) rises to >70% in this population. See, e.g., J. D. Doecke, et al.,Total A 42 / A 40 ratio in plasma predicts amyloid-PET status, independent of clinical ADdiagnosis. 94 NEUROLOGY 1580 (2020). A 42 / A 40 ratio may be useful in identifying thispopulation and following them throughout treatment (e.g., prophylactic treatment).

[0263] Thus, the present disclosure provides methods of modulating a ratio of A 42 / 40in a subject, comprising administering to the subject a composition comprising from about 20 mg to about 200 mg, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti-amyloid antibody once every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain ofSEQ ID NO: 12. In some embodiments, the modulating comprises increasing the ratio of A42 / 40 in the subject.

[0264] In some embodiments, the present methods include increasing a ratio of A 42 / 40in a subject, comprising administering to the subject a composition comprising from about 20 mg to about 200 mg, 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti- amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

[0265] In some embodiments, the present methods include increasing a ratio of A 42 / 40in a subject, comprising administering to the subject a composition comprising from about 10 mg to about 100 mg, about 100 mg to about 200 mg, or about 250 mg to about 350 mg of an anti-amyloid antibody twice about every 3-5 weeks (e.g., once about every 2 weeks), the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12.

[0266] In some embodiments, the present methods include increasing a ratio of A 42 / 40in a subject, including: (a) administering to the subject a composition comprising from about 20 mg to about 200, about 205 mg to about 400 mg, or about 405 mg to about 700 mg of an anti- amyloid antibody once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; and (b) determining an A 42 / 40 ratio value derived from a sample collected from thesubject, wherein the A 42 / 40 ratio value demonstrates an increase in the ratio of A42 / 40 in the subject.

[0267] In some embodiments, the present methods include increasing a ratio of A 42 / 40in a subject, including: (a) administering to the subject a composition comprising from about 10 mg to about 100 mg, about 100 mg to about 200 mg, or about 250 mg to about 350 mg of an anti- amyloid antibody twice about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12; and (b) determining an A 42 / 40 ratio value derived from a sample collected from thesubject, wherein the A 42 / 40 ratio value demonstrates an increase in the ratio of A42 / 40 in the subject.

[0268] In some embodiments, the A 42 / 40 ratio value increases at least about 10% (e.g.,about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%). In someembodiments, the A 42 / 40 ratio value increases about 10% to about 150% (e.g., about 20%to about 150%, about 30% to about 150%, about 10% to about 120%, about 20% to about 120%, about 30% to about 120%, about 10% to about 100%, or about 20% to about 100%).In some embodiments, the A 42 / 40 ratio value increases about 25% to about 100% (e.g.,about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 25% to about 90%, about 25% to about 80%, about 35% to about 90%, or about 35% to about80%). In some embodiments, the A 42 / 40 ratio value increases compared to baseline.Phospho-Tau

[0269] Phospho-tau (p-tau) species have emerged as the most promising biomarkers of Alzheimer's disease. See, e.g., S. Janelidze, et al., Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease.19 BRAIN 1591-1601 (2023). Hyperphosphorylation of tau is a hallmark of Alzheimer’s disease pathology, leading to self-aggregation of p-tau bundles in diseased subjects. See, e.g., C.-X. Gong, K. Iqbal, Hyperphosphorylation of Microtubule-Associated Protein Tau: A Promising Therapeutic Target for Alzheimer Disease, 15 CURRENT MED. CHEM.2331 (2009). Phospho-tau levels(e.g., in blood) correlate with amyloid beta (A ) pathology and disease severity, as well aswith established cerebrospinal fluid (CSF) and neuroimaging biomarkers. See, e.g., Kac, P.R., et al. Diagnostic value of serum versus plasma phospho-tau for Alzheimer’s disease.14 ALZ RES THERAPY 65 (2022). Phospho-tau further differentiates biomarker-positive AD dementiafrom other dementias as well as A -negative controls, thereby demonstrating specificity toAD versus non-AD neurodegenerative diseases. Thus, p-tau levels can inform clinical diagnosis and eligibility for therapies, including treatment with anti-amyloid antibodies. Further, p-tau species have the capacity to help expand access to AD diagnostics worldwide, as p-tau species can be measured in blood samples, which, in contrast to cerebrospinal fluid, do not require lumbar puncture to acquire. See, e.g., F. Gonzalez-Ortiz, et al., Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications. 18 MOL. NEURODEGENERATION 18 (2023).

[0270] Several phospho-tau species have been identified as biomarkers for Alzheimer’s disease, including p181-tau, p212-tau, p217-tau, p231-tau, and p235-tau. For example, plasma values of p-tau181, p-tau217 and p-tau231 have demonstrated associations with in vivo pathological hallmarks and autopsy-verified diagnosis. Several of these p-tau species are highly accurate at detecting brain amyloidosis and predicting whether patients will progress to cognitive impairment and neurodegeneration. Further, p-tau levels have been shown to change in subjects undergoing anti-amyloid therapy, correlating with amyloid clearance. See, e.g., F. Gonzalez-Ortiz (2023).

[0271] In some embodiments, the present methods include modulating an amount of phospho-tau in a subject, comprising administering to the subject a composition comprising from about 20 mg to about 200 mg (e.g., about 45 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg), about 205 mg to about 400 mg (e.g., about 205 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg), or about 405 mg to about 700 mg (e.g., about 405 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg) of an anti-amyloid antibody or antigen binding fragment thereof once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some aspects, the present disclosure provides a method of modulating an amount of phospho-tau in a subject, comprising administering to the subject a composition comprising from about 10 mg to about100 mg (e.g., about 25 mg, about 35 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 175 mg, or about 200 mg), 100 mg to about 200 mg (e.g., about 105 mg, about 110 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg), or about 250 mg to about 350 mg (e.g., about 250 mg, about 275 mg, about 300 mg, about 325 mg, or about 350 mg) of an anti-amyloid antibody or antigen binding fragment thereof twice about every 3-5 weeks (e.g., once about every 2 weeks), the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12. In some embodiments, the modulating comprises increasing the amount of phospho-tau in the subject.

[0272] Thus, in some embodiments, the biomarker comprises a phospho-tau value. In some embodiments, the phospho-tau value comprises at least one of the following: a p181-tau value, a p212-tau value, p217-tau value, a p231-tau value, and a p235-tau value. In some embodiments, the phospho-tau value comprises a p181-tau value. In some embodiments, the phospho-tau value comprises a p212-tau value. In some embodiments, the phospho-tau value comprises a p217-tau value. In some embodiments, the phospho-tau value comprises a p231- tau value. In some embodiments, the phospho-tau value comprises a p235-tau value.

[0273] In some embodiments, the phospho-tau value decreases about 5% to about 50% (e.g., about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 10% to about 45%, about 10% to about 40%, or about 10% to about 35%). In some embodiments, the phospho-tau value decreases about 10% to about 30% (e.g., about 15% to about 30%, about 20% to about 30%, about 10% to about 25%, about 15% to about 25%, or about 20% to about 30%). In some embodiments, the phospho-tau value decreases compared to baseline.

[0274] In some embodiments, the p181-tau value decreases about 5% to about 50% (e.g., about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 10% to about 45%, about 10% to about 40%, or about 10% to about 35%). In some embodiments, the p181-tau value decreases about 10% to about 30% (e.g., about 15% to about 30%, about 20% to about 30%, about 10% to about 25%, about 15% to about 25%, or about 20% to about 30%). In some embodiments, the p181-tau value decreases compared to baseline. In some embodiments, the p217-tau value decreases about 5% to about 50% (e.g., about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 10% to about 45%, about 10% to about 40%, or about 10% to about 35%). In some embodiments, the p217-tau value decreases about 10% to about 30% (e.g., about 15% to about 30%, about 20% to about30%, about 10% to about 25%, about 15% to about 25%, or about 20% to about 30%). In some embodiments, the p217-tau value decreases compared to baseline. Amyloid Related Imaging Abnormalities (ARIA)

[0275] Treatment with amyloid -targeted passive immunotherapy with (including, for example, aducanumab (Aduhelm), lecanemab, donanemab, and gantenerumab) comes with a significant risk of amyloid-related imaging abnormality (ARIA). See, e.g., M. Filippi, et al., Amyloid-Related Imaging Abnormalities and -Amyloid–Targeting Antibodies A Systematic Review.79 JAMA NEUROL.291 (2022). ARIA is the most common side effect of anti- amyloid antibodies, and can be classified as ARIA-E (cerebral edema, involving the breakdown of the tight endothelial junctions of the blood-brain barrier and subsequent accumulation of fluid) and ARIA-H (cerebral microhemorrhages (mH), small hemorrhages on the brain that are often accompanied by hemosiderosis). ARIA-E can be associated with acute neuroinflammation and overwhelming of the perivascular clearance systems, and ARIA-H may be related to vascular amyloid clearance and subsequence weakening and / or rupture of small blood vessels. See, e.g., H. Hampel, et al., Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics, 146 BRAIN 4414 (2023).

[0276] While often asymptomatic and detected only via MRI, in some instances ARIA may be symptomatic. For example, ARIA has been shown to include a number of side effects, such as headache, worsening confusion, dizziness, visual disturbances, nausea, and seizures. Further, at least one fatality related to ARIA-E during aducanumab treatment and at least one fatality due to ARIA-H during donanemab treatment has been reported to date. See, e.g., C.G. Withington & R.S. Turner, Amyloid-Related Imaging Abnormalities With Anti- amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease.13 FRONTIERS IN NEUROLOGY 1 (2022). The risk of ARIA-H increases with age and cerebrovascular disease, and ARIA rates are generally higher in ApoE4 homozygous patients (ApoE4 carriers) compared to either ApoE4 non-carriers or ApoE4 heterozygous patients. Furthermore, increased risk of ARIA-E has been observed at treatment initiation, and corresponds with higher dosage and with >4 of microhemorrhages on a baseline MRI.

[0277] In some embodiments, the treatment comprises a risk of ARIA-E that is less than about 70% (e.g., less than about 65%, less than about 60%, less than about 55%, or less than about 50%). In some embodiments, the treatment comprises a risk of ARIA-E that is less than about 45% (e.g., less than about 40%, less than about 35%, less than about 30%, less thanabout 25%, or less than about 20%). In some embodiments, the treatment comprises a risk of ARIA-E that is less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%).

[0278] In some embodiments, the treatment results in less than about 45% (e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, or less than about 20%) of subjects experiencing symptomatic ARIA-E. In some embodiments, the treatment results less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%) of subjects experiencing symptomatic ARIA-E. In some embodiments, the treatment results in less than about 10% (e.g., less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%) of subjects experiencing symptomatic ARIA-E.

[0279] In some embodiments, the risk of ARIA-E is a risk of severe ARIA-E. In some embodiments, the risk of ARIA-E is a risk of moderate+ ARIA-E. In some embodiments, the risk of ARIA-E is a risk of moderate ARIA-E. In some embodiments, the risk of ARIA-E is a risk of mild+ ARIA-E. In some embodiments, the risk of ARIA-E is a risk of mild ARIA-E. In some embodiments, the risk of ARIA-E comprises a risk of FLAIR hyper-intensity at more than one location, wherein each FLAIR location has an extent of 5-10 cm. In some embodiments, the risk of ARIA-E comprises a risk of FLAIR hyper-intensity at one location, wherein the FLAIR location has an extent of 5-10 cm. In some embodiments, the risk of ARIA-E comprises a risk of FLAIR hyper-intensity at more than one location, wherein each FLAIR location has an extent of less than 5 cm, and wherein each FLAIR location is confined to the sulcus, cortex, and / or subcortical white matter. In some embodiments, the risk of ARIA-E comprises a risk of FLAIR hyper-intensity at one location, wherein the FLAIR location has an extent of less than 5 cm, and wherein the FLAIR location is confined to the sulcus, cortex, and / or subcortical white matter.

[0280] In some embodiments, the subject is an APOE4 homozygous subject and the treatment comprises a risk of ARIA-E that is less than about 75% (e.g., less than about 70%, less than about 65%, less than about 60%, less than about 55%, or less than about 50%) in the APOE4 homozygous subject. In some embodiments, the subject is an APOE4 homozygous subject and the treatment comprises a risk of symptomatic ARIA-E that is less than about 30% (e.g., less than about 25%, less than about 20%, or less than about 15%) in the APOE4 homozygous subject

[0281] In some embodiments, the subject is an APOE4 heterozygous subject or an APOE4 negative subject and the treatment comprises a risk of ARIA-E that is less than about45% (e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, or less than about 20%) in the APOE4 heterozygous subject or the APOE4 negative subject. In some embodiments, the subject is an APOE4 heterozygous subject or an APOE4 negative subject and the treatment comprises a risk of symptomatic ARIA-E that is less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%) in the APOE4 heterozygous subject or the APOE4 negative subject. In some embodiments, the risk of ARIA-E is the risk after about 6 months (e.g., about 24 weeks) of treatment. In some embodiments, the risk of ARIA-E is the risk after about 12 months (e.g., about 48 weeks) of treatment. In some embodiments, the risk of ARIA-E is the risk after about 18 months (e.g., about 72 weeks) of treatment.

[0282] In some embodiments, the treatment comprises a risk of ARIA-H that is less than about 25% (e.g., less than about 22%, less than about 20%, less than about 18%, or less than about 16%). In some embodiments, the treatment comprises a risk of ARIA-H that is less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%).

[0283] In some embodiments, the risk of ARIA-H is a risk of severe ARIA-H. In some embodiments, the risk of ARIA-H is a risk of moderate ARIA-H. In some embodiments, the risk of ARIA-H is a risk of mild ARIA-H. In some embodiments, the risk of ARIA-H comprises a risk of 4 new incidents of microhemorrhages and / or a risk of 1 focal area of superficial siderosis. In some embodiments, the risk of ARIA-H comprises a risk of 9 new incidents of microhemorrhages and / or a risk of 2 focal area of superficial siderosis.

[0284] In some embodiments, the risk of ARIA-H is the risk after about 6 months (e.g., about 24 weeks) of treatment. In some embodiments, the risk of ARIA-H is the risk after about 12 months (e.g., about 48 weeks) of treatment. In some embodiments, the risk of ARIA-H is the risk after about 18 months (e.g., about 72 weeks) of treatment.

[0285] In some embodiments, the treatment results in less than about 25% (e.g., less than about 22%, less than about 20%, less than about 18%, or less than about 16%) of subjects experiencing ARIA-H. In some embodiments, the treatment results in less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%) of subjects experiencing ARIA-H.

[0286] In some embodiments, the ARIA-E and / or ARIA-H levels (e.g., % of subjects experiencing ARIA-E and / or ARIA E) are the ARIA-E and / or ARIA H levels after about 6 months (e.g., about 24 weeks) of treatment. In some embodiments the ARIA-E and / or ARIA-H levels are the ARIA-E and / or ARIA H levels after about 12 months (e.g., about 48 weeks) of treatment. In some embodiments, the ARIA-E and / or ARIA-H are the ARIA-E and / or ARIA H levels after about 18 months (e.g., about 72 weeks) of treatment.

[0287] ARIA-E and ARIA-H are readily detectable by MRI. MRI can identify edema and effusion through fluid-sensitive sequences like Fluid-Attenuated Inversion Recovery (FLAIR; FLAIR / T2), which highlight areas of abnormal fluid accumulation by suppressing normal cerebrospinal fluid (CSF) signals. Microhemorrhaging (ARIA-H) can be detected, e.g., through Susceptibility-Weighted Imaging (SWI) and Gradient Echo (GRE; T2* / gradient echo) Sequences, which are sensitive to magnetic susceptibility differences caused by blood products. Microhemorrhages and hemosiderin deposits appear as hypointense (dark) spots on these images.

[0288] In some embodiments, the subject does not experience symptomatic ARIA, as assessed by Magnetic Resonance Imaging (MRI). In some embodiments, the subject does not experience symptomatic ARIA-E, as assessed by MRI. In some embodiments, the subject does not experience symptomatic ARIA-H, as assessed by MRI. Magnetic Resonance Imaging Monitoring Regimes

[0289] A brain MRI scan is an effective tool for detecting changes in brain tissue due to its high resolution and sensitivity. While frequent MRIs may promote Alzheimer’s disease patient safety and informed consent through, e.g., early detection of treatment-related side effects, the assessment of treatment efficacy and dosing adjustments, over-testing is wasteful of time and resources, and undertesting increases patient risk through delayed detection of potential problems. Moreover, even seemingly similar biologic treatments can have wildly different pharmacokinetic, pharmacodynamic, and immunogenic characteristics rendering appropriate monitoring regimes non-obvious.

[0290] In embodiments of the inventions herein, a subject is administered a brain MRI, a subject undergoes a brain MRI, a subject receives a brain MRI, or brain MRI is obtained from a subject. In some embodiments, administration of a brain MRI, undergoes a brain MRI, receives a brain MRI, and a brain MRI is obtained are used interchangeably. For example: in some embodiments a subject is administered at least one brain MRI prior to administration of an anti-amyloid antibody or an antigen-binding fragment thereof; in some embodiments, a subject undergoes at least one brain MRI prior to administration of an anti-amyloid antibody or an antigen-binding fragment thereof; in some embodiments, a subject receives at least one brain MRI prior to administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and in some embodiments, at least one brain MRI is obtained from a subject prior to administration of an anti-amyloid antibody or an antigen-binding fragment thereof. For clarity, when a brain MRI is obtained from a subject, the MRI of the subject’s brain is obtained. In other words, MRI is obtained from the subject when a subject receives an MRI, when the subject undergoes an MRI, or when an MRI is administered to the subject.

[0291] In some embodiments, methods for treating Alzheimer’s disease are provided in which an MRI is administered to a subject prior to (i) the administration of a first administration (i.e., the initial dose) of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) one or more consecutive doses of an anti-amyloid antibody or an antigen-binding fragment. In some embodiments, the methods include two consecutive doses, and an MRI prior to the first and second doses. In some embodiments, the methods include three consecutive doses, and an MRI prior to the first, second, and third doses. In some embodiments, the methods include four consecutive doses, and an MRI prior to the first, second, third, and fourth doses. In some embodiments, the methods include five consecutive doses, and an MRI prior to the first, second, third, fourth, and fifth doses. In some embodiments, the methods include six consecutive doses, and an MRI prior to the first, second, third, fourth, fifth, and sixth doses. In some embodiments, the methods include seven consecutive doses, and an MRI prior to the first, second, third, fourth, fifth, sixth, and seventh doses. In some embodiments, the methods include eight consecutive doses, and an MRI prior to the first, second, third, fourth, fifth, sixth, seventh, and eighth doses. In some embodiments, the methods include nine consecutive doses, and an MRI prior to the first, second, third, fourth, fifth, sixth, seventh, eighth, and ninth doses. In some embodiments, the methods include ten consecutive doses, and an MRI prior to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, and tenth doses. In some embodiments, the methods include eleven consecutive doses, and an MRI prior to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, and eleventh doses. In some embodiments, the methods include twelve consecutive doses, and an MRI prior to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, and twelfth doses.

[0292] In an embodiment, six consecutive MRIs are administered, prior to the first, second, third, fourth, fifth and sixth doses of anti-amyloid antibody or an antigen-binding fragment.

[0293] In some embodiments, methods for treating Alzheimer’s disease are provided in which an MRI is administered to a subject prior to (i) the administration of a first (i.e., theinitial) administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) one or more non-consecutive doses of an anti-amyloid antibody or an antigen- binding fragment. In some embodiments, the methods include two MRIs prior to non- consecutive doses, for example, an MRI prior to the first and third doses, prior to the first and fourth doses, prior to the first and fifth doses, prior to the first and sixth doses, prior to the first and seventh doses, prior to the first and eighth doses, prior to the first and ninth doses, prior to the first and tenth doses, prior to the first and eleventh doses, or prior to the first and twelfth doses.

[0294] In some embodiments, two MRIs are administered, selected from the group consisting of: prior to the first and third doses, prior to the first and fourth doses, prior to the first and fifth doses, prior to the first and sixth doses, and prior to the first and seventh doses; and in some embodiments, wherein MRI are administered prior to the first and fourth doses.

[0295] In some embodiments, the methods include an MRI prior to three non-consecutive doses, for example an MRI prior to the first, third, and fifth doses, prior to the first, third, and sixth doses, prior to the first, third, and seventh doses, prior to the first, third, and eighth doses, prior to the first, third, and ninth doses, prior to the first, third, and tenth doses, prior to the first, third, and eleventh doses, or prior to the first, third, and twelfth doses. In some embodiments, the methods that include MRIs prior to three non-consecutive doses include an MRI prior to the first, fourth, and sixth doses, prior to the first, fourth, and seventh doses, prior to the first, fourth, and eighth doses, prior to the first, fourth, and ninth doses, prior to the first, fourth, and tenth doses, prior to the first, fourth, and eleventh doses, or prior to the first, fourth, and twelfth doses. In some embodiments, the methods that include MRIs prior to three non-consecutive doses include an MRI prior to the first, fifth, and seventh doses, prior to the first, fifth, and eighth doses, prior to the first, fifth, and ninth doses, prior to the first, fifth, and tenth doses, prior to the first, fifth, and eleventh doses, or prior to the first, fifth, and twelfth doses. In some embodiments, the methods that include MRIs prior to three non- consecutive doses include an MRI prior to the first, sixth, and eighth doses, prior to the first, sixth, and ninth doses, prior to the first, sixth, and tenth doses, prior to the first, sixth, and eleventh doses, or prior to the first, sixth, and twelfth doses. In some embodiments, the methods that include MRIs prior to three non-consecutive doses include an MRI prior to the first, seventh, and ninth doses, prior to the first, seventh, and tenth doses, prior to the first, seventh, and eleventh doses, or prior to the first, seventh, and twelfth doses. In some embodiments, the methods that include MRIs prior to three non-consecutive doses include an MRI prior to the first, eighth, and tenth doses, prior to the first, eighth, and eleventh doses, orprior to the first, eighth, and twelfth doses. In some embodiments, the methods that include MRIs prior to three non-consecutive doses include an MRI prior to the first, ninth, and eleventh doses, or prior to the first, ninth, and twelfth doses. In some embodiments, the methods that include MRIs prior to three non-consecutive doses include an MRI prior to the first, tenth, and twelfth doses.

[0296] In some embodiments, three MRIs are administered, selected from the group consisting of: prior to the first, third, and fifth doses, prior to the first, third, and sixth doses, prior to the first, third, and seventh doses, prior to the first, fourth, and sixth doses, and prior to the first, fourth, and seventh doses. In some embodiments, MRIs are administered prior to the first, third, and seventh doses, or prior to the first, fourth, and seventh doses.

[0297] In some embodiments, the methods include an MRI prior to four non-consecutive doses, for example, prior to the first, third, fifth, and seventh doses, prior to the first, third, fifth, and eighth doses, prior to the first, third, fifth, and ninth doses, prior to the first, third, fifth, and tenth doses, prior to the first, third, fifth, and eleventh doses, prior to the first, third, fifth, and twelfth doses, prior to the first, third, fifth, and thirteenth doses, or prior to the first, third, fifth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, third, sixth, and eighth doses, prior to the first, third, sixth, and ninth doses, prior to the first, third, sixth, and tenth doses, prior to the first, third, sixth, and eleventh doses, prior to the first, third, fifth, and twelfth doses, an MRI prior to the first, third, fifth, and thirteenth doses, or prior to the first, third, fifth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, third, seventh, and ninth doses, prior to the first, third, seventh, and tenth doses, prior to the first, third, seventh, and eleventh doses, prior to the first, third, seventh, and twelfth doses, prior to the first, third, seventh, and thirteenth doses, or prior to the first, third, seventh, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, third, eighth, and tenth doses, prior to the first, third, eighth, and eleventh doses, prior to the first, third, eighth, and twelfth doses, prior to the first, third, eighth, and thirteenth doses, or prior to the first, third, eighth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, third, ninth, and eleventh doses, prior to the first, third, ninth, and twelfth doses, prior to the first, third, ninth, and thirteenth doses, or prior to the first, third, ninth, and fourteenth doses.

[0298] In some embodiments, the methods that include MRIs prior to four non- consecutive doses include an MRI prior to the first, fourth, sixth, and eighth doses, prior to the first, fourth, sixth, and ninth doses, prior to the first, fourth, sixth, and tenth doses, prior to the first, fourth, sixth, and eleventh doses, prior to the first, fourth, sixth, and twelfth doses, prior to the first, fourth, sixth, and thirteenth doses, or prior to the first, fourth, sixth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non- consecutive doses include an MRI prior to the first, fourth, seventh, and ninth doses, prior to the first, fourth, seventh, and tenth doses, prior to the first, fourth, seventh, and eleventh doses, prior to the first, fourth, seventh, and twelfth doses, prior to the first, fourth, seventh, and thirteenth doses, or prior to the first, fourth, seventh, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, fourth, eighth, and tenth doses, prior to the first, fourth, eighth, and eleventh doses, prior to the first, fourth, eighth, and twelfth doses, prior to the first, fourth, eighth, and thirteenth doses, or prior to the first, fourth, eighth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, fourth, ninth, and eleventh doses, prior to the first, fourth, ninth, and twelfth doses, prior to the first, fourth, ninth, and thirteenth doses, or prior to the first, fourth, ninth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, fifth, seventh, and ninth doses, prior to the first, fifth, seventh, and tenth doses, prior to the first, fifth, seventh, and eleventh doses, prior to the first, fifth, seventh, and twelfth doses, prior to the first, fifth, seventh, and thirteenth doses, or prior to the first, fifth, seventh, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, fifth, eighth, and tenth doses, prior to the first, fifth, eighth, and eleventh doses, prior to the first, fifth, eighth, and twelfth doses, prior to the first, fifth, eighth, and thirteenth doses, or prior to the first, fifth, eighth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, fifth, ninth, and eleventh doses, prior to the first, fifth, ninth, and twelfth doses, prior to the first, fifth, ninth, and thirteenth doses, or prior to the first, fifth, ninth, and fourteenth doses. In some embodiments, the methods that include MRIs prior to four non-consecutive doses include an MRI prior to the first, fifth, tenth, and twelfth doses, prior to the first, fifth, tenth, and thirteenth doses, or prior to the first, fifth, tenth, and fourteenth doses.

[0299] In some embodiments, four MRI are administered, selected from the group consisting of: prior to the first, third, fifth, and seventh doses, and prior to the first, fifth, seventh, and fourteenth doses.

[0300] In some embodiments, the methods include MRIs prior to five non-consecutive doses, for example an MRI prior to the first, third, fifth, seventh, and ninth doses, prior to the first, third, fifth, seventh, and tenth doses, prior to the first, third, fifth, seventh, and eleventh doses, prior to the first, third, fifth, seventh, and twelfth doses, prior to the first, third, fifth, seventh, and thirteenth doses, or prior to the first, third, fifth, seventh, and fourteenth doses. In some embodiments, the methods that include MRIs prior to five non-consecutive doses include an MRI prior to the first, third, fifth, seventh, and ninth doses, prior to the first, fourth, seventh, tenth, and thirteenth doses, prior to the first, fourth, seventh, tenth, and fourteenth doses, or prior to the first, fifth, ninth, thirteenth, and seventeenth doses.

[0301] In some embodiments, methods for treating Alzheimer’s disease are provided in which an MRI is administered to a subject prior to (i) the administration a first (i.e., the initial) administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) one or more consecutive doses and at least one non-consecutive dose of an anti- amyloid antibody or an antigen-binding fragment. In some embodiments, the methods include an MRI prior to two consecutive doses and one non-consecutive doses, for example an MRI prior to the first, second and fourth doses, prior to the first, second and fifth doses, prior to the first, second and sixth doses, prior to the first, second and seventh doses, prior to the first, second and eighth doses, prior to the first, second and ninth doses, prior to the first, second and tenth doses, prior to the first, second and eleventh doses, prior to the first, second and twelfth doses, prior to the first, second and thirteenth doses, or prior to the first, second and fourteenth doses.

[0302] In some embodiments, a total of three MRI are administered, selected from the group consisting of: prior to the first, second and fourth doses, prior to the first, second and fifth doses, prior to the first, second and sixth doses, and prior to the first, second and seventh doses. In some embodiments, MRIs are administered prior to the first, second and seventh doses.

[0303] In some embodiments, the methods include MRIs prior to two consecutive doses and two non-consecutive doses, for example an MRI prior to the first, second, fourth, and sixth doses, prior to the first, second, fourth, and seventh doses, prior to the first, second, fourth, and eighth doses, prior to the first, second, fourth, and ninth doses, prior to the first, second, fourth, and tenth doses, prior to the first, second, fourth, and eleventh doses, prior tothe first, second, fourth, and twelfth doses, prior to the first, second, fourth, and thirteenth doses, prior to the first, second, fourth, and fourteenth doses. In some embodiments, the methods include MRIs prior to two consecutive doses and two non-consecutive doses, for example an MRI prior to the first, second, fifth, and seventh doses, prior to the first, second, fifth, and eighth doses, prior to the first, second, fifth, and ninth doses, prior to the first, second, fifth, and tenth doses, prior to the first, second, fifth, and eleventh doses, prior to the first, second, fifth, and twelfth doses, prior to the first, second, fifth, and thirteenth doses, prior to the first, second, fifth, and fourteenth doses. In some embodiments, the methods include MRIs prior to two consecutive doses and two non-consecutive doses, for example an MRI prior to the first, second, sixth, and eighth doses, prior to the first, second, sixth, and ninth doses, prior to the first, second, sixth, and tenth doses, prior to the first, second, sixth, and eleventh doses, prior to the first, second, sixth, and twelfth doses, prior to the first, second, sixth, and thirteenth doses, prior to the first, second, sixth, and fourteenth doses. In some embodiments, the methods include MRIs prior to two consecutive doses and two non- consecutive doses, for example an MRI prior to the first, second, seventh, and ninth doses, prior to the first, second, seventh, and tenth doses, prior to the first, second, seventh, and eleventh doses, prior to the first, second, seventh, and twelfth doses, prior to the first, second, seventh, and thirteenth doses, prior to the first, second, seventh, and fourteenth doses.

[0304] In some embodiments, the methods include MRIs prior to two consecutive doses and two non-consecutive doses, for example an MRI prior to the first, third, fourth, and sixth doses, prior to the first, third, fourth, and seventh doses, prior to the first, third, fourth, and eighth doses, prior to the first, third, fourth, and ninth doses, prior to the first, third, fourth, and tenth doses, prior to the first, third, fourth, and eleventh doses, prior to the first, third, fourth, and twelfth doses, prior to the first, third, fourth, and thirteenth doses, prior to the first, third, fourth, and fourteenth doses.

[0305] In some embodiments four MRI are administered, selected from the group consisting of: prior to the first, second, fourth, and seventh doses, prior to the first, second, fifth, and seventh doses, prior to the first, second, seventh, and thirteenth doses, prior to the first, third, fourth, and seventh doses, prior to the first, third, fourth, and eighth doses, and prior to the first, second, third, and seventh doses.

[0306] In some embodiments, the methods include MRIs prior to two consecutive doses and three non-consecutive doses, for example an MRI prior to the first, third, fourth, seventh, and tenth doses, or prior to the first, third, fourth, seventh and thirteenth doses. In some embodiments, the methods include MRIs prior to two consecutive doses and four non-consecutive doses, for example an MRI prior to the first, third, fourth, seventh, tenth, and thirteenth doses, or prior to the first, third, fourth, seventh, tenth, and fourteenth doses.

[0307] In some embodiments, five MRI are administered, selected from the group consisting of: prior to the first, third, fourth, seventh, and tenth doses, prior to the first, second, fifth, and seventh doses, prior to the first, second, seventh, and thirteenth doses, prior to the first, third, fourth, and seventh doses, prior to the first, third, fourth, and eighth doses, prior to the first, second, third, seventh, and ninth doses, prior to the first, second, third, seventh, and thirteenth doses, and prior to the first, second, third, fourth, and seventh doses.

[0308] In some embodiments, the methods include MRIs prior to three consecutive doses and one non-consecutive doses, for example an MRI prior to the first, second, third, and fifth doses, prior to the first, second, third, and sixth doses, prior to the first, second, third, and seventh doses, prior to the first, second, third, and eighth doses, prior to the first, second, third, and ninth doses, prior to the first, second, third, and tenth doses, prior to the first, second, third, and eleventh doses, prior to the first, second, third, and twelfth doses, prior to the first, second, third, and thirteenth doses, or prior to the first, second, third, and fourteenth doses.

[0309] In some embodiments, the methods include MRIs prior to three consecutive doses and two non-consecutive doses, for example an MRI prior to the first, second, third, fifth, and seventh doses, prior to the first, second, third, fifth, and eighth doses, prior to the first, second, third, fifth, and ninth doses, prior to the first, second, third, fifth, and tenth doses, prior to the first, second, third, fifth, and eleventh doses, prior to the first, second, third, fifth, and twelfth doses, prior to the first, second, third, fifth, and thirteenth doses, or prior to the first, second, third, fifth, and fourteenth doses. In some embodiments, the methods include MRIs prior to three consecutive doses and two non-consecutive doses, for example an MRI prior to the first, second, third, sixth, and seventh doses, prior to the first, second, third, sixth, and eighth doses, prior to the first, second, third, sixth, and ninth doses, prior to the first, second, third, sixth, and tenth doses, prior to the first, second, third, sixth, and eleventh doses, prior to the first, second, third, sixth, and twelfth doses, prior to the first, second, third, sixth, and thirteenth doses, or prior to the first, second, third, sixth, and fourteenth doses. In some embodiments, the methods include MRIs prior to three consecutive doses and two non- consecutive doses, for example an MRI prior to the first, second, third, seventh, and ninth doses, prior to the first, second, third, seventh, and tenth doses, prior to the first, second, third, seventh, and eleventh doses, prior to the first, second, third, seventh, and twelfth doses,prior to the first, second, third, seventh, and thirteenth doses, or prior to the first, second, third, seventh, and fourteenth doses.

[0310] In some embodiments, the methods include MRIs prior to three consecutive doses and three non-consecutive doses, for example an MRI prior to the first, second, third, fifth, seventh, and ninth doses, prior to the first, second, third, fifth, seventh, and tenth doses, prior to the first, second, third, fifth, seventh, and eleventh doses, prior to the first, second, third, fifth, seventh, and twelfth doses, prior to the first, second, third, fifth, seventh, and thirteenth doses, or prior to the first, second, third, fifth, seventh, and fourteenth doses. In some embodiments, the methods include MRIs prior to three consecutive doses and three non- consecutive doses, for example an MRI prior to the first, second, third, sixth, eighth, and tenth doses, prior to the first, second, third, sixth, eighth, and eleventh doses, prior to the first, second, third, sixth, eighth, and twelfth doses, prior to the first, second, third, sixth, eighth, and thirteenth doses, or prior to the first, second, third, sixth, eighth, and fourteenth doses. In some embodiments, the methods include MRIs prior to three consecutive doses and three non-consecutive doses, for example an MRI prior to the first, second, third, seventh, ninth, and eleventh doses, prior to the first, second, third, seventh, ninth, and twelfth doses, prior to the first, second, third, seven, ninth, and thirteenth doses, or prior to the first, second, third, seventh, ninth, and fourteenth doses. In some embodiments, six MRI are administered, prior to the first, second, third, seventh, ninth, and thirteenth doses.

[0311] In some embodiments, the methods include MRIs prior to four consecutive doses and one non-consecutive dose, for example an MRI prior to the first, second, third, fourth, and sixth doses, prior to the first, second, third, fourth, and seventh, prior to the first, second, third, fourth, and eighth doses, prior to the first, second, third, fourth, and ninth doses, prior to the first, second, third, fourth, and tenth doses, prior to the first, second, third, fourth, and eleventh doses, prior to the first, second, third, fourth, and twelfth doses, prior to the first, second, third, fourth, and thirteenth doses, or prior to the first, second, third, fourth, and fourteenth doses.

[0312] Similarly, in some embodiments, a patient receives up to eighteen doses of an anti-amyloid antibody or an antigen-binding fragment thereof, for example one, two three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen or eighteen doses. Such embodiments include an MRI prior to each dose, prior to every other dose, every third dose, every four dose, every firth dose, every six dose, every seventh dose, every eight dose or every nineth dose. In addition, a patient may receive one or more MRI’s after the last dose.

[0313] In some embodiments, an MRI is administered before at least one dose selected from the group consisting of: first, second, third, fourth, fifth, sixth, seventh, eighth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth doses.

[0314] In some embodiments, an MRI is administered before the first dose and at least one additional dose selected from the group consisting of: second, third, fourth, fifth, sixth, seventh, eighth, nineth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth doses.

[0315] In some embodiments, one or more MRIs are administered after the sixth dose, regardless of any one or more MRI’s administered prior to the sixth dose. For example, an MRI is administered after the seventh dose, after the seventh dose, after the seventh and thirteenth dose, after the seventh, thirteenth and nineteenth doses, after the seventh and nineteenth doses, after the thirteen dose, after the thirteenth and nineteenth dose, or after the nineteenth dose. In each of these embodiments, the patient may have received an MRI prior to any one or more of the first, second, third, fourth, first and sixth dose.

[0316] In some embodiments, a patient may have received one or more placebo doses prior to administration of an anti-amyloid antibody or an antigen-binding fragment thereof. For the purposes herein, a placebo does may be considered dose of the anti-amyloid antibody or an antigen-binding fragment thereof that is administered after the placebo dose. For example, a patient that receives six placebo doses and six doses of the an anti-amyloid antibody or an antigen-binding fragment thereof may be considered as receiving twelve dose of the antibody or an antigen-binding fragment thereof for the purposes of considering whether an MRI is administered prior to any dose. In other embodiments, the placebo does is not considered.

[0317] In the various embodiments of MRI monitoring regimes described herein, the methods optionally include administering one or more MRIs after administration of a final dose (e.g., post-treatment, after a deliberate or accidental pause in administration of an anti- amyloid antibody or an antigen-binding fragment thereof, and the like). Using one embodiment as an example, for a method including two consecutive doses and three non- consecutive doses (e.g., administering an MRI prior to the first, third, fourth, seventh, and tenth doses with q28d dosing – roughly monthly dosing), one or more MRI can be administered after a final dose (which may be the last dose listed in each series herein (here the tenth dose), or a later dose where MRI monitoring is not specified between the last listeddose in the series and a final dose). For this described embodiment, the final dose is dose 12 (essentially month 12). Post final dose MRI can be administered any number of days, weeks, or months after a final dose. Continuing with this example, a post dose MRI can be administered around month thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, to twenty- four (1 year post final dose), to 36 (2 years post final dose), and to 48 months (3 years post final dose). In one specific embodiment, an MRI is administered prior to the first, third, fourth, seventh, and tenth doses, and a post-dose MRI is administered around month 13, about one month after administration of a final dose.

[0318] In some embodiments, one MRI is administered after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered. In some embodiments, the MRI is administered between about two weeks and one year after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered, while in some embodiments, the MRI is administered about one month after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered.

[0319] In some embodiments, two MRI are administered after a final dose of anti- amyloid antibody or an antigen-binding fragment thereof is administered. In some embodiments, one MRI is administered between about two weeks and two months after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered, and a second MRI is administered between about two months and twelve months after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered.

[0320] In various embodiments, the subject receives the brain MRI to evaluate for the presence of amyloid related imaging abnormalities (ARIA), ARIA-edema (ARIA-E), and / or ARIA-hemosiderin deposition (ARIA-H). Depending upon the radiographic and clinical severity of any observed ARIA-E or ARIA-H, dosing and MRI monitoring regimes can change. In some embodiments, when (i) ARIA-E is present at a severity of Mild or Mild+ with an ARIA-E clinical severity of Moderate or Severe, or (ii) ARIA-E is present at a severity of Moderate, Moderate+ or Severe, or (iii) ARIA-H is present at a severity of Mild with an ARIA-H clinical severity of symptomatic, or (iv) ARIA-H is present at a severity of Moderate or Severe, the subject receives additional brain MRIs every 4 to 6 weeks until (a)resolution of ARIA E or stabilization of ARIA H or (b) for a period of up to 26 weeks.

[0321] In some embodiments, when (i) ARIA-E is present at a severity of Mild or Mild+ with an ARIA-E clinical severity of Moderate or Severe, or (ii) ARIA-E is present at a severity of Moderate, Moderate+ or Severe, or (iii) ARIA-H is present at a severity of Mild with an ARIA-H clinical severity of symptomatic, or (iv) ARIA-H is present at a severity ofModerate or Severe, administration of the anti-amyloid antibody or an antigen-bindingfragment is suspended until resolution of ARIA E or stabilization of ARIA H.Treatment Amenable Patients

[0322] The present disclosure includes the treatment and / or prevention of amyloidogenic diseases, including Alzheimer's disease, by administration of the antibodies, fragments and pharmaceutical compositions of the present disclosure. Further, the present disclosure provides the use of the anti-amyloid antibodies to generate a beneficial therapeutic responsein a patient (e.g., induction of phagocytosis of A , reduction of plaque burden, inhibition ofplaque formation, reduction of neuritic dystrophy, neutralization of soluble, toxic A species,improving cognitive function, and / or reversing, treating or preventing cognitive decline. The disclosure is also directed to the use of the disclosed antibodies and fragments in the manufacture of a medicament for the treatment or prevention of an amyloidogenic disease using, for example, dosing regimens of the present disclosure. For example, the use of the disclosed antibodies and fragments in the manufacture of a medicament for the treatment or prevention of an Alzheimer’s by administering (e.g., subcutaneously administering) to a patient a therapeutically effective amount (e.g., from 20 mg to 200 mg about once every 4 weeks, 45 mg about once every 4 weeks, 70 mg about once every 4 weeks, 100 mg about once every 4 weeks, 150 mg about once every 4 weeks, 200 mg about once every 4 weeks, 205 mg to 400 mg about once every 4 weeks, 250 mg about once every 4 weeks, 300 mg about once every 4 weeks, 405 mg to 700 mg about once every 4 weeks, 500 mg about once every 4 weeks, 600 mg about once every 4 weeks, 700 mg about once every 4 weeks, 100 mg about once every 2 weeks, 200 mg about once every 2 weeks, or 350 mg about once every 2 weeks) of the anti-amyloid antibody or fragment thereof. Such methods are useful for preventing or treating Alzheimer's disease in human patients.

[0323] Patients amenable to treatment include individuals at risk of disease but not showing symptoms, as well as patients presently showing symptoms. In the case of Alzheimer's disease, potentially anyone who lives long enough is at risk of Alzheimer's disease. Thus, the present methods include administering prophylactically to the general population without the need for any assessment of the risk of the subject patient. The present methods are especially useful for individuals who have a known genetic risk of Alzheimer's disease. Such individuals include those having relatives who have experienced this disease, and those whose risk is determined by analysis of genetic or biochemical markers. Genetic markers of risk toward Alzheimer's disease include mutations in the APP gene, particularlymutations at position 717 and positions 670 and 671 referred to as the Hardy and Swedish mutations, respectively. Other markers of risk are mutations in the presenilin genes, PS1 and PS2, and ApoE4, family history of AD, hypercholesterolemia or atherosclerosis. Individuals presently suffering from Alzheimer's disease can be recognized from characteristic dementia, as well as the presence of risk factors described above. In addition, a number of diagnostic tests are available for identifying individuals who have AD. These include measurement ofCSF tau and A 42 levels. Elevated tau and decreased A 42 levels signify the presence ofAD. Individuals suffering from Alzheimer's disease can also be diagnosed by ADRDA criteria as discussed in the Examples section.

[0324] Treatment in asymptomatic patients can begin at any age (e.g., 10, 20, 30). Usually, however, it is not necessary to begin treatment until a patient reaches 40, 50, 60, or 70. Treatment typically entails multiple dosages over a period of time. Treatment can be monitored by assaying antibody levels over time. If the response falls, a booster dosage is indicated. In the case of potential Down's syndrome patients, treatment can begin antenatally by administering therapeutic agent to the mother or shortly after birth.

[0325] In various embodiments, treatment amenable patients can be identified by screening for phospho-tau (p-tau) concentrations in samples derived from the subject (e.g., blood plasma, CSF). Thus, in some embodiments, the present disclosure provides utilizing phospho-tau biomarkers for identifying individuals for treatment with anti-amyloid antibodies of the present disclosure and subsequent treatment of those patients.

[0326] In some embodiments, the present methods include treating Alzheimer’s disease in a subject by administering to the subject about 20 mg to about 200 mg (e.g., about 45 mg, 70 mg, 100 mg, 150 mg, or 200 mg), about 205 mg to about 400 mg (e.g., about 205 mg, 250 mg, 300 mg, 350 mg, or 400 mg, about 405 mg to about 700 mg (e.g., about 405 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, or 700 mg) of an anti-amyloid antibody or an antigen- binding fragment thereof once about every 3-5 weeks, wherein it has previously been determined that a p-tau concentration in a sample derived from the patient is greater than or equal to a threshold p-tau concentration.

[0327] In some embodiments, the described methods of treating Alzheimer’s Disease in a subject include: (a) assessing a p-tau concentration in a sample derived from the subject; and (b) if the p-tau concentration in the sample is greater than or equal to a threshold p-tau concentration, administering to the subject about 20 mg to about 200 mg (e.g., about 45 mg, 70 mg, 100 mg, 150 mg, or 200 mg), about 205 mg to about 400 mg (e.g.,about 205 mg, 250 mg, 300 mg, 350 mg, or 400 mg, about 405 mg to about 700 mg (e.g., about 405 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, or 700 mg) of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks.

[0328] In some embodiments, the sample comprises a bodily fluid obtained from the subject. For example, in some embodiments, the sample comprises blood or a component thereof. In some embodiments, the sample comprises blood plasma. In some embodiments, the sample comprises blood serum. In some embodiments, the sample comprises CSF.

[0329] In some embodiments, the described methods of treating Alzheimer’s Disease in a subject include: (a) assessing a first p-tau concentration in a first sample derived from the subject; (b) if the first p-tau concentration in the first sample is greater than or equal to a threshold value, administering to the subject about 20 mg to about 200 mg (e.g., about 45 mg, 70 mg, 100 mg, 150 mg, or 200 mg), about 205 mg to about 400 mg (e.g., about 205 mg, 250 mg, 300 mg, 350 mg, or 400 mg, about 405 mg to about 700 mg (e.g., about 405 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, or 700 mg) of an anti-amyloid antibody or an antigen-binding fragment thereof once about every 3-5 weeks; and (c) assessing a second p-tau concentration in a second sample derived from the subject.

[0330] In some embodiments, treating Alzheimer’s Disease includes reducing p-tau concentration in subsequent samples (i.e., samples derived from the subject after treatment with the anti-amyloid antibody or an antigen-binding fragment thereof). For example, in some embodiments, the second p-tau concentration is lower than the first p-tau concentration.

[0331] In some embodiments, the threshold p-tau concentration is a threshold p217-tau concentration. In some embodiments, the threshold p-tau concentration is a threshold p217- tau blood plasma concentration.

[0332] In some embodiments, the threshold p-tau concentration is a threshold p181-tau concentration. In some embodiments, the threshold p-tau concentration is a threshold p181- tau blood plasma concentration.

[0333] In some embodiments, the threshold p-tau concentration is a threshold p212-tau concentration. In some embodiments, the threshold p-tau concentration is a threshold p212- tau blood plasma concentration.

[0334] In some embodiments, the threshold p-tau concentration is a threshold p1231-tau concentration. In some embodiments, the threshold p-tau concentration is a threshold p231- tau blood plasma concentration.

[0335] In some embodiments, the threshold p-tau concentration is a threshold p1235-tau concentration. In some embodiments, the threshold p-tau concentration is a threshold p235- tau blood plasma concentration.

[0336] In some embodiments, treating Alzheimer’s Disease includes slowing the increase in p-tau concentration in subsequent samples relative to a reference (e.g., an untreated population having comparable p-tau blood plasma concentrations). For example, in some embodiments, the second p-tau concentration is the same as or greater than the first p-tau concentration, but the second p-tau concentration is lower than a reference p-tau concentration (e.g., an average p-tau concentration observed in a patient and / or patient population having a similar initial p-tau blood plasma concentration whose disease has progressed for a similar period of time).

[0337] In some embodiments, assessing the p-tau concentration(s) in the sample(s) (e.g., the first p-tau concentration in the first sample and / or the second p-tau concentration in the second sample) is conducted after corresponding the p-tau concentration(s) were previously measured and / or quantified. In various embodiments, p-tau concentration(s) were measured and / or quantified using quantitative means known in the art (e.g., mass spectrometry, immunoassay) and the p-tau concentration(s) is subsequently transferred to a physician who makes the determination as to whether to proceed with treatment using antibodies of the present disclosure. For example, in some embodiments, p-tau concentration(s) are previously measured quantified using mass spectrometry (e.g., liquid chromatography mass spectrometry (LCMS)). For example, in some embodiments, p-tau concentration(s) are previously measured quantified using an immunoassay (e.g., liquid chromatography mass spectrometry (LCMS)). APOE4 Status

[0338] Subjects carrying the apolipoprotein E 4 allele (APOE4) are at increased risk of ARIA during treatment with anti-amyloid therapies. See, e.g., C. Dagostin, et al., Efficacy ofanti-amyloid- monoclonal antibody therapy in early Alzheimer’s disease: a systematicreview and meta-analysis. NEOLOGICAL SCIENCES (2023). Subjects homozygous for APOE4 are at highest risk, due in part to their increased burden of aggregated amyloid in cerebral microvessels. Furthermore, ongoing research suggests that, during treatment, APOE4 carriersexhibit a larger perivascular A clearance, leading to greater vascular permeability andextravasation of fluid and erythrocytes, thereby resulting higher in ARIA-E and ARIA-Hrates. See, e.g., M. Roytman, et al., Amyloid-Related Imaging Abnormalities: An Update.220 AM. J. ROENTGENOLOGY 562 (2023).

[0339] In some embodiments, the subject is an APOE4 heterozygous subject or an APOE4 negative subject. In some embodiments, the subject is an APOE4 homozygous subject. In some embodiments, the subject is an APOE4 heterozygous subject. In some embodiments, the subject is an APOE4 negative subject (non-carrier). In Vivo Detection

[0340] In another aspect, the disclosure provides methods for detecting amyloid plaques and deposits in a patient having or at risk of developing an amyloidogenic disease. Such methods are useful for diagnosing or confirming amyloidogenic disease or susceptibility to it. For example, the methods can be used in patients with dementia symptoms, wherein observation of abnormal amyloid deposits likely indicates Alzheimer's disease. The methods can also be used in asymptomatic patients. The presence of abnormal deposits of amyloid indicates susceptibility to future symptomatic disease.

[0341] In some embodiments, the method comprises administering to a subject / patient an antibody or fragment thereof of the disclosure and detecting the antibody or fragment thereofbound to A .

[0342] Antibody and / or antibody fragments thereof can be administered by any suitable means that results in delivery to the tissue to be visualized, e.g., administered directly into the brain by intravenous injection into the patient's body or by intracranial injection. Dosage of the antibody and / or fragment thereof can comprise a therapeutic dose, subtherapeutic dose or a supratherapeutic dose. In some embodiments the antibody or fragment thereof is labeled, comprising a fluorescent label, a paramagnetic label, or a radioactive label. The choice of label depends on the means of detection. For example, fluorescent labels are suitable for visual detection. The use of paramagnetic labels is suitable for tomographic detection without surgical intervention. In some embodiments, the radioactive label is detected using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

[0343] In another aspect, the disclosure provides methods for measuring the efficacy of treatment in a subject being treated for an amyloidogenic disease. In some embodiments, a first level of amyloid plaque in a subject is measured prior to treatment by administering an antibody or fragment thereof of the disclosure and detecting a first amount of the antibody orfragment thereof bound to A in the subject. A treatment can then be administered to thesubject, followed by measuring a second level of amyloid plaque in the subject, and detectingthe antibody or fragment thereof bound to A in the subject. In some embodiments, adecrease in the level of amyloid plaque indicates a positive response to treatment, and in some embodiments, no change in the level of amyloid plaque or a small increase in amyloid plaque indicates a positive response to treatment. In some embodiments, levels of amyloid plaque can be measured utilizing the methods of detecting amyloid plaques described herein.

[0344] In some embodiments, diagnosis of an amyloidogenic disease can be performed, for example, by comparing the number, size and / or intensity of labeled positions from a measured first level (i.e., baseline) to a subsequent second level of amyloid plaque in a subject. An increase over time indicates disease progression, no change indicates , and fewer or less intense amyloid plaques over time indicates remission.

[0345] Agents of the disclosure can optionally be administered in combination with other agents that are at least partly effective in treatment of amyloidogenic disease. In the case of Alzheimer's and Down's syndrome, in which amyloid deposits occur in the brain, agents of the disclosure can also be administered in conjunction with other agents that increase passage of the agents of the disclosure across the blood-brain barrier. EXAMPLES

[0346] The following examples have been included to illustrate modes disclosed herein. Certain aspects of the following examples are described in terms of techniques and procedures found or contemplated by the present co-inventors to work well in the practice disclosed herein. In light of the present disclosure and the general level of skill in the art, those of skill appreciate that the following examples are intended to be exemplary only and that numerous changes, modifications, and alterations may be employed without departing from the scope of the disclosure. Example 1. Reducing amyloid plaques in patients

[0347] To reduce amyloid plaques, which has been associated with inhibiting, reducing, and / or reversing the symptoms of Alzheimer’s disease, a pharmaceutically effective amountof an anti-A antibody (or antigen-binding fragment thereof) is administered to the patients,such as one or more of the antibodies described herein.

[0348] Patients: Individuals that are suspected of having or have been diagnosed with an amyloid plaque-associated disease, such as Alzheimer’s disease, are selected for treatmentwith an anti-A antibody.

[0349] Treatment: Patients are administered 45 mg, 70 mg, 200 mg, 400 mg, or 700 mgof anti-A antibody h2731 subcutaneously once about every 4 weeks.

[0350] Plaque reduction and improvement in symptoms of Alzheimer’s disease can be measured as described herein.

[0351] A patient with Alzheimer’s disease administered 45 mg, 70 mg, 200 mg, 400 mg,or 700 mg of anti-A antibody h2731 subcutaneously once about every 4 weeks is treated byreduction in amyloid plaque burden, measured by PET imaging. A patient is further treated by slowing of cognitive decline, measured using methods described herein. Example 2. Phase 1 single ascending dose study to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics of h2731

[0352] This example describes a phase 1, randomized, double-blind, placebo-controlled, single ascending dose (SAD) study to evaluate the safety, tolerability, and immunogenicity, of h2731 at doses of 70 mg, 200 mg, 400 mg and 700 mg. The purpose of this study is to characterize the plasma pharmacokinetics (PK) profile of h2731 in healthy volunteers (HV) and patients who have AD, and specifically AD patients who have parenchymal amyloid load confirmed by molecular imaging. AD subjects will be required to meet the National Institute on Aging and Alzheimer’s Association (NIA-AA) research criteria and guidelines for AD (McKhann, 2011) or mild cognitive impairment (MCI) due to AD (Albert, 2011). Study Rationale

[0353] Preclinical studies in transgenic mice that generate a surplus of A demonstratedthat antibodies targeting A N-terminus are able to enter the brain and decrease amyloiddeposits in brain tissue and cerebral vasculature (Bard, 2000). Clinical evidence shows that monoclonal antibodies directed towards N-terminus amyloid are able to remove and reducedeposition of A aggregates from the brain, and attenuate cognitive decline (Sevigny, 2016;Swanson, 2021; Aduhelm USPI, 2021).

[0354] Preclinical studies show that h2731 removed A plaques rapidly and robustly byenhancing microglial-mediated clearance mechanisms. See, e.g., US Patent No.11,440,953. These data suggest that h2731 has the potential to slow clinical decline in patients with AD. Doses of 70 mg, 200 mg, 400 mg and 700 mg for Phase 1 clinical testing is based on CNS fractional occupancy modeled from predictions of clinical exposure at these doses. Study Objectives

[0355] The primary objective of the study is to evaluate the safety and tolerability of h2731 when administered as a single dose, including (1) general safety, tolerability, andimmunogenicity in all subjects and (2) target-related safety and tolerability in subjects with confirmed presence of parenchymal amyloid.

[0356] A secondary objective of the study is to characterize the PK profile of h2731 and cerebrospinal fluid (CSF) PK profile of h2731 after SC administration as a single dose. Study Design

[0357] The study will comprise at least four dose cohorts of subjects with biologically confirmed AD (AD Cohort 1, AD Cohort 2, AD Cohort 3, and AD Cohort 4). The study will further comprise two healthy volunteer (“HV”) cohorts (HV Cohort A and HV Cohort B). These six cohorts include the following: AD Cohort 1 (70 mg), AD Cohort 2 (200 mg), AD Cohort 3 (400 mg), AD Cohort 4 (700 mg), HV Cohort A (70 mg), and HV Cohort B (200 mg), each of which will be dosed subcutaneously (“SC”) with their respective dose. The study also includes an optional fifth dose cohort of subjects with biologically confirmed AD (AD Cohort 5; dosed at up to 700 mg).

[0358] Following initial on-site observation, subjects will return for four follow-up visits over approximately 12 weeks during which safety assessments and PK collections will be completed. Selected cohorts (HV Cohort A and HV Cohort B) may additionally undergo CSF collection by lumbar puncture at Days 3 and 29. MRI scans will be taken on day zero (i.e., prior to the first dose) for all subjects, and additional MRI scans will be taken on days 29 and 85 for AD cohorts (AD Cohorts 1 to 4, and AD Cohort 5 if applicable) to assess ARIA rates. Endpoints

[0359] Primary endpoints will include: Safety and tolerability based on adverse event (“AE”) reporting (incidence of AEs, SAEs, and h2731-related AEs), ECGs, clinical laboratory tests, vital signs, and physical examinations Immunogenicity measured by the confirmed presence of ADAs in plasma Amyloid-related imaging abnormalities (ARIA-H and ARIA-E) and other emergent radiological findings

[0360] Secondary endpoints may include Plasma PK of h2731, including: Maximum observed concentration (Cmax) Time to achieveArea under the concentration-time curve from time 0 to 672 hours (AUC0-672)Area under the concentration-time curve from time 0 to last measured collection time (AUC0-last) Area under the concentration-time curve from time 0 to infinity (AUC0-) Terminal elimination rate constant ( z)Terminal elimination half-life (t1 / 2) Apparent volume of distribution (Vd) Apparent total body clearance (CL / F) Observed concentration (Cobs) of h2731 at each sampling time associated with CSF collection (HV subjects only) Estimated CSF / plasma concentration ratio (HV subjects only) CSF PK of h2731 Cobsof h2731 at each sampling time Inclusion Criteria

[0361] Each cohort will contain approximately eight subjects with body mass indices (BMI) between 18.0 and 32.0 kg / m2.

[0362] AD subjects will be selected according to inclusion criteria that include the following: (a) have a confirmed or suspected diagnosis of AD based on either probable AD with evidence of the AD pathophysiological process according to National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria (McKhann et al., Alzheimer’s Dement., 7(3):264-9, 2011) or high likelihood of AD according to NIA-AA criteria (Albert et al., Alzheimer’s Dement., 7(3):270-79, 2011); (b) have gradual and progressive change in memory function for 6 months reported by subject or study partner; (c) a screening Mini-Mental State Examination (MMSE) score 18; (d) evidence of AD pathological process, as confirmed on amyloid PET scan; and (e) MRI criteria for microhemorrhage and / or superficial siderosis. Exclusion Criteria

[0363] Subjects will be selected based on exclusion criteria that include the following. Subjects must not meet any of the exclusion criteria, including the following criteria: (a) Impaired coagulation (prothrombin time 1.2 × ULN) or other coagulopathy (b) History of severe, clinically significant (persistent neurologic deficit or structural brain damage) central nervous system (CNS) trauma (e.g., cerebral contusion), epilepsy(c) Have any contraindications for MRI studies, including claustrophobia, the presence of contraindicated metal (ferromagnetic) implants, or cardiac pacemaker (d) Anti-coagulation medications within 3 months of screening with no plans to initiate any prior to randomization or history of prolonged bleeding after minor trauma. Note: low dose aspirin is permitted (up to 162 mg / day). (e) History or presence of posterior reversible encephalopathy syndrome (PRES) (Fugate, et al, Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol.2015;14(9):914-25.) Clinical Laboratory Evaluations

[0364] Laboratory analysis of hematology, clinical chemistry, coagulation, urinalysis, plasma, biomarkers, and CSF will be conducted. Central and local pregnancy testing will be conducted.

[0365] Brain MRI will be read locally and the scan will be submitted to the centralized MRI vendor for final determination of MRI eligibility, and to provide central assessment of baseline ARIA findings. MRIs should be performed using 1.5 or 3.0-T scanners, and the same scanner should be used for an individual subject for the duration of the study. The first MRI will occur during the screening period as a baseline measure to confirm structural brain imaging-based eligibility criteria. MRI scans will include, but are not limited to, the following sequences: T2-weighted FLAIR, 2-dimensional (2D) T2*-weighted gradient echo (GRE) or susceptibility weighted imaging (SWI). Diffusion weighted, 3-dimensional (3D) T1-weighted GRE. MRI scans will be evaluated and read by a MRI central reader, which will provide the diagnostic reads and assessments of MRI outcome measures. MRI data (Day 29 MRI data from all subjects and any other available MRI and safety data) will be made available for the DSMB for confirmation of h2731 dose.

[0366] CSF Analysis, if performed, in Cohorts will undergo 2 LPs: the first LP on Day 3 (48 hours after study drug administration) and the second LP on Day 29. The CSF will be analyzed to determine levels of h2731. CSF samples with clear evidence of blood contamination should not be used for PK assessment. CSF analyses will also include but are not limited to standard analyses including pressure, color, glucose, proteins, lactate, red blood cells, and white blood cells.

[0367] Amyloid PET Imaging will be used for biological confirmation of diagnosis of AD as evidence of presence of pathological hallmark findings of -amyloid-composedneuritic plaques. Isotope-labelled compounds that show high affinity toward aggregated forms of -amyloid (tracers) can provide evidence of -amyloid in vivo. Three radioligand are being used for screening purposes: [18F]florbetapir / AV45 (Amyvid), [18F]flutemetamol (Vizamyl), and [18F]florbetaben (Neuraceq). Subjects in Cohorts 1-4, and Cohort 5 if applicable, will undergo amyloid PET acquisition to confirm biologically the diagnosis of AD. A positive PET scan using [18F]florbetapir / AV45, [18F]flutemetamol, or [18F]florbetaben acquired outside of this trial protocol within 18 months prior to the first screening visit may be permissible to confirm patient inclusion with confirmation by a central read.

[0368] APOE4 status (e.g., APOE4 / APOE4, APOE4 / APOE3, APOE3 / APOE3, APOE4 / APOE2, APOE3 / APOE2) will be determined by central assessment for subjects enrolling into Cohorts 1 to 4, and Cohort 5 if applicable. Additional Assessments

[0369] The Cogstate CBB (Maruff, 2013) will be administered to subjects at the first screening visit (Day -72 to -8). The CBB is a brief (approximately 15 minutes), computer- based cognitive test battery designed to measure memory, working memory psychomotor function, and attention. The CBB has been shown to be a sensitive tool for detecting AD- related cognitive decline in healthy older adults and in adults with amnestic mild cognitive impairment (Darby, 2002; Lim, 2013) as well as for improvement in cognition arising from treatment with cognition enhancing drugs (Davison, 2011; Jaeger, 2011; Nathan, 2013).

[0370] The MMSE (Folstein, 1975) will be administered to subjects at the first screening visit (Day -72 to -8), prior to the Cogstate CBB assessment, to determine if the subject meets entry criteria for cognitive impairment.

[0371] Subjects will undergo plasma sampling for Biomarkers of AD pathologyincluding, but not limited to A 42 / 40, and biomarkers associated with tau pathologyincluding, but not limited to, total tau, p181-tau, and p217-tau.

[0372] Subjects will undergo PK sampling for plasma and CSF h2731.

[0373] Plasma anti-h2731 antibody levels will be measured (antibodies detected with an electrochemiluminescent assay (ECLIA).

[0374] ARIA Assessment: a screening MRI scan will be used to exclude subjects with pre-existing vasogenic edema (ARIA-E), >2 microhemorrhages, or >1 area of superficial siderosis (ARIA H). MRIs will be scheduled prior to study drug administration (baseline) for all subjects and at the Day 29 and Day 85 visits (28- and 84-days post dose, respectively) for subjects with AD, and will be assessed, classified, and documented for radiographic evidenceof ARIA (see Table 4). In addition to scheduled MRIs, unscheduled MRIs may be obtained at the discretion of the Investigator upon suspicion of ARIA based on appearance of symptoms. Table 4Example 3: Phase 1 multiple dose study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of h2721 in subjects with Alzheimer’s Disease

[0375] This example describes a phase 1, randomized, double-blind, placebo-controlled, multiple dose (MD) study to assess the safety, tolerability, and immunogenicity, PK, and pharmacodynamics (PD) effects of h2731 in patients with AD. Study Objectives

[0376] As discussed in further detail below, the primary objective of the study is to evaluate the safety, tolerability, and immunogenicity of h2731 after multiple SC doses. The secondary objectives of the study are to characterize the PK profile of h2731 after multiple SC doses, to characterize the plasma and CSF PK profile of h2731 after multiple SC doses, and to assess the PD effects of h2731 on brain amyloid plaque deposition after multiple SC doses. Exploratory objectives of the study are to assess PD effects of h2731 on blood and CSF biomarkers after multiple CS doses and to assess ARIA findings by apolipoprotein E4 (APOE4) status. Study Population

[0377] The study consists of two parts, each studying a different group of subjects: Group A, subjects with AD who are heterozygous or non-carriers of apolipoprotein E4 (APOE4) alleles (referred to as the non-homozygote population) and Group B, subjects with AD who are homozygous for APOE4 (referred to as the homozygote population). The dose levels ofh2731 to be assessed will be the same for the non-homozygote (Group A) and homozygote (Group B) populations (45 mg to 400 mg).

[0378] Apolipoprotein E (APOE) genotype status has been demonstrated to impact the onset of AD (Corder, 1993; van Duijn,1994) as well as rates of ARIA following treatmentwith anti-A antibodies (Arrighi, 2016; Ketter, 2017; Muralidharan, 2022). Development ofARIA is dose-dependent, and most events occur within the first few months after initiation ofanti-A treatment (Muralidharan, 2022). Patients with AD who possess 1 copy of the APOE4allele may possess an elevated risk of anti-A antibody-mediated ARIA compared to APOE4non-carriers, although the risk demonstrated across clinical trials is somewhat inconsistent. However, patients who are APOE4 homozygous (possessing 2 alleles) consistently demonstrate higher incidents of ARIA compared to both APOE4 heterozygous and non- carrier patients. Rationale for Dose Selection

[0379] The proposed doses of 45 mg, 70 mg, 200 mg, and 400 mg (each subcutaneously administered once a month) and up to 200 mg administered subcutaneously twice a month, are based on analysis of estimated target engagement (fractional occupancy [fOcc]) levels resulting from simulated clinical drug exposure levels at these doses, balancing predictions of efficacious exposure and the potential for inducing ARIA. These doses are further supported by results from the completed nonclinical toxicity studies with repeated dose administration for up to 3 months, and will be confirmed based on the certain information from the single ascending dose (SAD) study of Example 2, including: All safety and tolerability data through Day 15 from selected cohorts dosed at 70 mg, 200 mg, 400 mg, and / or 700 mg; PK data through Day 29 from selected cohorts dosed at 70 mg, 200 mg, 400 mg, and / or 700 mg (approximately 12 subjects per cohort; 9 receiving h2731 and 3 receiving placebo); and Day 29 MRI results from selected cohorts dosed at 70 mg, 200 mg, 400 mg, and / or 700 mg (approximately 12 subjects; 9 receiving h2731 and 3 receiving placebo). Study Design

[0380] This Phase 1, randomized, double-blind, placebo-controlled, multiple dose study is being conducted in two dose cohorts in subjects with biologically confirmed AD to assess the safety, tolerability, immunogenicity, PK, and PD of h2731.

[0381] The study consists of two parts, each evaluating a different group of subjects: Group A, subjects with AD who are heterozygous or non-carriers of APOE4 alleles and Group B, subjects with AD who are homozygous for APOE4. The two dose cohorts for each group are described in Table 5, along with an optional expansion cohort. The study also includes an optional fourth Group B cohort dosed at between 45 mg and 400 mg, as well as an optional cohort (Group A, Group B, and / or Group A.X) treating patients with 200 mg once every two weeks (twice a month). Dose cohorts are listed in Table 5. Table 5

[0382] Subjects with AD who are APOE4 heterozygous or non-carriers of APOE4 alleles will be assigned to Group A; subjects who are homozygous for APOE4 will be assigned to Group B.

[0383] For each Group A core cohort, approximately 32 subjects will be randomly assigned to h2731 or placebo in a 3:1 ratio. Randomization will be stratified by APOE4 carrier status (APOE4 heterozygous or APOE4 non-carrier).

[0384] For each Group B cohort, approximately 12 subjects will be randomly assigned to h2731 or placebo in a 3:1 ratio: 9 subjects will receive h2731, and 3 subjects will receive placebo.

[0385] A total of up to approximately 100 subjects, cumulative, may be enrolled in the optional Group A expansion cohorts. Subjects in each expansion cohort will be randomly assigned to h2731 or placebo in a 3:1 ratio. Randomization will also be stratified by APOE4carrier status (APOE4 heterozygous or APOE4 non-carrier). The Expansion cohorts have a modified MRI schedule compared to the Core cohorts as described below. Inclusion Criteria

[0386] AD subjects will be selected according to inclusion criteria that include the following: Subjects between 55 and 85 years having a body mass index between 18.0 and 32.0 kg / m2, inclusive; Gradual and progressive change in memory function for 6 months reported by subjects or study partner; Alzheimer’s pathologic change with either mild cognitive impairment or mild dementia (Stage 2, 3 or 4) according to National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria (Jack, 2018; Appendix 3); Met prespecified CL-based PET imaging criteria; Met MRI criteria for microhemorrhage and / or superficial siderosis; and Screening MMSE score 18. Exclusion Criteria

[0387] Exclusion Criteria are essentially as described in Example 2.

[0388] Clinical laboratory evaluations, Cogstate assessment, MMSE assessment, PK sampling, biomarker analysis, and ARIA assessment will be performed using methods similar to those set forth in Example 2. Screening

[0389] Subject screening includes an MRI scan and an amyloid PET scan. The MRI scan is reviewed for ARIA. Treatment Period

[0390] Study drug (45 mg, 70 mg, 200 mg, 400 mg, 45 mg to 400 mg) will be administered every 4 weeks starting on Day 1 for a total of up to 6 doses (or 200 mg every 2 weeks). Subjects will receive the first dose of study drug (h2731 or placebo) administered subcutaneously on Day 1. Subjects will undergo safety assessments including adverse event (AE) monitoring, clinical laboratory tests, vital signs, physical examinations, and electrocardiograms (ECGs), as well as blood collections for PK, anti-drug antibody (ADA), and biomarker (BM) analysis, and imaging (MRI and PET). Subjects will be released from the study site 8 hours after dosing, after completing scheduled post-dose assessments.

[0391] Dosing will continue every 4 weeks (or 2 weeks for optional q14d cohorts). Safety assessments and blood collections for PK, ADA, and BM analysis will be completed. MRI findings, as assessed by the central reader, must be reviewed prior to dosing to evaluate for the presence of ARIA.

[0392] After the last administration of study drug, subjects will return to the study site for the Week 24 (Day 169) visit to complete an end of treatment (EOT) visit that includes safety assessments, blood collections for PK, ADA, BM analysis, MRI and amyloid PET imaging assessment.

[0393] Subjects who participate in the optional CSF collection will undergo two lumbar punctures (LPs): the first LP between Days -10 to -3 (before administration of study drug), and the second LP within 1 to 7 days after the Week 24 (Day 169) imaging visit (MRI and PET). The CSF will be used to measure biomarkers of AD pathology including but notlimited to A 42 / 40 ratio, p181-tau, and p217-tau and also to determine CSF levels ofh2731.Subjects may be released after 4 hours of observation.

[0394] Imaging

[0395] For Core cohorts A-1 to A-3, and B-1 to B-4, six MRI visits are scheduled during the Screening / Treatment Period: Screening (baseline), Week 3 (Day 22), Week 7 (Day 50), Week 11 (Day 78), Week 15 (Day 106), Week 19 (Day 134), and Week 24 (Day 169), i.e., before each of the six monthly administrations of h2731 and during the EOT visit.

[0396] For Core cohorts A-4 and A-5, four MRI visits are scheduled during the Screening / Treatment Period: Screening (baseline), Week 3 (Day 22), Week 7 (Day 50), Week 11 (Day 78), and Week 24 (Day 169), i.e., before each of the first four monthly administrations of...

Claims

WHAT IS CLAIMED IS:

1. A method of treating Alzheimer’s disease in a subject, comprising administering to the subject an anti-amyloid antibody or an antigen-binding fragment thereof, wherein (i) the subject is administered magnetic resonance imaging (MRI) of the brain before a first administration of the anti-amyloid antibody or an antigen-binding fragment thereof, and (ii) the subject is administered at least one additional brain MRI before at least one subsequent administration of the anti-amyloid antibody or an antigen-binding fragment thereof.

2. The method of claim 1, wherein an MRI is administered to a subject prior to (i) the first administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) to one or more consecutive doses of an anti-amyloid antibody or an antigen-binding fragment.

3. The method of claim 1, wherein an MRI is administered to a subject prior to (i) the administration of a first administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) to one or more non-consecutive doses of an anti-amyloid antibody or an antigen-binding fragment.

4. The method of claim 1, wherein an MRI is administered to a subject prior to (i) the administration a first administration of an anti-amyloid antibody or an antigen-binding fragment thereof; and (ii) to one or more consecutive doses and one or more non-consecutive dose of an anti-amyloid antibody or an antigen-binding fragment thereof, wherein (a) the MRIs prior to the consecutive doses precede the MRIs prior to the non-consecutive doses, or (b) the MRIs prior to the non-consecutive doses precede the MRIs prior to the consecutive doses.

5. The method of claim 2, wherein 2, 3, 4, 5, 6, or 7 MRI are administered.

6. The method of claim 2, wherein MRI are administered, prior to the first, second, third, fourth, fifth, and sixth dose of the anti-amyloid antibody or an antigen-binding fragment thereof, and optionally an MRI is administered prior to a seventh dose.

7. The method of claim 3, wherein 2, 3, 4, 5, 6, or 7 MRI are administered.

8. The method of claim 7, wherein 2 MRI are administered, selected from the group consisting of: prior to the first and third doses, prior to the first and fourth doses, prior to the first and fifth doses, prior to the first and sixth doses, and prior to the first and seventh doses.

9. The method of claim 8, wherein MRI are administered prior to the first and fourth doses.

10. The method of claim 7, wherein 3 MRI are administered, selected from the group consisting of: prior to the first, third, and fifth doses, prior to the first, third, and sixth doses, prior to the first, third, and seventh doses, prior to the first, fourth, and sixth doses, and prior to the first, fourth, and seventh doses.

11. The method of claim 10, wherein MRI are administered prior to the first, third, and seventh doses, and prior to the first, fourth, and seventh doses.

12. The method of claim 7, wherein 4 MRI are administered, selected from the group consisting of: prior to the first, third, fifth, and seventh doses, and prior to the first, fifth, seventh, and fourteenth doses.

13. The method of claim 4, wherein 3, 4, 5, or 6, MRI are administered.

14. The method of claim 13, wherein 3 MRI are administered, selected from the group consisting of: prior to the first, second and fourth doses, prior to the first, second and fifth doses, prior to the first, second and sixth doses, and prior to the first, second and seventh doses.

15. The method of claim 14, wherein MRI are administered prior to the first, second and seventh doses.

16. The method of claim 13, wherein 4 MRI are administered, selected from the group consisting of: prior to the first, second, fourth, and seventh doses, prior to the first, second, fifth, and seventh doses, prior to the first, second, seventh, and thirteenth doses, prior to thefirst, third, fourth, and seventh doses, prior to the first, third, fourth, and eighth doses, and prior to the first, second, third, and seventh doses.

17. The method of claim 13, wherein 5 MRI are administered, selected from the group consisting of: prior to the first, third, fourth, seventh, and tenth doses, prior to the first, second, fifth, and seventh doses, prior to the first, second, seventh, and thirteenth doses, prior to the first, third, fourth, and seventh doses, prior to the first, third, fourth, and eighth doses, prior to the first, second, third, seventh, and ninth doses, prior to the first, second, third, seventh, and thirteenth doses, and prior to the first, second, third, fourth, and seventh doses.

18. The method of claim 13, wherein 6 MRI are administered, prior to the first, second, third, seventh, ninth, and thirteenth doses.

19. The method of any one of claims 1-18, wherein at least one MRI is administered after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered.

20. The method of claim 19, wherein one MRI is administered after a final dose of anti- amyloid antibody or an antigen-binding fragment thereof is administered.

21. The method of claim 20, wherein the MRI is administered between about two weeks and one year after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered.

22. The method of claim 21, wherein the MRI is administered about one month after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered.

23. The method of claim 19, wherein two MRIs are administered after a final dose of anti- amyloid antibody or an antigen-binding fragment thereof is administered.

24. The method of claim 23, wherein one MRI is administered between about two weeks and two months after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered, and a second MRI is administered between about two months andtwelve months after a final dose of anti-amyloid antibody or an antigen-binding fragment thereof is administered.

25. The method of any one of claims 1-24, wherein the subject receives the brain MRI to evaluate for the presence of amyloid related imaging abnormalities (ARIA), ARIA-edema (ARIA-E), and / or ARIA-hemosiderin deposition (ARIA-H).

26. The method of claim 25, wherein when (i) ARIA-E is present at a severity of Mild or Mild+ with an ARIA-E clinical severity of Moderate or Severe, or (ii) ARIA-E is present at a severity of Moderate, Moderate+ or Severe, or (iii) ARIA-H is present at a severity of Mild with an ARIA-H clinical severity of symptomatic, or (iv) ARIA-H is present at a severity of Moderate or Severe, the subject receives additional brain MRIs every 4 to 6 weeks until (a)resolution of ARIA E or stabilization of ARIA H or (b) for a period of up to 26 weeks.

27. The method of claim 25, wherein when (i) ARIA-E is present at a severity of Mild or Mild+ with an ARIA-E clinical severity of Moderate or Severe, or (ii) ARIA-E is present at a severity of Moderate, Moderate+ or Severe, or (iii) ARIA-H is present at a severity of Mild with an ARIA-H clinical severity of symptomatic, or (iv) ARIA-H is present at a severity of Moderate or Severe, administration of the anti-amyloid antibody or an antigen-bindingfragment is suspended until resolution of ARIA E or stabilization of ARIA H.

28. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27 wherein about 45 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof are administered to the subject once about every 3-5 weeks.

29. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 45 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof are administered once about every 3-5 weeks, and wherein brain amyloid beta plaque is reduced in the subject.

30. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 45 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered once about every 3-5 weeks, and wherein the subject is converted from amyloid positive to amyloid negative.

31. The method of any one of claims 28-30, wherein the method comprises administering about 100 mg to about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

32. The method of any one of claims 28-30, wherein the method comprises administering about 150 mg to about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

33. The method of any one of claims 28-30, wherein the method comprises administering about 100 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

34. The method of any one of claims 28-30, wherein the method comprises administering 150 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

35. The method of any one of claims 28-30, wherein the method comprises administering about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

36. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27 wherein about 205 mg to about 400 mg of an anti-amyloid antibody or an antigen-binding fragment thereof are administered to the subject once about every 3-5 weeks.

37. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 205 mg to about 400 mg of an anti-amyloid antibody or an antigen-binding fragment thereof are administered once about every 3-5 weeks, and wherein brain amyloid beta plaque is reduced in the subject.

38. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 205 mg to about 400 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered once about every 3-5 weeks, and wherein the subject is converted from amyloid positive to amyloid negative.

39. The method of any one of claims 36-38, wherein the method comprises administering about 300 mg to about 400 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

40. The method of any one of claims 36-38, wherein the method comprises administering about 350 mg to about 400 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

41. The method of any one of claims 36-38, wherein the method comprises administering about 300 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

42. The method of any one of claims 36-38, wherein the method comprises administering 350 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

43. The method of any one of claims 36-38, wherein the method comprises administering about 400 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

44. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27 wherein about 405 mg to about 700 mg of an anti-amyloid antibody or an antigen-binding fragment thereof are administered to the subject once about every 3-5 weeks.

45. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 405 mg to about 700 mg of an anti-amyloid antibody or an antigen-binding fragment thereof are administered once about every 3-5 weeks, and wherein brain amyloid beta plaque is reduced in the subject.

46. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 405 mg to about 700 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered once about every 3-5 weeks, and wherein the subject is converted from amyloid positive to amyloid negative.

47. The method of any one of claims 44-46, wherein the method comprises administering about 500 mg to about 700 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

48. The method of any one of claims 44-46, wherein the method comprises administering about 600 mg to about 700 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

49. The method of any one of claims 44-46, wherein the method comprises administering about 500 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

50. The method of any one of claims 44-46, wherein the method comprises administering 600 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

51. The method of any one of claims 44-46, wherein the method comprises administering about 700 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

52. The method of any one of claims 28-51, wherein the anti-amyloid antibody is administered once about every 4 weeks.

53. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27 wherein about 35 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks.

54. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 35 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks, and wherein brain amyloid beta plaque is reduced in a subject.

55. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 35 mg to about 100 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks, and wherein the subject is converted from amyloid positive to amyloid negative.

56. The method of any one of claims 53-55, wherein the method comprises administering about 50 mg to about 100 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

57. The method of any one of claims 53-55, wherein the method comprises administering about 100 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

58. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 100 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks.

59. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 100 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks, and wherein brain amyloid beta plaque is reduced in a subject.

60. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 100 mg to about 200 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks, and wherein the subject is converted from amyloid positive to amyloid negative.

61. The method of any one of claims 58-60, wherein the method comprises administering about 150 mg to about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

62. The method of any one of claims 58-60, wherein the method comprises administering about 200 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

63. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks.

64. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks, and wherein brain amyloid beta plaque is reduced in a subject.

65. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-27, wherein about 250 mg to about 350 mg of an anti-amyloid antibody or an antigen-binding fragment thereof is administered twice about every 3-5 weeks, and wherein the subject is converted from amyloid positive to amyloid negative.

66. The method of any one of claims 37-39, wherein the method comprises administering about 300 mg to about 350 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

67. The method of any one of claims 64-66, wherein the method comprises administering about 350 mg of the anti-amyloid antibody or antigen-binding fragment thereof.

68. The method of any one of claims 53-67, wherein the anti-amyloid antibody or antigen-binding fragment thereof is administered once about every 2 weeks.

69. The method of any one of claims 28-68, wherein the anti-amyloid antibody or anantigen-binding fragment thereof binds to an epitope located within the N-terminus of an Apeptide, and the epitope includes at least one amino acid selected from amino acids 1-10 ofthe A peptide.

70. The method of claim 69, wherein the anti-amyloid antibody or an antigen-binding fragment thereof binds to an epitope comprising at least one amino acid selected from aminoacids 1-7 of the A peptide.

71. The method of any one of claims 28-70, wherein the anti-amyloid antibody or an antigen-binding fragment thereof binds to amyloid 1-42 protofibrils with an apparent KD of about 5 nM or less.

72. The method of any one of claims 28-70, wherein the anti-amyloid antibody or an antigen-binding fragment thereof binds to amyloid 1-42 protofibrils with an apparent KD of about 1 nM or less.

73. The method of any one of claims 28-72, wherein the anti-amyloid antibody or an antigen-binding fragment thereof binds to amyloid 1-28 monomers with an apparent KD of about 10 nM or less.

74. The method of any one of claims 28-73, wherein the anti-amyloid antibody or antigen-binding fragment thereof is administered as a pharmaceutical composition comprising the anti-amyloid antibody or antigen-binding fragment thereof and a pharmaceutically acceptable diluent.

75. The method of any one of claims 28-74, wherein the administration is intravenous or subcutaneous.

76. The method of claim 75, wherein the administration is subcutaneous.

77. The method of any one of claim 28-76, wherein the anti-amyloid antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 and a light chain variable region comprising light chain CDR1, CDR2, and CDR3, wherein heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO: 3, heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO: 4, heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO: 5, light chain CDR1 comprises the amino acid sequence of SEQ ID NO: 6, light chain CDR2 comprises the amino acid sequence of SEQ ID NO: 7, and light chain CDR3 comprises the amino acid sequence of SEQ ID NO:

8.

78. The method of claim 77, wherein the heavy chain variable region, excluding the CDRs, is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region, excluding the CDRs, is at least 95% identical to the amino acid sequence of SEQ ID NO:

2.

79. The method of claim 78, wherein the heavy chain variable region, excluding the CDRs, is at least 98% identical to the amino acid sequence of SEQ ID NO: 1, and the light chain variable region, excluding the CDRs, is at least 98% identical to the amino acid sequence of SEQ ID NO: 2.

80. The method of claim 79, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:

2.

81. The method of claim 80, wherein the heavy chain variable region consists of SEQ ID NO: 1, and wherein the light chain variable region consists of the amino acid sequence of SEQ ID NO:

2.

82. The method of any one of claims 28-81, wherein the anti-amyloid antibody is a humanized IgG1.

83. The method of any one of claims 28-81, wherein the anti-amyloid antibody is a full antibody, a chimeric antibody, a CDR-grafted antibody, or a recombinant antibody.

84. The method of any one of claims 28-83, wherein the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO: 9 and / or a light chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO:

10.

85. The method of any one of claims 28-84, wherein the anti-amyloid antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO: 9 and / or a light chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO:

10.

86. The method of any one of claims 28-85, wherein the anti-amyloid antibody comprises a heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 9, with or without the C-terminal lysine, and a light chain constant region comprising an amino acid sequence of SEQ ID NO:

10.

87. The method of any one of claims 28-86, wherein the anti-amyloid antibody comprises a heavy chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 9, with or without the C-terminal lysine, and a light chain constant region consisting essentially of an amino acid sequence of SEQ ID NO: 10.

88. The method of any one of claims 28-87, wherein the anti-amyloid antibody comprises a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

89. The method of any one of claims 28-88, wherein the anti-amyloid antibody is h2731.

90. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 100 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

91. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 150 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

92. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 200 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

93. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 50 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

94. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 75 mg of an anti-amyloid antibody is administeredsubcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

95. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 100 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

96. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 200 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

97. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 100 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

98. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 300 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

99. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 350 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12.

100. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 400 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

101. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 100 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

102. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 150 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

103. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 200 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

104. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 400 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

105. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 200 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 2 weeks; the anti-amyloid antibodycomprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

106. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 500 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

107. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 600 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

108. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 700 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

109. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 350 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

110. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 500 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

111. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 600 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

112. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 700 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 4 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

113. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 350 mg of an anti-amyloid antibody is administered subcutaneously to the subject once about every 2 weeks; the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, and wherein amyloid plaque is reduced in the subject.

114. The method of treating Alzheimer’s disease in a subject according to any one ofclaims 1-25, wherein an amount of an anti-A antibody sufficient to achieve an averageconcentration over the dosing interval (Cavevalue) of about 20 μg / mL to about 40 μg / mL isadministered subcutaneously to the subject, the anti-A antibody comprising a heavy chain ofSEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO:

12.

115. The method of treating Alzheimer’s disease in a subject according to any one ofclaims 1-25, wherein an amount of an anti-A antibody sufficient to achieve an area underthe concentration-time curve for dosing interval value (AUC0-tau value) of about 15,000 hr*ug / mL to about 30,000 hr*ug / mL is administered subcutaneously to the subject, the anti-A antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminallysine, and a light chain of SEQ ID NO:

12.

116. The method of any one of claims 28-115, wherein a maximum concentration over a dosing interval (Cmax) of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 30 μg / mL to about 60 μg / mL.

117. The method of any one of claims 28-115, wherein a Cmax value of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 50 μg / mL to about 60 μg / mL.

118. The method of any one of claims 28-115, wherein a Cmaxvalue of the anti-amyloid antibody or antigen binding fragment thereof in the subject does not exceed about 60 μg / mL.

119. The method of any one of claims 116-118, wherein the Cmaxvalue is a serum Cmaxvalue.

120. The method of any one of claims 116-118, wherein the Cmax value is a plasma Cmax value.

121. The method of any one of claims 28-120, wherein a Cave value of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 20 μg / mL to about 40 μg / mL.

122. The method of any one of claims 28-120, wherein a Cavevalue of the anti-amyloid antibody or antigen binding fragment thereof in the subject is about 30 μg / mL to about 40 μg / mL.

123. The method of any one of claims 28-120, wherein a Cavevalue of the anti-amyloid antibody or antigen binding fragment thereof in the subject does not exceed about 40 μg / mL.

124. The method of any one of claims 114 and 121-123, wherein the Cave value is a serum Cave value.

125. The method of any one of claims 114 and 121-123, wherein the Cave value is a plasma Cave value.

126. The method of any one of claims 28-125, wherein an AUC0-tau value of the anti- amyloid antibody or antigen binding fragment thereof in the subject is about 15,000 hr*ug / mL to about 30,000 hr*ug / mL.

127. The method of any one of claims 28-126, wherein an AUC0-tau value of the anti- amyloid antibody or antigen binding fragment thereof in the subject is about 20,000 hr*ug / mL to about 30,000 hr*ug / mL.

128. The method of any one of claims 28-127, wherein an AUC0-tauvalue of the anti- amyloid antibody or antigen binding fragment thereof in the subject is does not exceed about 30,000 hr*ug / mL.

129. The method of any one of claims 115 and 126-128, wherein the AUC0-tauvalue is a serum AUC0-tau value.

130. The method of any one of claims 115 and 126-128, wherein the AUC0-tau value is a plasma AUC0-tau value.

131. The method of any one of claims 28-130, wherein brain amyloid beta plaque in the subject is reduced.

132. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131, wherein the reduction of brain amyloid beta plaque comprises a reduction of at least about 30 centiloids to about 70 centiloids.

133. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131, wherein the reduction of brain amyloid beta plaque comprises a reduction of from about 45 centiloids to about 80 centiloids.

134. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131, wherein the reduction of brain amyloid beta plaque comprises a reduction of about 50 centiloids to about 85 centiloids.

135. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131, wherein the reduction of brain amyloid beta plaque comprises a reduction of at least about 40% to about 90%.

136. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131, wherein the reduction of brain amyloid beta plaque comprises a reduction of from about 60% to about 100%.

137. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131, wherein the reduction of brain amyloid beta plaque comprises a reduction of about 65% to about 100%.

138. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131- 137, wherein the reduction of brain amyloid beta plaque is a reduction compared to baseline.

139. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131- 138, wherein the reduction of brain amyloid beta plaque is a reduction compared to the subject prior to the administration of the anti-amyloid antibody.

140. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131- 139, wherein the reduction of brain amyloid beta plaque is achieved after 6 months of treatment.

141. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131- 139, wherein the reduction of brain amyloid beta plaque is achieved after about 12 months of treatment.

142. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131- 139, wherein the reduction of brain amyloid beta plaque is achieved after about 18 months of treatment.

143. The method of any one of claims 29, 30, 37, 38, 45, 46, 54, 55, 59, 60, 64, 65, or 131- 142, wherein the reduction of brain amyloid beta plaque is assessed by Positron Emission Tomography (PET).

144. The method of any one of claims 28-143, wherein the subject is converted from amyloid positive to amyloid negative.

145. The method of any one of claims 28-144, wherein treating comprises increasing a probability of converting the subject from amyloid positive to amyloid negative.

146. The method of any one of claims 28-145, wherein treating comprises a probability of converting the subject from amyloid positive to amyloid negative by about 10% to about 40%.

147. The method of any one of claims 28-145, wherein treating comprises a probability of converting the subject from amyloid positive to amyloid negative by about 30% to about 60%.

148. The method of any one of claims 28-145, wherein treating comprises a probability of converting the subject from amyloid positive to amyloid negative by about 40% to about 80%.

149. The method of any one of claims 146-148, wherein the probability of converting the subject from amyloid positive to amyloid negative is a probability after about 6 months of treatment.

150. The method of any one of claims 146-148, wherein the probability of converting the subject from amyloid positive to amyloid negative is a probability after about 12 months of treatment.

151. The method of any one of claims 146-148, wherein the probability of converting the subject from amyloid positive to amyloid negative is a probability after about 18 months of treatment.

152. The method of any one of claims 28-151, wherein treating comprises slowing, halting, or reversing decline in cognitive function.

153. The method of claim 152, wherein treating comprises slowing decline in cognitive function.

154. The method of claim 152 or 153, wherein cognitive function is measured by at least one of the following CRD-SB, ADAS-Cog14, ADCOMS, and ADCS MCI-ADL.

155. The method of claim 154, wherein cognitive function is measured by ADCOMS.

156. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 45 mg to about 200 mg of an anti-amyloid antibody is administered to the subject once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, wherein a biomarker is modulated in the subject.

157. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 205 mg to about 400 mg of an anti-amyloid antibody is administered to the subject once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, wherein a biomarker is modulated in the subject.

158. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 405 mg to about 700 mg of an anti-amyloid antibody is administered to the subject once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and a light chain of SEQ ID NO: 12, wherein a biomarker is modulated in the subject.

159. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 45 mg to about 200 mg of an anti-amyloid antibody is administered to the subject once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and alight chain of SEQ ID NO: 12, wherein a ratio of A 42 / 40 is increased in a subject.

160. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 205 mg to about 400 mg of an anti-amyloid antibody is administered to the subject once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and alight chain of SEQ ID NO: 12, wherein a ratio of A 42 / 40 is increased in a subject.

161. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 405 mg to about 700 mg of an anti-amyloid antibody is administered to the subject once about every 3-5 weeks, the anti-amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C-terminal lysine, and alight chain of SEQ ID NO: 12, wherein a ratio of A 42 / 40 is increased in a subject.

162. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 45 mg to about 200 mg of an anti-amyloid antibody or antigen binding fragment thereof is administered to the subject once about every 3-5 weeks, the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12, and wherein an amount of phospho-tau is decreased in the subject.

163. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 205 mg to about 400 mg of an anti-amyloid antibody or antigen binding fragment thereof is administered to the subject once about every 3-5 weeks, the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12, and wherein an amount of phospho-tau is decreased in the subject.

164. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 405 mg to about 700 mg of an anti-amyloid antibody or antigen binding fragment thereof is administered to the subject once about every 3-5 weeks, the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12, and wherein an amount of phospho-tau is decreased in the subject.

165. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 35 mg to about 100 mg of an anti-amyloid antibody or antigen binding fragment thereof is administered to the subject twice about every 3-5 weeks, the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12, and wherein an amount of phospho-tau is decreased in the subject.

166. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 100 mg to about 200 mg of an anti-amyloid antibody or antigen binding fragment thereof is administered to the subject twice about every 3-5 weeks, the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12, and wherein an amount of phospho-tau is decreased in the subject.

167. The method of treating Alzheimer’s disease in a subject according to any one of claims 1-25, wherein about 250 mg to about 350 mg of an anti-amyloid antibody or antigen binding fragment thereof is administered to the subject twice about every 3-5 weeks, the anti- amyloid antibody comprising a heavy chain of SEQ ID NO: 11, with or without the C- terminal lysine, and a light chain of SEQ ID NO: 12, and wherein an amount of phospho-tau is decreased in the subject.

168. The method of any one of claims 156-167, wherein the administration comprises a single subcutaneous injection.

170. The method of any one of claims 28-168, wherein a biomarker in the subject is modulated.

171. The method of claim 170, wherein the biomarker in the subject is modulated compared to baseline.

172. The method of any one of claims 28-171, wherein the method further comprises detecting a biomarker in a sample collected from the subject.

173. The method of any one of claims 28-172, wherein the method further comprises quantifying a biomarker in a sample collected from the subject.

174. The method of any one of claims 156-158 and 170-173, wherein the biomarkercomprises the ratio of A 42 / 40 in the subject.

175. The method of any one of claims 159-161 and 174, wherein the ratio of A 42 / 40 inthe subject increases at least 25%.

176. The method of any one of claims 159-161 and 174, wherein the ratio of A 42 / 40 inthe subject increases at least 50%.

177. The method of any one of claims 159-161 and 174, wherein the ratio of A 42 / 40 inthe subject increases about 25% to about 100%.

178. The method of any one of claims 159-161 and 174, wherein the ratio of A 42 / 40 inthe subject increases about 50% to about 100%.

179. The method of any one of claims 156-158 and 170-173, wherein the biomarker comprises a phospho-tau value.

180. The method of any one of claims 162-167 and 179, wherein the phospho-tau value comprises at least one of the following: a p181-tau value, a p212-tau value, p217-tau value, a p231-tau value, and a p235-tau value.

181. The method of any one of claims 162-167 and 179, wherein the phospho-tau value comprises a p181-tau value.

182. The method of any one of claims 162-167 and 179, wherein the phospho-tau value comprises a p212-tau value.

183. The method of any one of claims 162-167 and 179, wherein the phospho-tau value comprises a p217-tau value.

184. The method of any one of claims 162-167 and 179, wherein the phospho-tau value comprises a p231-tau value.

185. The method of any one of claims 162-167 and 179, wherein the phospho-tau value comprises a p235-tau value.

186. The method of any one of claims 162-167 and 179-185, wherein the phospho-tau value decreases.

187. The method of any one of claims 162-167 and 185, wherein the phospho-tau value decreases at least about 10%.

188. The method of any one of claims 162-167 and 185, wherein the phospho-tau value decreases about 10% to about 30%.

189. The method of any one of claims 162-167 and 185, wherein the phospho-tau value decreases about 20% to about 30%.

190. The method of claim 172 or 173, wherein the sample comprises blood or a portion thereof collected from the subject.

191. The method of claim172 or 173, wherein the sample comprises plasma collected from the subject.

192. The method of claim 172 or 173, wherein the sample comprises serum collected from the subject.

193. The method of claim 172 or 173, wherein the sample comprises cerebral spinal fluid (“CSF”) collected from the subject.

194. The method of any one of claims 28-193, wherein the method comprises a risk of ARIA-E that is less than about 45%.

195. The method of any one of claims 28-193, wherein the method comprises a risk of ARIA-E from about 25% to about 45%.

196. The method of any one of claims 28-193, wherein the method comprises a risk of ARIA-E of less than about 75%.

197. The method of any one of claims 28-193, wherein the method comprises a risk of ARIA-E of about 50% to about 75%.

198. The method of any one of claims 28-193, wherein the method comprises a risk of symptomatic ARIA-E that is less than about 15%.

199. The method of any one of claims 28-193, wherein the method comprises a risk of symptomatic ARIA-E that is less than about 30%.

200. The method of any one of claims 194-199, wherein the risk of ARIA-E is a risk of severe ARIA-E.

201. The method of any one of claims 194-199, wherein the risk of ARIA-E is the risk after about 6 months of treatment.

202. The method of any one of claims 194-199, wherein the risk of ARIA-E is the risk after about 12 months of treatment.

203. The method of any one of claims 194-199, wherein the risk of ARIA-E is the risk after about 18 months of treatment.

204. The method of any one of claims 28-203, wherein the subject does not experience symptomatic ARIA-E during treatment.

205. The method of any one of claims 28-204, wherein the method comprises a risk of ARIA-H that is less than about 35%.

206. The method of any one of claims 28-204, wherein the method comprises a risk of ARIA-H from about 10% to about 35%.

207. The method of claim 205 or 206, wherein the risk of ARIA-H is a risk of severe ARIA-H.

208. The method of any one of claims 205-207, wherein the risk of ARIA-H is the risk after about 6 months of treatment.

209. The method of any one of claims 28-208, wherein the subject does not experience symptomatic ARIA-H during treatment.

210. The method of any one of claims 28-209, wherein the subject is an APOE4 homozygous subject.

211. The method of any one of claims 28-209, wherein the subject is an APOE4 heterozygous subject or an APOE4 noncarrier.

212. The method of any one of claims 28-211, wherein the method further comprises determining the APOE4 status of the subject prior to administration.

213. The method of any one of claims 28-212, wherein the duration of the treatment is at least 6 months.

214. The method of any one of claims 28-212, wherein the duration of the treatment is at least 12 months.

215. The method of any one of claims 28-212, wherein the duration of the treatment is at least 18 months.

216. The method of any one of claims 28-215, wherein the administration is performed using a syringe.

217. The method of any one of claims 28-215, wherein the administration is performed using an autoinjector.

218. The method of any one of claims 28-217, wherein the subject is a mammal.

219. The method of any one of claims 28-218, wherein the subject is a human.

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