METHOD OF TREATING ALZHEIMER'S DISEASE USING ANTI-N3pGlu AMYLOID BETA ANTIBODIES

Abstract

The invention pertains to a method for reducing amyloid plaques in the brain of a human suffering from a disease characterized by Aβ plaques in the brain. It also concerns the treatment or prevention of diseases characterized by Aβ deposition in the brain, such as Alzheimer's disease, Alzheimer's disease in Down syndrome, and cerebral amyloid angiopathy. Certain aspects of the invention involve methods, doses, or dosing regimens that decrease the risk, frequency, severity, or occurrence of amyloid-related imaging abnormalities (ARIA) in subjects undergoing the described treatments. These aspects ensure that while reducing ARIA-related issues, the methods still effectively remove amyloid β plaques from the subject's brain. Additionally, the methods, doses, or dosing regimens disclosed herein aim to reduce ARIA risks, frequency, severity, or events, in human subjects with one or two alleles of APOE4.

Description

METHOD OF TREATING ALZHEIMER’S DISEASE USING ANTI-N3pGluAMYLOID BETA ANTIBODIESREFERENCE TO A SEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “31247. xml” created August 12, 2025, and is 10,602 bytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] This disclosure pertains to methods, dosages, or dosing regimens aimed at reducing amyloid beta ( A|3) plaques in patients with Alzheimer's disease (AD). Additionally, it involves methods, dosages, or dosing regimens for preventing or treating conditions marked by amyloid beta (A|3) plaques. The invention also covers methods, dosages, or dosing regimens designed to lower risk, frequency, severity, or occurrence of amyloid- related imaging abnormalities (ARIA).BACKGROUND OF THE INVENTION

[0003] Donanemab-azbt (KISUNLA™) was approved by the Food and Drug Administration (FDA) on Jul 2, 2024, for the treatment of Alzheimer’s disease in patients with mild cognitive impairment or mild dementia stage of disease with the confirmed presence of amyloid-beta. The standard donanemab dosing regimen used in clinical studies for donanemab and granted approval (as well as described in the United States Prescribing Information; “USPI”) is 700 mg administered by IV infusion over 30 mins every 4 weeks for the first three doses, and 1400 mg administered by IV infusion over 30 mins every 4 weeks thereafter. KISUNLA™ dosing can be stopped based on reduction of amyloid plaques to minimal levels on amyloid PET imaging.

[0004] Finding a treatment for Alzheimer's disease (AD) is one of our society’s most critical unmet needs. The formation of amyloid-|3 peptide into brain amyloid plaques marks an early and essential step in Alzheimer's disease, leading to neurodegeneration and eventually clinical symptoms such as cognitive and functional impairment.

[0005] Amyloid beta results from the proteolytic cleavage of a larger glycoprotein called amyloid precursor protein (APP). APP is an integral membrane protein found in many tissues, especially neurotransmitter synapses. APP is cleaved by y-secretase to release theAp peptide, which comprises peptides ranging from 37-49 amino acid residues. Ap monomers aggregate into structures including oligomers, protofibrils, and amyloid fibrils. Soluble amyloid oligomers can spread throughout the brain, while larger, insoluble amyloid fibrils further aggregate to form amyloid plaques. The amyloid plaques in humans include a diverse mixture of Ap peptides, some undergoing N-terminal truncations and modifications like an N-terminal pyroglutamate residue (pGlu). N3pGlu Ap (also called N3pG Ap, N3pE Ap, Ap pEs-42, or Ap PG3-42) is a truncated form found only in amyloid plaques, lacking the first two amino acid residues at the N-terminus and having a pyroglutamate derived from glutamic acid at the third position. Although a minor component, N3pGlu Ap peptide aggressively aggregates and accumulates early.

[0006] Chronic antibody administration against Ap, including N3pGlu Ap, has been shown to disrupt Ap aggregates and clear plaques in animal models. Antibodies to N3pGlu Ap exist in the art. For instance, U.S. Patent No. 8,679,498 discloses anti-N3pGlu Ap antibodies and methods of treating diseases like AD. Donanemab, disclosed in U.S. Patent No. 8,679,498, targets the pyroglutamate modification of the third amino acid of amyloid beta (N3pGlu AP) specific to brain amyloid plaques.

[0007] Donanemab’ s treatment strategy involves targeting N3pGlu Ap in early symptomatic AD patients with existing brain amyloid load, based on the amyloid hypothesis of AD which posits that Ap production and deposition is an early necessary event in AD pathogenesis. However, sometimes anti-Ap antibody (e.g., amyloid-targeted therapy) administration leads to adverse effects like amyloid-related imaging abnormalities (ARIA), vasogenic edema, microhemorrhages, infusion-related reactions, hypersensitivity, and immunogenicity. The exact cause of ARIA is unclear, but it is believed that antibody treatment disrupts the blood-brain barrier through interaction with cerebral vascular amyloid, leading to a leaky barrier and patient edema in some instances.

[0008] Given the serious nature and the few disease-modifying treatments for AD, there is an unmet need for finding measures that minimize risk of adverse effects without compromising on efficacy. Thus, there remains a need for improved doses, dosing regimens, or methods to treat subjects without exacerbating adverse events or cause a reduction in adverse events.SUMMARY OF THE INVENTION

[0009] One aspect of the present disclosure provides for methods, doses, or dosing regimens of the anti-N3pG Ap antibodies for prevention or treatment of Alzheimer’s disease. Insome embodiments, the methods, doses, or dosing regimens of the present invention reduce ARIA in human subjects suffering from AD. In some embodiments, the methods, doses, or dosing regimens reduce ARIA risk, ARIA frequency, ARIA severity, or ARIA events associated with amyloid-targeted therapy in the human subject. In some embodiments, the methods, doses, or dosing regimens cause no change or minimal change in the rate of reduction of Ap plaques in the human subject (e.g., when compared to standard dosing regimen, wherein the subject is administered three doses of 700 mg of the anti-N3pG A antibody at a frequency of once every 4 weeks, and, four weeks after the administration of the 700 mg dose, the subject is administered one or more doses of 1400 mg of the anti-N3pG Ap antibody at a frequency of once every 4 weeks).

[0010] One aspect of the present invention is related to a method of reducing amyloid beta (AP) plaques in the brain of a human subject suffering from Alzheimer’ s disease (AD) comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0011] Another aspect of the present invention is related to a method of reducing ARIA risk, ARIA frequency, ARIA severity, or ARIA events in a human subject wherein the subject’s brain has amyloid beta (AP) plaques, or the subject is suffering from Alzheimer’s disease comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu AP antibody comprises a light chain variable region (LCVR) and a heavychain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0012] Another aspect of the present invention is related to a method of treating or preventing Alzheimer’s disease (AD) in a human subject comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG A[3 antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG A[ antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A[ antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG A|3 antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu A|3 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0013] Another aspect of the present invention is related to a method of slowing disease progression in a human subject suffering from Alzheimer’s disease, comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG A[3 antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A[3 antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti- N3pG A[3 antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu A antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0014] In some embodiments, the methods, doses, or dosing regimens disclosed herein reduce the risk of ARIA, ARIA frequency, ARIA severity, or ARIA events in human subjects associated with amyloid-targeted therapy. In some embodiments, the human subjects who are administered the anti-N3pG Ap antibody of the present disclosure are at high-risk of ARIA. In some embodiments, the high-risk human subjects are those that have at least one APOE4 allele, have two APOE4 alleles, have cerebral amyloid angiopathy (CAA),microhemorrhages, or superficial siderosis. In some embodiments, the high-risk human subjects are those that have a genetic mutation leading to high risk of AD.

[0015] The antibodies of the present disclosure bind selectively to N3pGlu A| found primarily in deposited A[3 plaque in human subjects. The prevalence of the N3pGlu Ap peptide in deposited parenchymal plaque is very low relative to other Ap peptide species (~1 to 2%) where the majority is full-length AP1-42. Thus, the total number of binding sites for the antibodies of the present disclosure relative to other plaque binding Ap antibodies is dramatically lower. Biochemical analysis of CAA, the amyloid depositing along CNS blood vessels, demonstrated a similar low prevalence of N3pGlu peptides (~2%). The methods, doses, or dosing regimens described in the present invention achieve effective dose levels with lower incidence rates of adverse events, such as ARIA, compared to other methods, doses, or dosing regimens known in the art. The anti-N3pGlu Ap antibodies and their dosing protocols detailed in this disclosure promote rapid brain amyloid clearance while minimizing the risk, occurrence, and / or severity of ARIA. Clinical studies have shown that the doses, dosing regimens, and methods outlined herein result in rapid amyloid plaque removal from patient’s brains while reducing the risk, occurrence, and / or severity of ARIA.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 shows the distribution of ARIA-E maximum radiographic severity across the 4 treatment arms. The treatment arms are described in Example 1 (e.g., in Table 3).

[0017] Figure 2 shows amyloid PET changes in study AACQ at week 24.

[0018] Figure 3 shows plasma P-tau-217 levels in study AACQ through week 24.

[0019] Figure 4 shows an embodiment of the study design for Study AACQ extension.

[0020] Figure 5 shows the clinical trial dosing scheme for Study AACM of treatment with donanemab in cognitively unimpaired participants with evidence of AD pathology for preclinical Alzheimer’s disease. “SP” is the Study Period, of which there are four total; superscript “a” is the duration of each Study Period, and superscript “b” is the time measurement in weeks for each part of the dosing scheme, reset to “0” once the participant enters a new Study Period. “Q4W” is every 4 weeks, “Q52W” is once every 52 weeks, “Q12M” is once every 12 months, and “SP IV” refers to the treatment extension or maintenance dosing period within the fourth Study Period of the trial.DETAILED DESCRIPTION OF THE INVENTION

[0021] In some aspects, the methods, doses, or dosing regimens of the present disclosure are related to reducing Ap plaques or A[3 load, preventing memory loss, and slowing or preventing cognitive / functional decline in a patient having a disease characterized by A |B plaques. Some aspects of the present disclosure are related to a method of treating or preventing a disease characterized by A plaques in a human subject comprising administering to the subject an anti-N3pGlu Ap antibody as a means to reduce Ap plaques. Such treatment results in decrease or reduction in the amyloid deposits, amyloid beta plaques, or Ap load in brain of the patient.

[0022] In some embodiments, such treatment results in decrease or reduction in the tau levels in brain of the patient, decrease or reduction in plasma tau levels, or slowing of accumulation of tau pathophysiology, as measured by brain tau PET and / or blood plasma P-tau. In some embodiments, the treatment results in decrease or reduction in P-tau levels in a patient.

[0023] In some embodiments, the methods, doses, or dosing regimens of the present disclosure are related to a method of preventing or delaying onset of symptomatic stages of AD in clinically asymptomatic subjects or cognitively unimpaired subjects with evidence of AD pathology. In some embodiments, the present disclosure is related to a method of treating or preventing a disease characterized by Ap plaques in a human subject wherein the human subject is clinically asymptomatic. The clinically asymptomatic subjects have an Alzheimer’s disease-causing genetic mutation, such as a PSEN1 E280A Alzheimer's disease-causing genetic mutation (Paisa mutation), a genetic mutation that causes autosomal-dominant Alzheimer’s disease, Down syndrome, or are at higher risk for developing AD by virtue of carrying one or two APOE4 alleles. In some embodiments, the methods, doses, or dosing regimens of the present disclosure are related to a method of treating or preventing a disease characterized by amyloid [3 plaques in the brain of a human subject who has been determined to have one or two alleles of APOE4.

[0024] The anti-N3pG A [3 antibodies described in various aspects of the present disclosure include:• an anti-N3pGlu A|3 antibody comprising: light chain complementarity determining region 1 (LCDR1) having an amino acid sequence of SEQ ID NO: 5, light chain complementarity determining region 2 (LCDR2) having an amino acid sequence of SEQ ID NO: 6, and light chain complementarity determiningregion 3 (LCDR3) having an amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 95% homology to light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 5, an amino acid sequence having at least 95% homology to light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, and an amino acid sequence having at least 95% homology to light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 7;• an anti-N3pGlu A0 antibody comprising: heavy chain complementarity determining region 1 (HCDR1) having an amino acid sequence of SEQ ID NO: 8, heavy chain complementarity determining region 2 (HCDR2) having an amino acid sequence of SEQ ID NO: 9, and heavy chain complementarity determining region 3 (HCDR3) having an amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10;• an anti-N3pGlu A0 antibody comprising: light chain complementarity determining region 1 (LCDR1) having an amino acid sequence of SEQ ID NO: 5, light chain complementarity determining region 2 (LCDR2) having an amino acid sequence of SEQ ID NO: 6, light chain complementarity determining region 3 (LCDR3) having an amino acid sequence of SEQ ID NO: 7, heavy chain complementarity determining region 1 (HCDR1) having an amino acid sequence of SEQ ID NO: 8, heavy chain complementarity determining region 2 (HCDR2) having an amino acid sequence of SEQ ID NO: 9, and heavy chain complementarity determining region 3 (HCDR3) having an amino acid sequence of SEQ ID NO: 10 or amino acid sequence having at least 95% homology to light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 5, amino acid sequence having at least 95% homology to light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, amino acid sequence having at least 95% homology to light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 7, amino acidsequence having at least 95% homology to heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, amino acid sequence having at least 95% homology to heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and amino acid sequence having at least 95% homology to heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10;• an anti-N3pGlu Af> antibody comprising: a LCVR and a HCVR, wherein said LCVR comprises: LCDR1, LCDR2 and LCDR3 and HCVR comprises HCDR1, HCDR2 and HCDR3, which are selected from the group consisting of: LCDR1 is SEQ ID NO: 5, LCDR2 is SEQ ID NO: 6, LCDR3 is SEQ ID NO: 7, HCDR1 is SEQ ID NO: 8, HCDR2 is SEQ ID NO: 9, and HCDR3 is SEQ ID NO: 10; or a LCVR and a HCVR, wherein said LCVR comprises LCDR1, LCDR2 and LCDR3 and HCVR comprises HCDR1, HCDR2 and HCDR3, which are selected from the group consisting of: LCDR1 having at least 95% homology to SEQ ID NO: 5, LCDR2 having at least 95% homology to SEQ ID NO: 6, LCDR3 having at least 95% homology to SEQ ID NO: 7, HCDR1 having at least 95% homology to SEQ ID NO: 8, HCDR2 having at least 95% homology to SEQ ID NO: 9, and HCDR3 having at least 95% homology to SEQ ID NO: 10;• an N3pGlu A [3 antibody comprising a light chain (LC) comprising: the amino acid sequence of SEQ ID NO: 3 or amino acid sequence having at least 95% homology to SEQ ID NO: 3;• an N3pGlu A|3 antibody comprising a heavy chain (HC) comprising: the amino acid sequence of SEQ ID NO: 4 or amino acid sequence having at least 95% homology to SEQ ID NO: 4;• an anti-N3pGlu A0 antibody comprising a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 3 and the HC comprises the amino acid sequence of SEQ ID NO: 4, or wherein the LC comprises amino acid sequence having at least 95% homology to SEQ ID NO: 3 and the HC comprises amino acid sequence having at least 95% homology to SEQ ID NO: 4;• an anti-N3pGlu Af> antibody comprising two light chains and two heavy chains, wherein the LC comprises amino acid sequence of SEQ ID NO: 3or amino acid sequence having at least 95% homology to SEQ ID NO: 3, and the HC comprises the amino acid sequence of SEQ ID NO: 4 or amino acid sequence having at least 95% homology to SEQ ID NO: 4;• an N3pGlu A [3 antibody comprising a LCVR comprising the amino acid sequence of SEQ ID NO: 1 or amino acid sequence having at least 95% homology to SEQ ID NO: 1 ;• an N3pGlu A|3 antibody comprising a HCVR comprising the amino acid sequence of SEQ ID NO: 2 or amino acid sequence having at least 95% homology to SEQ ID NO: 2;• an N3pGlu A[i antibody comprising a LCVR and a HCVR wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 or amino acid sequence having at least 95% homology to SEQ ID NO: 1; and the HCVR comprises the amino acid sequence of SEQ ID NO: 2 or amino acid sequence having at least 95% homology to SEQ ID NO: 2; or• the anti-N3pG Ap antibodies as described in U.S. Patent Nos. 8,679,498 or 8,961,972, which are hereby incorporated by reference in their entireties.

[0025] In some embodiments, the anti-N3pGlu A antibody is administered intravenously. In some embodiments, the anti-N3pGlu AP antibody is administered subcutaneously.

[0026] In some embodiments, the subject has a disease characterized by Ap deposits / plaques in the brain. The methods, doses, or dosing regimens of the present invention can be used for subject suffering from preclinical Alzheimer’s disease, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, AD due to Down syndrome, clinical cerebral amyloid angiopathy, or pre-clinical cerebral amyloid angiopathy. In some embodiments, the subject is an early symptomatic AD patient. In some embodiments, the subject has prodromal AD and / or mild dementia due to AD. Some aspects of the present disclosure provide for human subjects that are responsive to treatment or prevention of a disease characterized by amyloid beta plaques in the brain of a human subject. In some embodiments, the anti- N3pGlu Ap antibody of the present disclosure is administered to the responsive human subjects for treatment or prevention of a disease characterized by amyloid beta plaques in the brain of a human subject. In some embodiments, the anti-N3pGlu Ap antibody of the present disclosure is administered to the human subjects for treatment or prevention of a disease characterized by amyloid beta plaques in the brain of a human subject. In some embodiments, the present disclosure is related to a method of treating or preventingpreclinical AD (cognitively unimpaired subjects with evidence of AD pathology), prodromal AD (sometimes also referred to as Ap-related mild cognitive impairment, MCI, or MCI due to AD), mild AD, moderate AD and severe AD. In some embodiments, the subject according to the methods or dosing regimens of the present invention has early symptomatic Alzheimer’s disease. In some embodiments, the subject according to the methods or dosing regimens of the present invention has mild cognitive impairment or mild dementia stage of Alzheimer’s disease. In some embodiments, the subject according to the methods or dosing regimens of the present invention has preclinical Alzheimer’ s disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, or severe AD.

[0027] One aspect of the present invention is related to a method of reducing amyloid beta ( A[3) plaques in the brain of a human subject suffering from Alzheimer’ s disease (AD) comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; hi) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0028] In some aspects, the present invention is related to an anti-N3pG Ap antibody for use in reducing amyloid beta (AP) plaques in the brain of a human subject suffering from Alzheimer’s disease (AD) comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of-l ithe amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0029] In some aspects, the present invention is related to use of an anti-N3pGlu A 0 antibody in the manufacture of a medicament for reducing amyloid beta (A0) plaques in the brain of a human subject suffering from Alzheimer’s disease (AD) comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG A0 antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG A0 antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A [3 antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG A0 antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu A0 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0030] Another aspect of the present invention is related to a method of reducing ARIA risk, ARIA frequency, ARIA severity, or ARIA events in a human subject wherein the subject’s brain has amyloid beta (A0) plaques, or the subject is suffering from Alzheimer’s disease comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG A[3 antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG A0 antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A0 antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG A0 antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu A0 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0031] In some aspects, the present invention is related to an anti-N3pG A|3 antibody for use in reducing ARIA risk, ARIA frequency, ARIA severity, or ARIA events in a human subject wherein the subject’s brain has amyloid beta (A0) plaques, or the subject is suffering from Alzheimer’s disease comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG A0 antibody; ii) about four weeks after administration ofthe 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Af> antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A > antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu A antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0032] In some aspects, the present invention is related to use of an anti-N3pGlu Ap antibody in the manufacture of a medicament for reducing ARIA risk, ARIA frequency, ARIA severity, or ARIA events in a human subject wherein the subject’s brain has amyloid beta (AP) plaques, or the subject is suffering from Alzheimer’s disease comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti- N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0033] Another aspect of the present invention is related to a method of treating or preventing Alzheimer’s disease (AD) in a human subject comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region(HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0034] Another aspect of the present invention is related to an anti-N3pG A|3 antibody for use in treating Alzheimer’s disease (AD) in a human subject comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG A | antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu AP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0035] Another aspect of the present invention is related to use of an anti-N3pGlu AP antibody in the manufacture of a medicament for treating Alzheimer’s disease (AD) in a human subject comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0036] Another aspect of the present invention is related to a method of slowing disease progression in a human subject suffering from Alzheimer’s disease, comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg ofthe anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti- N3pG A antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0037] Another aspect of the present invention is related to an anti-N3pG Ap antibody for use in slowing disease progression in a human subject suffering from Alzheimer’s disease, comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG AP antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0038] Another aspect of the present invention is related to use of an anti-N3pGlu Ap antibody in the manufacture of a medicament for slowing disease progression in a human subject suffering from Alzheimer’s disease, comprising: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

[0039] Another aspect of the present invention is related to a method of treating or preventing preclinical AD. In some embodiments, the method comprises: i) administering to thesubject a dose of about 350 mg of an anti-N3pG A0 antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti- N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one dose of about 1400 mg of the anti-N3pG Ap antibody; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject two doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti- N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG AP antibody;iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A0 antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject three doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu A antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG AP antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject four doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject five doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti- N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG AP antibody; and iv) about four weeks after theadministration of the 1050 mg dose, administering to the subject six doses of about 1400 mg of the anti-N3pG AP antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu A antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, a subject is suffering from preclinical AD or is at risk of preclinical AD. In some embodiments, the subject has preclinical AD and is administered 1 dose of about 350 mg, 1 dose of about 700 mg, 1 dose of about 1050 mg, and 6 doses of about 1400 mg of the antibody at the frequency of one dose every 4 weeks.

[0040] Another aspect of the present invention is related to a method of treating or preventingAD in subjects with Down syndrome, Dominantly Inherited AD (DIAD), or Autosomal Dominant AD (AD AD). In some embodiments, the method of treating or preventing AD in subjects with Down syndrome, DIAD, or AD AD comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, a subject is suffering from Down syndrome or is at risk of Down syndrome. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject one dose of about 1400 mg of the anti-N3pG Ap antibody; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists ofthe amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG A0 antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG A antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject two doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti- N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject three doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject four doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG APantibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG A[3 antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject five doses of about 1400 mg of the anti-N3pG A antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti- N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the method comprises: i) administering to the subject a dose of about 350 mg of an anti-N3pG AP antibody; ii) about four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; iii) about four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and iv) about four weeks after the administration of the 1050 mg dose, administering to the subject six doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose about every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: I and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, this aspect of the method includes administering a total of six doses of 1400 mg of the anti-N3pG Ap to the subject at a frequency of about every four weeks.

[0041] Table 1 provided below describes some dosing regimens of the anti-N3pG Ap antibodies of the present invention. The dosing regimen includes regimens where the dosing with 1400 mg of the antibody may continue further for about 52, 72, or 76 weeks. In some embodiments, the dosing regimen includes regimens where the dosing with 1400 mg of the antibody may continue further for about 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years or 4 years.Table 1:

[0042] In some embodiments, the dosing regimen of the anti-N3pG A [3 antibody of the present invention is as shown in the Titration dosing regimen of Table 1. In some embodiments, the dosing regimen of the anti-N3pG A|3 antibody of the present invention is as shown in the Standard dosing regimen of Table 1.

[0043] In certain embodiments, the reduction rate of amyloid plaques in a patient receiving the anti-N3pG A0 antibody dosing regimen (e.g., the Titration dosing regimen in Table 1) described herein is comparable to, matches, or exceeds that of a patient following the standard dosing regimen (refer to Table 1 for details on the standard regimen). In some embodiments, the reduction rate for patients on the dosing regimens of the present invention is comparable to, matches, or exceeds that of those on the skipping dosing regimen (refer to Table 1 for details on the skipping regimen). Additionally, the dosing regimen of the present invention shows a reduction rate that is comparable to, matches, or exceeds that seen in patients administered the Cmax dosing regimen (refer to Table 1 for details on the Cmax regimen).

[0044] Amyloid 0 burden in the human brain can be used to determine whether administration of the anti-N3pGlu A0 antibody or the dosing regimen should be discontinued. For instance, slowing in rate of removal of A|3, a stop in reduction of A0 levels, prevention of further increase in A [3 levels, or slowing of the rate of A0 accumulation in the brain can be used as metric to determine the duration of administration of the anti-N3pGlu A[3 antibody. In some embodiments, administration of the anti-N3pGlu A0 antibody of the present disclosure is stopped if A|3 plaques in the brain of the subject reach normal levels (i.e., amyloid levels are visually negative on a PET scan) or A0 plaques level in the brain of the subject stop reducing. In some embodiments, the anti-N3pG A0 antibody is administered until A [3 plaques present in the subject’s brain are cleared (i.e., the amyloid levels are <24 CL as determined by positron emission tomography, PET, optionally with 18 F florbetapir), within normal range (i.e., amyloid levels are visually negative on a PET scan), at minimal levels (i.e., the amyloid levels are <11 CL), or stop reducing (i.e., thepatient does not experience further reduction in amyloid levels or the amyloid levels reach a plateau). In some embodiments, the 1400 mg dose of anti-N3pG AP antibody of the present invention is administered until A plaques present in the subject’s brain are cleared (i.e., the amyloid levels are <24 CL), within normal range (i.e., amyloid levels are visually negative on a PET scan), at minimal levels (i.e., the amyloid levels are <11 CL), or stop reducing (i.e., the patient does not experience further reduction in amyloid levels or the amyloid levels reach a plateau). In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 25 to about 150 centiloids reduction in amyloid plaque in the brain of the subject. See, e.g., Klunk et al., “The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET,” Alzheimer’s & Dementia 11.1 : 1-15 (2015) and Navitsky et al., “Standardization of Amyloid Quantitation with Florbetapir Standardized Uptake Value Ratios to the Centiloid Scale,” Alzheimer’s & Dementia 14.12: 1565-1571 (2018), which are hereby incorporated by reference in their entireties.

[0045] In certain embodiments, the anti-N3pG Ap antibody is administered over a period not exceeding about 24, 52, 72, or 76 weeks, with an optional frequency of about once every 4 weeks. In other scenarios, the 1400 mg dose of the anti-N3pG Ap antibody may be delivered within those same time frames at the same frequency. Additionally, in some embodiments, the administration of anti-N3pG Ap antibody extends up to about I, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 years, optionally with doses (e.g., 1400 mg dose of the antibody) given about every 4 weeks. Similarly, the 1400 mg dose can also be administered for these extended durations. Furthermore, the anti-N3pGlu Ap antibody can be given over approximately about 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, or 76 weeks. The anti-N3pGlu Ap antibody may also be administered over approximately about 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, or 120 weeks in specific cases.

[0046] In some embodiments, the human subject being administered the dosing regimen of the anti-N3pG Ap antibody of the present invention has i) a lower risk of ARIA, ARIA frequency, lower severity of ARIA, and / or lower number of ARIA events than a human subject being administered the standard dosing regimen of the anti-N3pG Ap antibody, and / or ii) a rate of reduction of amyloid plaques that is not lower than a human subject being administered the standard dosing regimen of the anti-N3pG Ap antibody. In some embodiments, the human subject being administered the dosing regimen of the anti-N3pG AP antibody of the present invention has i) a lower risk of ARIA, ARIA frequency, lowerseverity of ARIA, and / or lower number of ARIA events than a human subject being administered the skipping dosing regimen of the anti-N3pG AP antibody, and / or ii) a rate of reduction of amyloid plaques that is not lower than a human subject being administered the skipping dosing regimen of the anti-N3pG A antibody. In some embodiments, the human subject being administered the dosing regimen of the anti-N3pG Ap antibody of the present invention has i) a lower risk of ARIA, lower severity of ARIA, ARIA frequency, and / or lower number of ARIA events than a human subject being administered the Cmax dosing regimen of the anti-N3pG Ap antibody, and / or ii) a rate of reduction of amyloid plaques that is not lower than a human subject being administered the Cmax dosing regimen of the anti-N3pG Ap antibody.

[0047] In some embodiments, the methods, doses, or dosing regimens disclosed herein reduce the risk of ARIA, ARIA frequency, ARIA severity, or ARIA events in human subjects, e.g., in subjects having a disease characterized by Ap plaques or in subjects being treated with the anti-N3pG Ap antibodies of the present invention.

[0048] Certain human subjects have a high-risk of ARIA due to various factors. In some embodiments, the high-risk human subjects are those that have at least one APOE4 allele, have two APOE4 alleles, have cerebral amyloid angiopathy (CAA), microhemorrhages, or superficial siderosis. In some embodiments, the human subjects who have high risk of ARIA can be treated by the methods, doses, or dosing regimens described here. Such treatment can result in reduction in i) risk of ARIA, ii) incidence of ARIA, or iii) severity of ARIA in those high-risk patients upon treatment with the anti-N3pG Ap antibodies.

[0049] In some embodiments, the methods or the dosing regimens described here in further include a step of evaluating the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events. A brain MRI scan may be administered to the human subject to monitor / evaluate a human subject (e.g., for ARIA-edema (ARIA-E) or ARIA-hemosiderin deposits (ARIA-H)). In some embodiments, a brain MRI scan can be administered to the human subject to diagnose / evaluate / monitor adverse event(s) caused by administration of anti-N3pGlu Ap antibody, e.g., ARIA. In some embodiments, the human subject is administered a brain MRI scan in between administration of doses of the anti-N3pGlu Ap antibody (e.g., about once every 4 weeks). In some embodiments, a baseline brain MRI is obtained prior to initiating treatment with the anti-N3pGlu Ap antibodies. In some embodiments, the human subject is administered a brain MRI scan after the first dose of the anti-N3pGlu AP antibody. In some embodiments, the step includes evaluation of thesubject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events a) before or after the administration of each dose; b) after the administration of 350 mg dose; c) after the administration of 700 mg dose; d) after the administration of 1050 mg dose; or e) after the administration of 1400 mg dose. In some embodiments, the step includes evaluation of the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks after the initiation of the administration of the anti- N3pG A antibody. In some embodiments, the step includes evaluation of the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events about 4 weeks after the initiation of the administration of the anti-N3pG Ap antibody. In some embodiments, the step includes evaluation of the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events about 12 weeks after the initiation of the administration of the anti-N3pG A antibody. In some embodiments, the step includes evaluation of the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events about 24 weeks after the initiation of the administration of the anti-N3pG Ap antibody. In some embodiments, the step includes evaluation of the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events a) before the administration of the 350 mg dose; b) after the administration of the 350 mg dose and before administering the 700 mg dose; c) after the administration of the 700 mg dose and before administering the 1050 mg dose; d) after the administration of the 1050 mg dose and before administering the 1400 mg dose; or e) after the administration of the 1400 mg dose.

[0050] In some embodiments, the step of evaluating the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events includes i) evaluating the subject’s brain’s magnetic resonance image (MRI); and / or ii) evaluating the subject after the subject presents with symptoms consistent with or suggestive of ARIA.

[0051] In some aspects, the methods, doses, or dosing regimens of the present disclosure are related to a method of treating Alzheimer’s disease in a subject in need thereof until symptoms consistent with ARIA-E occur. In certain aspects, the methods or dosing regimens of this invention may be modified based on whether the subject has ARIA or exhibits symptoms indicative of ARIA. If ARIA is present or symptoms of ARIA occur, administration of the anti-N3pG Ap antibody may be stopped, and / or corticosteroids may be given to the subject. Alternatively, treatment might be paused until ARIA symptoms resolve or MRI scans show stabilization. Upon stabilization, the anti-N3pGlu Ap antibody administration can resume. Some examples of the corticosteroids include dexamethasone,methylprednisolone, and prednisone. The corticosteroids may be administered intravenously or orally.

[0052] ARIA can manifest as ARIA-E (ARIA-edema) or ARIA-H (ARIA-hemosiderin deposit). In some embodiments, moderate, severe, or symptomatic ARIA-E could lead to stopping or pausing treatment with anti-N3pGlu Ap antibodies. In some embodiments, for mild or moderate asymptomatic ARIA-E treatment might only be interrupted temporarily or reduced from 1400 mg to a lower dose temporarily (e.g., 350 mg, 700 mg, or 1050 mg). In some embodiments, supportive care like corticosteroids may be administered. Once ARIA symptoms subside or MRI stabilization is observed, treatments may resume.

[0053] When ARIA-H occurs, it typically appears alongside ARIA-E and is managed similarly. A brain MRI may be required before increasing dose from a lower dose to a higher dose or if ARIA-H symptoms surface. Supportive care, including corticosteroids, could also be given. Treatment resumption can follow upon symptom improvement or radiographic confirmation of ARIA resolution.

[0054] In some embodiments, the antibody of the present disclosure is administered to the subject until there is a reduction in the level of Ap plaque in the brain of the subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, or 70% as measured by amyloid PET imaging.

[0055] In some embodiments, the antibody of the present disclosure is administered to the subject until there is a reduction in the level of Ap plaque in the brain of the subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, or 70% as measured by amyloid PET imaging within 24 weeks from the initiation of the treatment with the anti-N3pG Ap antibody. In some embodiments, the antibody of the present disclosure is administered to the subject until there is a reduction in the level of Ap plaque in the brain of the subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, or 70% as measured by amyloid PET imaging within 52 weeks from the initiation of the treatment with the anti-N3pG Ap antibody. In some embodiments, the antibody of the present disclosure is administered to the subject until there is a reduction in the level of Ap plaque in the brain of the subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, or 70% as measured by amyloid PET imaging within 72 weeks from the initiation of the treatment with the anti-N3pG Ap antibody. In some embodiments, the antibody of the present disclosure is administered to the subject until there is a reduction in the level of Ap plaque in the brain of the subject by at least about 10%, 20%, 30%, 40%, 50%, 60%, or 70% as measured by amyloid PETimaging within 76 weeks from the initiation of the treatment with the anti-N3pG A|3 antibody. In some embodiments, the reduction of the AP plaques in the brain in achieved in 24 weeks from the initiation of the treatment with the anti-N3pG A antibody. In some embodiments, the reduction of the Ap plaques in the brain in achieved in about 24-76 weeks from the initiation of the treatment with the anti-N3pG Ap antibody.L0056J In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 25 to about 150 centiloids reduction in Ap plaques in the brain of the subject as measured by PET. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140 or about 150 centiloids (CL) reduction in AP deposit in the brain of the subject as measured by PET. In some embodiments, the reduction of the Ap plaques in the brain in achieved in about 24, about 52 weeks, about 72 weeks, or about 76 weeks from the initiation of the treatment with the anti-N3pG Ap antibody. In some embodiments, the reduction of the Ap plaques in the brain in achieved in about 24-76 weeks from the initiation of the treatment with the anti-N3pG Ap antibody.

[0057] In some embodiments, the antibody of the present disclosure is administered to the subject until there is an average of about 25 to about 150 centiloids reduction in Ap deposit in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is an average of about 25 to about 150 centiloids reduction in Ap deposit in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is an average of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 centiloids reduction in Ap deposit in the brain of the subject. In some embodiments, the reduction of the Ap plaques in the brain in achieved in about 24 weeks from the initiation of the treatment with the anti-N3pG Ap antibody. In some embodiments, the reduction of the Ap plaques in the brain in achieved in about 24-76 weeks from the initiation of the treatment with the anti- N3pG Ap antibody.

[0058] In some embodiments, the methods or the dosing regimens of the present invention reduce Ap plaques by about an average of about 25 centiloids (CL) to about 150 centiloids as compared to Ap plaques prior to administering the anti-N3pGlu Ap antibody, wherein the AP plaques are measured by amyloid PET imaging scan. In some embodiments, themethods or the dosing regimens of the present invention result in LS Mean Change reduction in AP plaques by about 40-60 centiloids from baseline over about 24 weeks, wherein the Ap plaques are measured by amyloid PET imaging scan. In some embodiments, the methods or the dosing regimens of the present invention result in LS Mean Change reduction in Ap plaques by about 56.3 centiloids from baseline over 24 weeks, wherein the Ap plaques are measured by amyloid PET imaging scan. In some embodiments, the anti-N3pG Ap antibody of the present invention is administered according to the dosing regimens described herein and about 24 weeks of administering the anti-N3pGlu Ap antibody reduces the Ap plaque by at least 50% to 80%. In some embodiments, the anti-N3pG Ap antibody of the present invention is administered according to the dosing regimens described herein and about 24 weeks of administering the anti-N3pGlu Ap antibody reduces the Ap plaque by at least 60% to 70%. In some embodiments, the anti-N3pG Ap antibody of the present invention is administered according to the dosing regimens described herein and about 24 weeks of administering the anti-N3pGlu Ap antibody reduces the Ap plaque by at least 67.5%.

[0059] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in reduction of Ap plaques in the brain of a human subject. In some embodiments, the Ap plaques are reduced by about 20-100% post treatment. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 20-100% reduction in Ap plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until the Ap plaques in the brain of the subject are reduced by about 20%, 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%, or about 100%. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 20% reduction in Ap plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 25% reduction in Ap plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 30% reduction in Ap plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 35% reduction in Ap plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject untilthere is about 40% reduction in A|3 plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 50% reduction in A plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 75% reduction in Ap plaques in the brain of the subject. In some embodiments, the antibody of the present disclosure is administered to the subject until there is about 100% reduction in Ap plaques in the brain of the subject.

[0060] In some embodiments, the level of Ap plaques in the brain of the subject is sustained at normal levels for at least about 52 weeks after the administration of the anti-N3pGlu Ap antibody is stopped. In some embodiments, administering the anti-N3pGlu Ap antibody reduces the level of AP plaques in the brain of the subject to normal levels by about 24 weeks. In some embodiments, the level of Ap plaques in the brain of the subject is sustained at normal levels for at least about 52 additional weeks.

[0061] In some embodiments, the subject has a baseline MMSE (Mini-Mental State Exam) score of 20 to 28 prior to administering the anti-N3pGlu Ap antibody.

[0062] In some embodiments, the administration of the anti-N3pG Ap antibody, the methods, or the dosing regimens: a) slow disease progression by at least about 15% as compared to being untreated estimated by Disease Progression Model (DPM), wherein disease progression is measured by iADRS or CDR-SB; b) slow disease progression by at least 15% as compared to being untreated estimated by a mixed-model repeated-measures analysis (MMRM), wherein disease progression is measured by iADRS or CDR-SB; c) slow disease progression by at least about 15% as compared to being untreated, wherein disease progression is measured by Integrated Alzheimer’s disease Rating Scale (iADRS); d) slow disease progression by at least 3 as compared to being untreated, wherein disease progression is measured by Integrated Alzheimer’s disease Rating Scale (iADRS); e) slow disease progression by at least about 20% as compared to being untreated, wherein the disease progression is measured by Clinical Dementia Rating Scale - Sum of Boxes (CDR- SB) g) reduce plasma P-tau-217 by at least about 5% from baseline.

[0063] In some embodiments, the present disclosure results in about 15 to about 50 percent slowing of decline in the cognitive-functional composite endpoints from baseline. In some embodiments, the present disclosure results in about 15 to about 50 percent slowing of decline in the cognitive-functional composite endpoints from baseline over a duration of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks.

[0064] In some embodiments, the present disclosure results in about 15 to about 50 percent slowing of decline in the cognitive-functional composite endpoints from baseline over a duration of 76 weeks. In some embodiments, the slowing of decline in the cognitive- functional composite endpoints from baseline is provided from the mixed-model repeated- measures (MMRM) model or the Bayesian Disease Progression Model (DPM). In some embodiments, the antibody of the present disclosure is administered to the subject till it reaches about 15 to about 50 percent slowing of decline in the cognitive-functional composite endpoints from baseline. In some embodiments, the first or the second dose of the present disclosure is administered to the subject till it reaches about 15 to about 50 percent slowing of decline in the cognitive-functional composite endpoints from baseline.

[0065] In some embodiments, the administration of the anti-N3pGlu A|3 antibody of the present disclosure to the subject slows disease progression by about 15% to about 50% as compared to untreated subject, wherein the disease progression is measured by DPM. In some embodiments, the administration of the anti-N3pGlu A[3 antibody of the present disclosure to the subject slows disease progression by at least about 15% as compared to untreated subject, wherein the disease progression is measured by DPM. In some embodiments, the administration of the anti-N3pGlu Af> antibody of the present disclosure to the subject slows disease progression by at least about 20% as compared to untreated subject, wherein the disease progression is measured by DPM. In some embodiments, the administration of the anti-N3pGlu A[3 antibody of the present disclosure to the subject slows disease progression by at least about 25% as compared to untreated subject, wherein the disease progression is measured by DPM. In some embodiments, the administration of the anti-N3pGlu A[> antibody of the present disclosure to the subject slows disease progression by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40% at least about 45%, or at least about 50% as compared to untreated subject, wherein the disease progression is measured by DPM.

[0066] In some embodiments, the administration of the anti-N3pGlu A[> antibody of the present disclosure to the subject slows disease progression by about 15% to about 50% as compared to untreated subject, wherein the disease progression is measured by MMRM. In some embodiments, the administration of the anti-N3pGlu A[3 antibody of the presentdisclosure to the subject slows disease progression by at least about 15% as compared to untreated subject, wherein the disease progression is measured by MMRM. In some embodiments, the administration of the anti-N3pGlu Ap antibody of the present disclosure to the subject slows disease progression by at least about 20% as compared to untreated subject, wherein the disease progression is measured by MMRM. In some embodiments, the administration of the anti-N3pGlu A antibody of the present disclosure to the subject slows disease progression by at least about 25% as compared to untreated subject, wherein the disease progression is measured by MMRM. In some embodiments, the administration of the anti-N3pGlu Ap antibody of the present disclosure to the subject slows disease progression by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% as compared to untreated subject, wherein the disease progression is measured by MMRM.

[0067] In some embodiments, the present disclosure results in about 15 to about 60 percent slowing of decline or disease progression on the Integrated Alzheimer’s disease Rating Scale (iADRS) from baseline or as compared to untreated subject. In some embodiments, the present disclosure results in about 15 to about 60 percent slowing of decline or disease progression on the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject over a duration of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks. In some embodiments, the slowing of decline as measured by iADRS is provided from the mixed-model repeated- measures (MMRM) model or the Bayesian Disease Progression Model (DPM).

[0068] In some embodiments, the present disclosure results in about 20 percent, about 25 percent, about 30 percent, about 32 percent, about 35 percent, about 40 percent, about 45 percent, about 50%, about 55%, or about 60% slowing of decline or disease progression in the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject.

[0069] In some embodiments, the present disclosure results in about 15 to about 60 percent slowing of decline on the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject over a duration of about 76 weeks. In a particular embodiment, the present disclosure results in about 32 percent slowing of decline on thereintegrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject over a duration of about 76 weeks. In some embodiments, the antibody of the present disclosure is administered to the subject till it reaches about 15 to about 60 percent slowing of decline on the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject. In some embodiments, the first or the second dose of the present disclosure is administered to the subject till it reaches about 15 to about 60 percent slowing of decline on the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject.

[0070] In some embodiments, the present disclosure results in about 3 to about 6 points slowing of decline or disease progression on the Integrated Alzheimer’s disease Rating Scale (iADRS) from baseline or as compared to untreated subject. In some embodiments, the present disclosure results in about 3 to about 6 points slowing of decline or disease progression on the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject over a duration of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or about 76 weeks.

[0071] In some embodiments, the present disclosure results in about 3, about 4, about 5, or about 6 points slowing of decline or disease progression in the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated subject. In some embodiments, the present disclosure results in 3 to about 6 points slowing of decline or disease progression on the Integrated Alzheimer’s disease Rating Scale from baseline or as compared to untreated over a duration of 76 weeks.

[0072] In some embodiments, the slowing of disease progression as measured by iADRS is provided from the mixed-model repeated-measures (MMRM) model or the Bayesian Disease Progression Model (DPM).

[0073] In some embodiments, the cognitive functional composite endpoint, including iADRS, of the subject is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0074] In some embodiments, the present disclosure results in about 20 to about 40 percent slowing of decline or disease progression on Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) from baseline or as compared to untreated subject. In some embodiments, the present disclosure results in about 20 to about 40 percent slowing of decline or disease progression on CDR-SB from baseline or as compared to untreated over a duration of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks. In some embodiments, the present disclosure results in about 20 percent, about 25 percent, about 30 percent, about 35 percent, or about 40 percent slowing of decline or disease progression on CDR-SB from baseline or as compared to untreated subject.

[0075] In some embodiments, the present disclosure results in about 20 to about 40 percent slowing of decline on CDR-SB from baseline or as compared to untreated subject over a duration of about 76 weeks. In some embodiments, the antibody of the present disclosure is administered to the subject till it reaches about 20 to about 40 percent slowing of decline or disease progression on CDR-SB from baseline or as compared to untreated subject. In some embodiments, the first or the second dose of the present disclosure is administered to the subject till it reaches about 20 to about 40 percent slowing of decline or disease progression on CDR-SB from baseline or as compared to untreated subject. In some embodiments, the slowing of disease progression as measured by CDR-SB is provided from the mixed-model repeated-measures (MMRM) model or the Bayesian Disease Progression Model (DPM).

[0076] In some embodiments, a subject is positive for (or has) amyloid plaques when amyloid is detected in the brain by methods, such as, amyloid imaging with radiolabeled PET compounds or using a diagnostic that detects A [3 or a biomarker for A[ . Exemplary methods that can be used to measure the brain amyloid load / burden include, e.g., Florbetapir (Carpenter, et al., “The Use of the Exploratory IND in the Evaluation and Development of 18 F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: A Review of One Company's Experience,” Quarterly Journal of Nuclear Medicine and Molecular Imaging 53.4:387 (2009), which is hereby incorporated by reference in its entirety); Florbetaben (Syed et al., “[18F]Florbetaben: A Review in 0-Amyloid PET Imaging in Cognitive Impairment,” CNS Drugs 29, 605-613 (2015), which is herebyincorporated by reference in its entirety); and Flutemetamol (Heurling et al., “Imaging 0- amyloid Using [18F] Flutemetamol Positron Emission Tomography: From Dosimetry to Clinical Diagnosis,” European Journal of Nuclear Medicine and Molecular Imaging 43.2: 362-373 (2016), which is hereby incorporated by reference in its entirety).

[0077] F 18 florbetapir can provide a qualitative and quantitative measurement of brain plaque load in patients, including patients with prodromal AD or mild AD dementia. For example, the absence of significant F 18 florbetapir signal on a visual read indicates patients clinically manifesting cognitive impairment have sparse to no amyloid plaques. As such, F 18 florbetapir also provides a confirmation of amyloid pathology (see, e.g., Clark, et al., “Use of Florbetapir-PET for Imaging 0-amyloid Pathology,” JAMA 305.3: 275-283 (2011), which is hereby incorporated by reference in its entirety). F 18 florbetapir PET also provides quantitative assessment of fibrillar amyloid plaque in the brain and, in some embodiments, can be used to assess amyloid plaque reductions from the brain by antibodies of the present disclosure. The F 18 florbetapir methods can also be automated (see, e.g., Joshi, et al., “A Semiautomated Method for Quantification of F 18 Florbetapir PET Images,” J. Nuclear Medicine 56.11 : 1736-1741 (2015), which is hereby incorporated by reference in its entirety).

[0078] Amyloid imaging with radiolabeled PET compounds can also be used to determine if A0 deposit in the brain of a human patient is reduced or increased (e.g., to calculate the percentage reduction in A0 deposit post treatment or to assess the progression of AD). A person of skill in the art can correlate the standardized uptake value ratio (SUVr) values obtained from amyloid imaging (with radiolabeled PET compounds) to calculate the % reduction in A0 deposit in the brain of the patient before and after treatment. The SUVr values can be converted to standardized centiloid units, where 100 is average for AD and 0 is average for young controls, allowing comparability amongst amyloid PET tracers, and calculation of reduction according to centiloid units (Klunk et al., “The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET,” Alzheimer’ s & Dementia 11.1: 1-15 (2015) and Navitsky et al., “Standardization of Amyloid Quantitation with Florbetapir Standardized Uptake Value Ratios to the Centiloid Scale,” Alzheimer's & Dementia 14.12: 1565-1571 (2018), which are hereby incorporated by reference in their entireties). In some embodiments, the change in brain amyloid plaque deposition from baseline is measured by F 18 florbetapir PET scan.

[0079] This disclosure encompasses the use of biomarkers indicative of diseases marked by A0 plaques in the human brain, such as Alzheimer’s disease. These biomarkers include, for instance, amyloid deposits, amyloid plaque, Ap in CSF, Ap in plasma, brain tau deposition, tau in plasma, and tau in cerebrospinal fluid. They can be applied in screening, diagnosing, treating, or preventing these conditions. Potential uses of these biomarkers include: 1) identifying individuals at risk or in the preclinical stages of a disease; 2) reducing disease heterogeneity in clinical trials or epidemiological studies; 3) reflecting the natural history of the disease across induction, latency, and detection phases; and 4) selecting subjects for clinical trials or treatment / prevention of the disease.

[0080] Biomarkers may be employed to determine whether a subject can be treated with the antibodies, dosing regimen, or methods described herein. They might also assess if prevention of the disease is feasible using these antibodies, regimens, or methods. Additionally, biomarkers could evaluate the subject's responsiveness to the treatment or prevention approaches mentioned. Furthermore, they can be used to stratify or categorize subjects, identifying which groups respond to the treatment / prevention strategies involving the antibodies, dosing regimens, or methods discussed here. Biomarkers might also gauge the disease state of a subject and determine how long the antibodies, or their doses should be administered.

[0081] Subjects may possess a genetic mutation leading to autosomal-dominant Alzheimer’s disease or may he at higher risk for developing AD due to having one or two APOE4 alleles. Specifically, the subject could be heterozygous or homozygous for APOE4 alleles.

[0082] Cerebrospinal fluid or plasma-based analysis of P-amyloid can also be used to measure the amyloid load / burden for the purposes of the present disclosure. For example, A [>42 can be used to measure brain amyloid (Palmqvist, S. et al., “Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Beta-amyloid 42: a Cross- validation Study Against Amyloid Positron Emission Tomography,” JAMA Neurol 71, 1282-1289 (2014), which is hereby incorporated by reference in its entirety). In some embodiments, the ratio of AP42 / AP40 or AP42 / AP38 can be used as a biomarker for amyloid beta (Janelidze et al., “CSF Abeta42 / Abeta4o and Abeta42 / Abeta38 Ratios: Better Diagnostic Markers of Alzheimer Disease,” Ann. Clin. Transl. Neurol. 3, 154-165 (2016), which is hereby incorporated by reference in its entirety).

[0083] In some embodiments, deposited brain amyloid plaque or Ap in CSF or plasma can be used to stratify subjects into groups and to identify which group of subjects is responsiveto treatment / prevention of a disease (as described herein) using the antibodies, the dosing regimen, or the methods described herein.

[0084] In some embodiments, the subject of the present invention is pretreated or concomitantly treated with a corticosteroid, antihistamine, or a non-steroidal antiinflammatory drug. The corticosteroid can be dexamethasone, prednisone, or methyl prednisone.

[0085] In some embodiments, the corticosteroid is administered at a dose of 10 mg IV. In some embodiments, the corticosteroid is administered 30 minutes to one hour prior to the administration of the antibody.

[0086] In some embodiments, the subject is pretreated with dexamethasone and the pretreatment with dexamethasone 10 mg IV may be performed monthly (or Q4W) for the first 6 treatments with donanemab infusion (e.g., 350 mg donanemab infusion at week 0, 700 mg donanemab infusion at week 4, 1050 mg donanemab infusion at week 8, and 1400 mg donanemab infusion at weeks 12, 16, and 20). In some embodiments, the patient population may include all participants with mild-cognitive impairment due to Alzheimer’s disease (MCI due to AD), stratified by APOE4 carrier status (homozygous versus heterozygous, or may additionally be limited to include participants with MCI due to AD by APOE4 carrier status alone.

[0087] As used herein, an “antibody” is an immunoglobulin molecule comprising two HC and two LC interconnected by disulfide bonds. The amino terminal portion of each LC and HC includes a variable region responsible for antigen recognition via the complementarity determining regions (CDRs) contained therein. The CDRs are interspersed with regions that are more conserved, termed framework regions. Assignment of amino acids to CDR domains within the LCVR and HCVR regions of the antibodies of the present disclosure is based on the following: Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)), and North numbering convention (North et al., “A New Clustering of Antibody CDR Loop Conformations,” Journal of Molecular Biology, 406:228-256 (201 1)).Following the above method, the CDRs of the antibodies of the present disclosure were determined.

[0088] The antibodies of the present disclosure are monoclonal antibodies (“mAbs”).Monoclonal antibodies can be produced, for example, by hybridoma technologies,recombinant technologies, phage display technologies, synthetic technologies, e.g., CDR- grafting, or combinations of such or other technologies known in the art. The monoclonal antibodies of the present disclosure are human or humanized. Humanized antibodies can be engineered to contain one or more human framework regions (or substantially human framework regions) surrounding CDRs derived from a non-human antibody. Human framework germline sequences can be obtained from 1MGT®, the international ImMunoGeneTics information system® via their website, (imgt.org), or from The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, Academic 25 Press, 2001, ISBN 012441351. Techniques for generating human or humanized antibodies are well known in the art. In another embodiment of the present disclosure, the antibody, or the nucleic acid encoding the same, is provided in isolated form. As used herein, the term “isolated” refers to a protein, peptide or nucleic acid that is not found in nature and is free or substantially free from other macromolecular species found in a cellular environment. “Substantially free”, as used herein, means the protein, peptide or nucleic acid of interest comprises more than 80% (on a molar basis) of the macromolecular species present, preferably more than 90% and more preferably more than 95%.

[0089] The anti-N3pGlu A[3 antibody of the present disclosure is administered as a pharmaceutical composition. The pharmaceutical composition comprising an antibody of the present disclosure can be administered to a subject at risk for, or exhibiting, diseases or disorders as described herein by parental routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular). Subcutaneous and intravenous routes are preferred. In some embodiment, the anti-N3pGlu Ap antibody is administered by intravenous infusion.

[0090] The terms “treatment,” “treating” or “to treat” and the like include restraining, slowing, or stopping the progression or severity of an existing symptom, condition, disease, or disorder in a subject. The term “subject” refers to a human.

[0091] The term “prevention” means prophylactic administration of the antibody of the present disclosure to an asymptomatic subject or a subject with pre-clinical Alzheimer’s disease to prevent onset or slow progression of the disease.

[0092] The terms “disease characterized by deposition of A|3” or a “disease characterized by A[) plaques” are used interchangeably and refer to a disease that is pathologically characterized by A plaques in the brain or in brain vasculature. This includes diseases such as Alzheimer’s disease, Down syndrome, and cerebral amyloid angiopathy. A clinical diagnosis, staging or progression of Alzheimer’s disease can be readily determined by theattending diagnostician or health care professional, as one skilled in the art, by using known techniques and by observing results. This generally includes brain plaque imaging, mental or cognitive assessment (e.g., Clinical Dementia Rating - summary of boxes (CDR-SB), Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), or Alzheimer’s disease Assessment Scale-Cognitive (ADAS-Cog)) or functional assessment (e.g., Alzheimer’s disease Cooperative Study- Activities of Daily Living (ADCS-ADL)). The cognitive and functional assessment can be used to determine changes in a patient’s cognition (e.g., cognitive decline) and function (e.g., functional decline). “Clinical Alzheimer’s disease” as used herein is a diagnosed stage of Alzheimer’s disease. It includes conditions diagnosed as prodromal Alzheimer’s disease, mild Alzheimer’s disease, moderate Alzheimer’s disease, and severe Alzheimer’s disease. The term “pre- clinical Alzheimer’s disease” is a stage that precedes clinical Alzheimer’s disease, where measurable changes in biomarkers (such as CSF AP42 levels or deposited brain plaque by amyloid PET) indicate the earliest signs of a patient with Alzheimer’s pathology, progressing to clinical Alzheimer’s disease. This is usually before symptoms such as memory loss and confusion are noticeable. Pre-clinical Alzheimer’s disease also includes pre-symptomatic autosomal dominant carriers, as well as patients with higher risk for developing AD by virtue of carrying one or two AP0E4 alleles.

[0093] As used herein, early symptomatic Alzheimer’s disease encompasses the mild cognitive impairment stage of AD (also known as prodromal AD) and the mild dementia stage of AD. The National Institute on Aging and Alzheimer’s Association (NIA-AA) created a framework to help define Alzheimer’s disease (see, Jack et al., “NIA-AA Research Framework: Toward a Biological Definition of Alzheimer’s disease,” Alzheimer’s & Dementia: The Journal of the Alzheimer's Association 14(4) 535-562 (2018), which is hereby incorporated by reference in its entirety).

[0094] As used herein, mild cognitive impairment is defined as cognitive performance below expected range for that individual based on all available information. This may be based on clinical judgment and / or on cognitive test performance. Cognitive performance is usually in the impaired / abnormal range based on population norms, but this is not required if the performance is below the range expected for that individual. In addition to evidence of cognitive impairment, evidence of decline in cognitive performance from baseline must also be present. This may be reported by the individual or by an observer or observed by change on longitudinal cognitive testing / behavioral assessments or by a combination ofthese. In this stage, the individual performs daily life activities independently, but cognitive difficulty may result in detectable but mild functional impact on the more complex activities of daily life, either self-reported or corroborated by a study partner. As used herein, mild dementia is defined as substantial progressive cognitive impairment affecting several domains, and / or neurobehavioral disturbance. This is documented by the individual’s report or by observer (e.g., study partner) report or by change on longitudinal cognitive testing. This stage includes clear functional impact on daily life, affecting mainly instrumental activities, and the individual is no longer fully independent / requires occasional assistance with daily life activities. An individual no longer is considered to have mild AD dementia when the AD has worsened to the point of a) extensive functional impact on daily life with impairment in basic activities and b) is no longer independent and requires frequent assistance with daily life activities.

[0095] As used herein, the term “about” means up to ±10%.

[0096] The terms “human subject,” “subject,” and “patient” are used interchangeably in the present disclosure. In some embodiments, the subject has a disease characterized by A[3 deposits / plaques in the brain. The subject is selected from preclinical Alzheimer’s disease, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down syndrome, clinical cerebral amyloid angiopathy, or pre-clinical cerebral amyloid angiopathy. In some embodiments, the subject is an early symptomatic AD patient. In some embodiments, the subject has prodromal AD and / or mild dementia due to AD.

[0097] The phrases “slowing of decline” and “slowing disease progression” are used interchangeably in the present disclosure.

[0098] As used herein, “methods of treatment” are equally applicable to use of a composition for treating the diseases or disorders described herein and / or compositions for use and / or uses in the manufacture of a medicaments for treating the diseases or disorders described herein.

[0099] The following Examples further illustrate the present disclosure. It should be understood however, that the Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.EXAMPLESExample 1: Investigating the Effect of Different Donanemab Dosing Regimens on ARIA- E and Amyloid Lowering in Adults with Early Symptomatic Alzheimer’s Disease

[0100] Study AACQ (hereafter referred to as “the Study,” “Study AACQ,” or “AACQ;” Protocol Number: I5T-MC-AACQ, Trailblazer-ALZ 6, NCT05738486) is a multicenter, randomized, double -blind, Phase Illb study in adults with early symptomatic AD. The Study investigated three alternative donanemab dosing regimens and compared those to the standard donanemab dosing regimen (i.e., the FDA approved dosing regimen for K1SUNLA™) and their effect on the frequency and severity of AR1A-E (with the potential to reduce ARIA) in adults with early symptomatic AD. In addition, the Study measured amyloid removal and explored novel imaging and blood biomarkers that may be related to or predictive of ARIA incidents. Table 2, shown below, describes the primary, secondary, and tertiary / exploratory objectives and endpoints for the Study. Participants (n=843) were stratified by APOE4 genotype and baseline amyloid levels and randomly assigned at 1 : 1 : 1 : 1 to a standard dosing arm and 3 alternative dosing arms, namely the dose-skipping arm, the titration arm, and the Cmax arm, respectively. Before week 16, the four treatment arms varied in donanemab dosage per infusion and frequency of dosing but the total donanemab exposure by week 16 were the same. After Week 16, all participants were targeted to receive 1400 mg monthly of donanemab until dose stopping criteria met or until the end of the study.

[0101] Relative risk reduction of ARIA-E by week 24 was analyzed through Bayesian logistic regression models to compare each alternate dosing regimen with the standard dosing approach. A mixture prior specification was used to enable a formal dynamic use of historical data from other donanemab clinical studies for the ARIA-E frequency by Week 24 in the standard dosing regimen. Brain amyloid level (as measured by positron emission tomography (PET)) and plasma P-tau-217 levels were also assessed.Table 2: Study AACQ Objectives and EndpointsAbbreviations: Ap = amyloid-beta peptide; ADA = antidrug antibody; ARIA = amyloid-related imaging abnormalities; hsCRP = high-sensitivity C-reactive protein; GFAP = glial fibrillary acidic protein; IRR = infusion-related reactions; NfL = neurofilament light chain; PK = pharmacokinetic; P-tau = phosphorylated tan; sTREM2 = soluble triggering receptor expressed on myeloid cells 2.

[0102] The study duration was up to approximately 91 weeks and included a screening period, double-blind treatment period, and post-treatment follow-up. Primary outcome was evaluated at 24 weeks. The standard donanemab dosing regimen has a titration schedule of700 mg IV Q4W for the first 3 doses and then 1400 mg IV Q4W. This study investigated three alternative dosing regimens that may potentially reduce the frequency and / or severity of ARIA-E. The doses and frequency were carefully selected based on human safety, efficacy, PK, and PD data. These dosing regimens included either built-in dosing pause of 8 weeks between infusions (the dose-skipping arm), or a more gradual dose titration with a lower starting dose (the titration arm) or administering a lower dose more frequently (every two weeks, Q2W) (the Cmax dose), resulting in a lower maximum concentration but with the same monthly exposure compared to the standard donanemab regimen. All the dosing regimens were anticipated to result in robust plaque clearance. It was hypothesized that 8-week dosing interval will allow time for potential asymptomatic ARIA to resolve and lead to decrease the risk of ARIA exacerbation. Administering a lower dose, compared with the standard donanemab regimen, was hypothesized to result in a lower maximum concentration (Cmax). It was hypothesized that a lower Cmax and a slower increase in serum concentration may reduce ARIA risk.

[0103] Phase 2 Study I5T-MC-AACG: ARIA Events Summary: Study I5T-MC-AACG (hereafter referred to as AACG, NCT03367403) was a Phase 2, double-blind, placebo- controlled study of participants with early symptomatic AD with intermediate brain tau burden. In Study AACG, ARIA (-E, -H, or both) was observed in a higher percentage of participants treated with donanemab, compared to participants treated with placebo. A majority of ARIA-E and ARIA-H events were first observed within 12 weeks of treatment initiation, with most events observed by 24 weeks. In Study AACG, ARIA-E occurred in 26.7% of participants treated with donanemab, with 6.1% of cases being symptomatic. Symptoms associated with ARIA-E included, but were not limited to, worsening of headache, altered mental status, confusion, and difficulty expressing themselves. Serious symptomatic ARIA-E requiring hospitalization occurred in 1.5% of participants treated with donanemab.

[0104] AACQ Treatment Arms and Titration Regimen Outline: Characterizing the frequency, severity, onset, and resolution of ARIA events, in relation to dosing, is an important overall goal in understanding the benefit / risk of using amyloid lowering treatments for patients with early symptomatic AD. All participants received a dosing regimen that included donanemab, but at different dose levels and frequency of dosing. Placebo was given at specific visits to preserve the blind for the different dosing regimens. Participants were stratified at baseline by amyloid PET scan results (>24.1 and <54centiloids; >54 and <79 centiloids; >79 and <107 centiloids; >107 centiloids) and APOE genotype (heterozygous carrier, homozygous carrier, and noncarrier). The following Table 3 describes the dosing regimens for the first 16 weeks. After Week 16, all participants were targeted to receive 1400 mg monthly of donanemab until they met the dose stopping criteria, or until the end of the study.Table 3:

[0105] Study AACQ allowed all participants to continue or change their symptomatic AD standard of care concomitant medications during the study. Physical and neurological examinations, MRI assessments, and assessments of Suicidal Ideation and Behavior (SIB) were included to facilitate a comprehensive safety evaluation, in addition to AE reporting, safety measures such as laboratory assessments, immunogenicity testing, vital signs, and weight monitoring.

[0106] Inclusion / Exclusion Criteria: Participant eligibility for enrollment in the study was based on the criteria listed below. The inclusion and exclusion criteria used to determine eligibility applied only at screening or other specified visits, and not continuously throughout the study. Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, was not permitted.

[0107] Participants were eligible to be included in the study only if all the following criteria were met:• 60 to 85 years of age inclusive, at the time of signing the informed consent;• have gradual and progressive change in memory function reported by the participant or informant for >6 months from time of signing the informed consent;• have an MMSE score of 20 to 28 (inclusive) at Visit 1 ;• have an amyloid PET scan result from central read, consistent with the presence of amyloid pathology. A historical amyloid PET scan may be submitted for consideration for eligibility if performed <12 months of Visit 2, randomization. The acceptance of a historical scan is at the discretion of the Sponsor;• women not of childbearing potential and males were allowed to participate in this study;• capable of giving signed informed consent;• have a study partner who will provide written informed consent to participate, is in frequent contact with the participant, and will accompany the participant to study visits or be available by telephone at designated times; and• were reliable and willing to make themselves available for the duration of the study and were able and willing to follow study procedures.

[0108] Participants were ineligible for this study if any of the following criteria applied:• have significant neurological disease affecting the central nervous system other than AD, that may affect cognition or ability to complete the study, including but not limited to, other dementias, serious infection of the brain, Parkinson’s disease, multiple concussions, or epilepsy or recurrent seizures, except febrile childhood seizures;• have a condition that in the investigator’s opinion could interfere with the analyses of this study, or a current serious or unstable illness, including cardiovascular, hepatic, renal, gastroenterological, respiratory, endocrinologic, neurologic other than AD, psychiatric, immunologic, or hematologic;• have a life expectancy of less than 24 months;• have a presence or history of malignant neoplasms within the past 5 years prior to Visit 1;• Exceptions: a. non-metastatic basal- or squamous-cell skin cancer, b. Stage 0 non-invasive carcinoma of the cervix, c. Stage 0 non-invasive prostate cancer, or d. other cancers with low risk of recurrence or spread; are in the investigator’s opinion, actively suicidal and deemed a significant risk for suicide;• have a diagnosis of alcohol or drug use disorder, except tobacco use disorder, within 2 years of Visit 1 ;• have a history of clinically significant multiple or severe drug allergies, significant atopy, or severe posttreatment hypersensitivity;• have a screening MRI that shows evidence of significant abnormality suggesting another potential etiology for progressive dementia or a clinically significant finding that may impact the participant’s ability to safely participate in the study;• have any contraindications for MRI, including claustrophobia or the presence of contraindicated metal (ferromagnetic) implants or a cardiac pacemaker;• at Visit 1 , have a centrally read MRI demonstrating the presence of ARIA-E, >4 cerebral microhemorrhages, >1 area of cortical superficial siderosis, any macrohemorrhage, or severe white matter disease;• have a contraindication to the PET procedure or sensitivity to the amyloid PET tracer;• have present or planned exposure to ionizing radiation that, in combination with the planned administration of study PET ligands, would result in a cumulative exposure that exceeds local recommended exposure limits;• have laboratory values, in relation to the reference range, of ALT >2.5X ULN, AST >2.5X ULN, and ALP >2.0X ULN, or• TBL >1.5X ULN, except for participants diagnosed with Gilbert’s syndrome;• have had prior treatment with a passive anti-amyloid immunotherapy <5 half-lives prior to randomization;• have received active immunization against A in any other study;• have previously received donanemab;• are currently enrolled in any other interventional clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study;• have participated in a clinical study involving an investigational study intervention and have received an intervention within the last 30 days of Visit 1; or• have previously completed or withdrawn from this study. This did not apply to participants allowed to rescreen before randomization in this study.

[0109] Dose reductions were not permitted in Study AACQ.

[0110] Discontinuation of Study Intervention: In this Study, the investigator could temporarily discontinue intervention if the participant developed treatment- emergent ARIA-H or ARIA-E to an extent deemed clinically significant by the investigator. Reinitiating intervention was considered after resolution of ARIA-E and stabilization of ARIA-H-imaging findings and the resolution of any associated symptoms. Both the decision to stop and restart intervention was discussed with the Sponsor-designated medical monitor.

[0111] When necessary, a participant was permanently discontinued from study intervention. If study intervention was permanently discontinued, the participant remained in the study for safety evaluations and biomarker collection.

[0112] A participant may be permanently discontinued from study intervention if the participant or participant’s designee requests to discontinue the study intervention; the participant requires an excluded treatment; the participant answered “yes” to Question 4 or Question 5 on the “Suicidal Ideation” portion of the C-SSRS; the participant answered “yes” to any of the suicide-related behaviors on the Suicidal Behavior portion of the C- SSRS (a psychiatrist or appropriately trained professional may have assisted in the decision to discontinue the participant); in the opinion of the investigator, the participant should permanently discontinue the study intervention for safety reasons or for severe noncompliance to the study protocol; and ARIA.

[0113] In instances of systemic hypersensitivity or infusion-related reactions, dosing rechallenge was contraindicated in participants that have experienced a suspected or possible anaphylactic reaction, a reaction involving 2 or more organ systems (for example, mucocutaneous, respiratory, cardiovascular, or gastrointestinal systems), or that occurred very close to a prior dose.

[0114] For systemic hypersensitivity reactions or IRRs, which are not suspicious for anaphylaxis, after review of the data, and at the investigator’s discretion, the participant may have been rechallenged. If rechallenge was planned, the participant may have been premedicated with an appropriate medication for subsequent doses at the investigator discretion and according to local practice guidelines. Any premedication given was documented as a concomitant therapy. Prior to initiating premedication or rechallenging, the investigator may have consulted with the Sponsor.

[0115] Screening Mini-Mental State Examination (MMSE): The MMSE was a brief instrument used to assess cognitive function in participants. The MMSE was used forscreening in this study. The instrument measured orientation, memory, and attention and the ability of the participant to name objects, follow verbal and written commands, write a sentence, and copy figures. The range for the total MMSE score was 0 to 30, with lower scores indicating greater level of impairment.

[0116] Amyloid Plaque Reduction: If a participant met amyloid plaque reduction criteria defined by the Sponsor, measured by amyloid PET scan, at Visit 12 (Week 24) or Visit 19 (Week 52), the participant discontinued study intervention and stayed in the study for the remaining study visits.

[0117] Efficacy Assessment (Amyloid PET Scan): Amyloid PET scans provided a quantitative assessment of amyloid plaque deposition in the brain and served as a biomarker of clearance of amyloid deposits. Part of the study eligibility criteria was determined by amyloid PET scans. Additional amyloid PET scans were performed. Only 1 of the beta-amyloid tracers, either florbetapir Fl 8 or Florbetaben Fl 8, was used at a given amyloid PET scan visit.

[0118] Safety Assessments: A complete physical examination included, at a minimum, assessments of these systems: cardiovascular, respiratory, gastrointestinal, and neurological. The investigator conducted a complete physical / neurological examination at any time a participant presents with physical complaints and when this was considered necessary, with special attention paid to clinical signs related to previous serious illnesses. Vital signs, including temperature, was measured at all visits.

[0119] Magnetic Resonance Imaging: Magnetic resonance imaging of the brain was performed and as clinically indicated. The investigator could perform unscheduled MRIs if necessary. This technology was used to check for evidence of ARIA-H or ARIA-E, and other clinically relevant safety findings. The following Table 4 describes the MRI activities for standard and exploratory sequences and the respective timing throughout the Study (Standard MRI sequences were used to determine participant eligibility, care and safety; exploratory MRI sequences were used for exploratory analyses only and were not used for participant management).Table 4:Abbreviations: DTI = diffusion tensor imaging; DWI = diffusion-weighted imaging; ED = early discontinuation visit; FLAIR = fluid-attenuated inversion recovery; FMRI = functional magnetic resonance imaging;GRE = gradient echo; SWI = susceptibility weighted imaging; UV = unscheduled visit. a Performed either with screening MRI or another time prior to first infusion at Visit 2. b Performed when or where available.

[0120] Specific analyses of the scans, including assessments of ARIA-H and ARIA-E, were interpreted by a centralized MRI vendor for data analysis and report- writing purposes. Results of centrally read MRIs regarding participant care or safety were reported back to the investigator. Any clinically significant findings noted by the initial review by the investigator at screening that result in a diagnosis were recorded as a preexisting condition or AE. The centralized MRI vendor determined final MRI eligibility at screening and reported the MRI results to the investigator as “does” or “does not” meet MRI eligibility criteria.

[0121] ARIA and MRI Identification Guidance: While most cases of ARIA are asymptomatic, serious and life-threatening cases were reported. Symptoms present in association with these imaging abnormalities may include, but are not limited to, headache, vomiting, unsteadiness, dizziness, tremor, confusion, visual disturbances, speech disturbances, worsening cognitive function, alteration of consciousness, and seizures. If a participant simultaneously developed more than 1 of the symptoms suggestive of ARIA-E, an unscheduled MRI was performed. A single symptom suggestive of ARIA-E of sufficient severity may have also warranted an unscheduled MRI. If symptoms were reported, and ARIA-E was suspected, the abnormality may have been best detected by FLAIR sequences on MRI. If symptoms were reported, and ARIA-H was suspected, the abnormality may have been best detected with the T2 gradient-recalled echo on MRI. If ARIA is present, repeat MRIs were recommended every 4 to 6 weeks until resolution of ARIA- E or stabilization of ARIA-H. For asymptomatic or mild symptoms,the participant was observed; for moderate symptoms associated with ARIA-E, the use of oral or IV steroids was considered or used. In the case of severe symptoms associated with ARIA-E, it was recommended to hospitalize the participant for close observation and the use of IV steroids such as high-dose dexamethasone or a similar agent were considered or used.[0122J Serum Samples for Pharmacokinetics (PK) Analysis: Predose serum samples were collected for measurement of serum concentrations of donanemab at weeks, 4, 8, 12, 24, 52, and post dose serum samples were collected for measurement of serum concentrations of donanemab at weeks 0 (at baseline), 4, 12, 24, and 52. If donanemab infusion was permanently discontinued but the participant remained in the study, 1 PK sample was collected at the soonest scheduled visit. Dosing dates and times were recorded. Subsequent PK sample collection followed the above protocol unless the scheduled visit exceeded 6 months since discontinuation of infusions. No additional PK sample collection was required once the participant exceeded 6 months since discontinuation of infusions. The sampling timing may have been altered during the study based on newly available data, for example, to obtain data closer to the time of peak plasma concentrations, to ensure appropriate monitoring. Instructions for the collection and handling of biological samples was provided by the Sponsor. The actual date and time of each sample was recorded. Bioanalytical samples remaining after the bioanalyses may be used in future exploratory analyses, such as metabolism, protein binding, or bioanalytical method development or validation work.

[0123] Blood Samples for AD Biomarker Analyses, Exploratory Biomarkers, and Immunogenicity (Anti-Drug Antibodies, ADAs): Samples for AD biomarker measurement, including for neurofilament light chains (NfL), glial fibrillary acidic protein (GFAP), A(340 and A[342, and plasma P-tau-217, were collected at weeks 0 (at baseline), 4, 8, 12, 24, 36, 52, 64, and 76. These samples were collected only where available and allowed per local regulations. Additionally, blood samples for exploratory biomarker analyses were collected at weeks 0 (at baseline), 4, 8, 12, 24, 36, 52, 64, 76, and at early discontinuation, for future analyses. Blood samples for immunogenicity to measure the concentration of anti-drug antibodies to donanemab were obtained at weeks 0 (at baseline), 4, 8, 12, 24, 36, 52, 64, 76, and at early discontinuation.

[0124] Primary Endpoint Analysis: The primary endpoint was based on the ARIA-E events as diagnosed by the scheduled or unscheduled MRIs up to and including at week 24. Theprimary analysis used a Bayesian logistic regression model to estimate and compare the relative reduction in ARIA-E rates by week 24 for the alternative donanemab regimens versus the standard donanemab regimen. The logistic regression model included the fixed effects for treatment, ApoE e4 status, and baseline amyloid level. The treatment effects will be presented in terms of the estimated odds ratios and relative reduction in ARIA-E rates by Week 24 for the alternative regimens relative to the standard regimen. The primary analysis model will have the ability to leverage information on the ARIA-E rate of the standard donanemab regimen by Week 24 through the construction of an informative prior using historical data. A mixture prior specification was used to dynamically incorporate information based on the similarity in the ARIA-E rates of the standard regimen by Week 24 compared to the historical data. A secondary analysis using the Bayesian logistic regression model for the primary endpoint will be fit using data from Study AACQ only, that is, without using historical data on the ARIA-E rate by Week 24.

[0125] Secondary Endpoint Analyses: Descriptive statistics were presented for all primary and secondary ARIA-related endpoints. Bayesian modeling as described above for the primary endpoint was performed for the secondary endpoint of ARIA-E frequency at 52 weeks. Further modeling was performed on the other ARIA-related endpoints, such as ARIA-H. The frequency and severity of ARIA-E and of ARIA-H events was summarized by symptomatic and asymptomatic events. Time to first occurrence of ARIA-E or other ARIA-related events, such as symptomatic ARIA- E, were analyzed and compared across the donanemab dosing regimens using a log-rank test for survival data. A Cox proportional-hazards model was used to analyze the data on time to event of first ARIA- related incidence. To assess the effect of each alternative donanemab dosing regimen versus standard donanemab dosing regimen on brain amyloid deposition, a test of noninferiority was performed on the mean absolute change from baseline in brain amyloid plaque, from the amyloid PET scan, at weeks 24, 52, and 76.Example 2: Results of Study AACQ After 24 Weeks

[0126] A total of 843 participants were enrolled in study AACQ, with 207 (standard arm), 210 (dose skipping arm), 212 (titration arm), and 213 (Cmax arm) participants assigned to the 4 treatment arms. Baseline characteristics were generally balanced across the four treatment arms with mean age of 73.6 years, 57.8% of women, and 64.6% of APOE e4 carriers.

[0127] The primary outcome at 24 weeks indicated that study AACQ met its primary endpoint. By week 24, the frequency of ARIA-E was 23.7% for the standard dosing arm, and 18.6% for dose skipping arm, 13.7% for titration arm, and 18.3% for the Cmax arm. The dosing regimen of the titration arm with the lowest ARIA-E (13.7%) had a 95% probability of achieving at least 20% reduction in relative ARIA-E risk compared to the standard dosing arm. The frequency of symptomatic ARIA-E was numerically reduced compared to the standard arm (2.8% versus 4.8%). Table 5 below provides a summary of ARIA and macrohemorrhage events by week 24 based on MRI or TEAE cluster in the AACQ study.Tab e 5:

[0128] The ARIA-E severity in the titration arm was significantly less than the standard dosing arm with 0%, 9.0% and 4.7% of severe, moderate and mild ARIA-E compared to1.9%, 12.6% and 9.2%, respectively, in the standard dosing arm. The ARIA-E severity in the other 2 arms was not significantly different from the standard arm (see Figure 1).

[0129] Overview of Safety: Serious adverse events, discontinuations, or treatment-related adverse events in the alternative dosing arms were largely comparable to the standard dosing arm (see Table 6 that provides an overview and summary of adverse events).Table 6:Abbreviations: N = number of subjects in the analysis population; n = number of subjects with at least one adverse event per event type; - = not calculable; Trt A = 1 -Standard Regimen; Trt B = 2-Dose Skipping; Trt C = 3-Titration; Trt D = 4-Cmax*a - Subjects may be counted in more than one category.*b - Deaths are also included as serious adverse events and discontinuations due to adverse events.*c - Includes events that were considered related to study treatment as judged by the investigator.

[0130] One participant in the titration arm with an ongoing ARIA-E presented stroke-like symptoms and, after receiving tissue plasminogen activator treatment, died due to cerebral intraparenchymal hemorrhage. The frequencies of infusion-related reactions (IRR) in the alternative dosing arms were not significantly different from the standard arm, as shown below in Table 7. There is a numerically higher frequency of IRR in the Titration and Cmax arms, but mostly with mild and moderate severity. The serious hypersensitivity, anaphylactic and infusion-Related Reactions events are also numerically higher in the alternative dosing arms compared to the standard dosing arm.Table 7:0131] Pharmacodynamic effect (Amyloid PET): All arms had significant decreases in brain amyloid levels at 24 weeks with adjusted mean Centiloids (Standard deviation, SD) change of 58.8 (1.8) in the standard arm, and 58.7 (1.7) in the skipping arm, 56.3 (1.7) in the titration arm, and 51.0 (1.7) in the Cmax dosing arms (Figure 2). The number and percentages of participants who reached amyloid clearance or met dose stopping criteria at 24 weeks are shown below in Table 8.Table 8:0132] Plasma P-tau-217: Plasma P-tau217 levels were significantly reduced from baseline in all 4 arms at 24 weeks with LS mean change (loglO) of -0.14 (standard arm), -0.11 (skipping arm), -0.14 (titration arm), and -0.12 (Cmax arm) in the standard arm and the 3 alternative dosing arms (Figure 3).

[0133] Conclusions: Study AACQ evaluated 3 alternative dosing arms in addition to the standard dosing arm on their effect on ARIA-E frequency and pharmacodynamic effect on amyloid levels and plasma P-tau-217 levels. The results at 24 weeks indicated that study AACQ met its primary endpoint. Of the three alternative dosing regimens tested, the titration arm significantly reduced the frequency and severity of ARIA-E at 24 weeks compared to the standard arm. Amyloid and plasma P-tau-217 reduction was similar across all arms. The overall safety profile is similar across the 4 arms. This study suggests that a titration approach (as shown in the titration arm) may reduce ARIA risk while maintaining sufficient amyloid reduction.Example 3: Results of Study AACQ obtained after 52 weeks and 76 weeks and a comparison with 24-week Results.

[0134] This example provides the results of 24-week, 52- week and 72-week donanemab treatment periods in study AACQ. As noted in Example 2, the AACQ study investigated whether different donanemab dosing regimens — standard, modified titration (also referred to herein as titration dosing), dose skipping, and Cmax — could reduce the frequency and severity of ARIA with edema / effusions (ARIA-E) while maintaining donanemab’s pharmacological effect (amyloid removal). Based on the data disclosed here, the modified titration arm met the primary endpoint of ARIA-E reduction while maintaining amyloid removal.

[0135] At 24 weeks, the ARIA-E frequencies for the standard, modified titration, dose skipping, and Cmax arms were 23.7%, 13.7%, 18.6%, and 18.3%, respectively. At 52 weeks, the ARIA-E frequencies for the standard, modified titration, dose skipping, andCmax arms were 24.2%, 15.6%, 18.6%, and 18.8%, respectively. At 76 weeks, the ARIA- E frequencies for the standard, modified titration, dose skipping, and Cmax arms were 24.2%, 15.6%, 18.6%, and 19.2%, respectively. The modified titration met the 24- week primary outcome with a 94% probability of achieving >20% RRR (relative risk reduction) versus the standard arm. It also had significantly lower ARIA-E severity, but similar cumulative exposure and mean amyloid reduction compared to the standard arm. Gradual up-titration of the dose in the modified titration dosing significantly reduced ARIA-E risk while demonstrating comparable pharmacokinetics / pharmacodynamics to standard dosing.

[0136] ARIA-E: The primary outcome was ARIA-E frequency and RRR at 24 weeks. The percent of participants who experienced ARIA-E was 23.7% for the standard arm, and 13.7%, 18.6%, and 18.3% for the three alternative dosing arms (modified titration, dose skipping, and Cmax, respectively). The modified titration arm met the primary objective (>80% probability of achieving at least 20% RRR) with a posterior risk reduction (SD) of 0.405 (0.123) and a 94.1% probability that the RRR was >20%. The other alternative dosing regimens did not meet the prespecified success criteria.

[0137] At 52 weeks, the percent of participants who experienced ARIA-E was 24.2% for the standard arm, and 15.6%, 18.6%, and 18.8% for the three alternative dosing arms (modified titration, dose skipping, and Cmax, respectively). At 52 weeks the RRR of the modified titration arm was still significant (87% probability of achieving >20% RRR versus the standard arm). The modified titration arm also met the secondary outcome measure of improved ARIA-E severity at 24 weeks. Radiographic severity of ARIA-E was significantly reduced compared to the standard arm (P = 0.011 at 24 weeks vs. 0.015 at 52 weeks, Cochran-Mantel-Haenszel test). Notably, 86.3% of participants in the modified titration arm had no ARIA-E by MRI through week 24 (compared to 76.3% in the standard arm) and no radiographically severe events were observed. Similarly, 84.4% of participants in the modified titration arm had no ARIA-E by MRI through week 52 (compared to 75.8% in the standard arm) and no radiographically severe events were observed.

[0138] At 76 weeks, the percent of participants who experienced ARIA-E was 24.2% for the standard arm, and 15.6%, 18.6%, and 19.2% for the three alternative dosing arms (modified titration, dose skipping, and Cmax, respectively). At 76 weeks the RRR of the modified titration arm was still significant (87.1% probability of achieving >20% RRR versus the standard arm). The modified titration arm also met the secondary outcomemeasure of improved ARIA-E severity at 24 weeks. Radiographic severity of ARIA-E was significantly reduced compared to the standard arm (P = 0.011 at 24 weeks vs. P = 0.015 at 76 weeks, Cochran-Mantel-Haenszel test). Notably, 86.3% of participants in the modified titration arm had no ARIA-E by MRI through week 24 (compared to 75.8% in the standard arm) and no radiographically severe events were observed. Similarly, 84.4% of participants in the modified titration arm had no ARIA-E by MRI through week 76 (compared to 75.8% in the standard arm) and no radiographically severe events were observed.

[0139] Cox proportional hazard analysis of time to first ARIA-E based on MRI showed a significantly (P = 0.016) lower percentage of participants with ARIA-E risk in the modified titration arm compared to the standard arm through 24 weeks.

[0140] When the impact of APOE e4 genotypes was assessed, ARIA-E was numerically less frequent in the modified titration arm than in the standard arm regardless of genotype. The biggest difference (both relative and absolute) in ARIA-E frequency was observed in those homozygous for APOE s4 (57.1% in the standard arm compared to 19.0% in the modified titration arm). The frequency of symptomatic ARIA-E in homozygous, heterozygous, and noncarrier participants was 4.8%, 8.0%, and 0%, respectively, in the standard arm and 0%, 3.5%, and 2.7%, respectively, in the modified titration arm.

[0141] ARIA-H and macrohemorrhage: Compared to 25. 1 % of participants in the standard arm at 24 weeks, the modified titration arm resulted in 20.3% participants experiencing ARIA-H. The posterior probability that the RRR was >20% was 47.9% in the modified titration arm, which did not meet the predefined threshold of 80%. Consistent with the non-significant ARIA-H result, the frequency of microhemorrhage was not significantly different in the modified titration arm versus the standard arm. Cortical superficial siderosis, on the other hand, was significantly reduced in the modified titration arm compared to the standard arm with a 45% RRR and a 92.3% probability that the RRR was >20%. For ARIA-H events that were concurrent with ARIA-E (15.5% and 9.9% of events in the standard and modified titration arms, respectively), the modified titration arm also had a significantly lower relative risk (33.7%) and an 80.5% probability that the RRR was >20%. ARIA-H radiographic severities were not significantly different between the standard and modified titrations arms. Macrohemorrhage occurred in one (0.5%) participant in the standard arm and two (0.9%) participants in the modified titration arm.

[0142] Safety: The frequency of serious adverse events was 8.7% in the standard arm and 9.9% in the modified titration arm. The frequency of treatment-emergent adverse events was similar in both arms (84.5% in the standard arm compared to 85.4% in the modified titration arm). The five most frequently reported treatment-emergent adverse events in either the standard or modified titration arm, respectively, were ARIA-E (23.7% and 13.7%), headache (19.8% and 15.1%), AR1A-H (15.9% and 13.2%), infusion-related reaction (13.5% and 17.0%), and fall (7.7% and 9.0%).

[0143] Pharmacokinetics: The planned and observed cumulative doses, cumulative AUC(o-i2 weeks) and Caverage, ss, in the standard and modified titration arms were comparable between the 24 weeks, 52 weeks, and 76 weeks. Donanemab concentration-time profiles following standard and modified titration arms overlap completely after week 12, where the same once-monthly 1400 mg dosing regimen is used for both arms for the remainder of the study.

[0144] Pharmacodynamics and biomarkers: Participants had significant and highly comparable amyloid reduction from baseline to 24 weeks with an adjusted mean (SE) change of 58.8 (1.8) CL in the standard arm, and 56.3 (1.7) CL in the modified titration arm. Approximately 56.7% and 50.7% of participants in the standard regimen and modified titration regimen, respectively, reached an amyloid threshold level below 24.1 CL by week 24. Approximately 33% of participants (32.3% in the modified titration arm; 34.0% in the standard arm) met the eligibility criteria for dose cessation at week 24 by achieving amyloid levels below 11 CL. Plasma P-tau-217, assessed as an exploratory objective, was significantly reduced from baseline at 24 weeks and the reductions were similar in the standard and modified titration arms. In the standard arm, least squares mean change (loglO) difference from baseline ± SE at week 24 was 0.136 + 0.012 and in the modified titration arm was 0.145 ± 0.012 (P < .0001).

[0145] Discussion: The modified titration arm had a lower frequency of ARIA-E (13.7%) compared to the standard arm (23.7%) and met the primary objective, with a 40.5% lower relative ARIA-E risk and a 94.1% probability that the RRR was >20%. Furthermore, the modified titration arm showed a significantly lower severity of ARIA-E and risk of cortical superficial siderosis compared to the standard arm. Importantly, the standard and modified titration arms had a similar amyloid reduction from baseline as assessed by PET scans (adjusted mean change at 24 weeks: -58.8 CL versus -56.3 CL, respectively). Thestandard arm and modified titration arm also had similar cumulative exposure and biomarker P-tau-217 response.

[0146] The 52-week and 76-week results were consistent with the 24-week results suggesting that ARIA-E was reduced rather than delayed in the modified titration arm. In addition, the amyloid reduction remained similar between the standard and the modified titration arm at week 52 (adjusted mean change at 52 weeks: -71.2 CL versus -70.3 CL, respectively) and at week 76 (adjusted mean change at 76 weeks: change -72.1 CL versus -70.9 CL, respectively).

[0147] To achieve the goal of reducing ARIA-E frequency while maintaining comparable amyloid reduction, the rational design and selection of the alternative dosing regimens in this disclosure were based on human safety, efficacy, pharmacokinetic, and pharmacodynamic data from donanemab phase 1-3 studies. The comparable cumulative exposure and the pharmacodynamic effect observed between the standard and modified titration arms validated the dosing regimen selection. Moreover, the randomization and stratification approaches in this study were designed to balance ARIA risk factors; thus, APOE s4 genotype, baseline amyloid levels, baseline microhemorrhage, and cortical superficial siderosis were equal across arms. As a result, the standard arm provides a reliable internal comparison for the alternative dosing arms.

[0148] While the modified titration dosing regimen significantly reduced the relative ARIA-E risk there was no significant reduction in ARIA-H risk, although it was numerically lower. For ARIA-H events that are concurrent with ARIA-E, which are mostly treatment induced, the modified titration regimen demonstrated significantly reduced risk, with >80% probability of achieving at least 20% RRR.

[0149] The standard arm in this study differed from the donanemab arm in TRAILBLAZER- ALZ 2 as the standard arm incorporated additional placebo infusions to maintain the study blind (Cmax dosing was bi-weekly for the first 16 weeks). This bi-weekly infusion schedule, as opposed to once monthly, as well as the participants’ awareness of receiving donanemab as opposed to blinded placebo-controlled trials might have influenced the observed infusion-related reaction frequency.

[0150] Cumulative dose, cumulative exposure, and pharmacodynamic measures of amyloid lowering and P-tau-217 lowering were similar between the standard arm (as used in TRAILBLAZER-ALZ 2) and all three alternative dosing arms at weeks 24, 52, and 76.Example 4: Pretreatment with Corticosteroids in Study AACQ Extension.

[0151] This example describes an extension of Study AACQ using the modified titration arm (350 mg infusion of donanemab at week 0, 700 mg infusion of donanemab at week 4, 1050 mg infusion of donanemab at week 8, and 1400 mg infusion of donanemab every 4 weeks thereafter) to investigate the impact on ARIA-E with pre-treatment or concomitant administration of corticosteroids with donanemab versus the modified titration arm of donanemab alone. Various pretreatments with, for example but not limited to, corticosteroids, antihistamines, and non-steroidal anti-inflammatory drugs such as acetaminophen may be used in real world settings with amyloid-targeted therapies to mitigate infusion-related reactions (IRRs) and may serve to reduce the rates and severity of ARIA-E. The potential benefits of pre-treatment / concomitant treatment with a corticosteroid include, but may not be limited to, a 30-50% decrease in ARIA-E events with donanemab modified titration infusion every 4 weeks, reduction in IRRs, and reduction of anti-drug antibodies (AD As) or reduced titers of donanemab during the treatment cycle. The Study AACQ Extension aims to investigate the reduction on rates and severity of ARIA-E while maintaining amyloid reduction at 24, 52, and 76 weeks with the modified titration of donanemab with and without pre-treatment of a corticosteroid. Inclusion and exclusion criteria for Study AACQ Extension are described in Example 1 above.

[0152] Study AACQ Extension is a double-blinded, placebo-controlled, randomized, traditional two-arm design 1 :1 with modified titration treatment of donanemab with pretreatment of corticosteroid, such as dexamethasone 10 mg IV, versus the donanemab modified titration alone, for up to 76 weeks to allow for full donanemab treatment. For example, pre-treatment with dexamethasone 10 mg IV about 30 min to one hour before donanemab infusion may be used. The pre-treatment with dexamethasone 10 mg IV may be performed monthly for the first 6 monthly treatments with donanemab infusion (e.g., 350 mg donanemab infusion at week 0, 700 mg donanemab infusion at week 4, 1050 mg donanemab infusion at week 8, and 1400 mg donanemab infusion at weeks 12, 16, and 20). The patient population may include all participants with mild-cognitive impairment due to Alzheimer’s disease (MCI due to AD), stratified by APOE4 carrier status (homozygous versus heterozygous, or may additionally be limited to include participants with MCI due to AD by APOE4 carrier status alone.

[0153] Primary and secondary endpoints and objectives of Study AACQ Extension are shown in Table 9. One embodiment of study design for the Study AACQ Extension, includingsuggested MRI timepoints to evaluate ARIA and amyloid PET scans using florbetapir, is shown in Figure 4.Table 9. Study AACQ Extension Objectives and Endpoints

[0154] Additionally, other corticosteroids or other anti-inflammatory agents may be administered via IV infusion or orally (PO) prior to infusion with donanemab, and may include, but are not limited to, dexamethasone, prednisone, and methyl prednisone at doses and frequencies to be determined.Example 5: A Study of Donanemab Versus Placebo in Participants at Risk for Cognitive and Functional Decline of Alzheimer's Disease

[0155] Study AACM (hereafter referred to as “Study AACM,” or “AACM;” Protocol Number: I5T-MC-AACM, TRAILBLAZER-ALZ 3, NCT05026866) is a multicenter, randomized, double -blind, Phase 3 study in adults that are cognitively unimpaired with evidence of AD pathology (preclinical Alzheimer’s disease) (see, e.g., AD Stages 1-2; Sabbagh MN, Hendrix S, Harrison JE, “FDA position statement “Early Alzheimer's Disease: Developing Drugs for Treatment, Guidance for Industry,” Alzheimer’s & Dementia 5:13-19 (2019), which is hereby incorporated by reference in its entirety).

[0156] Study AACM will include participants with a Clinical Dementia Rating- Global Score (CDR-GS) of 0 with evidence of AD pathology (^-amyloid plaque) based on P-tau (P-tau- 181 or P-tau-217) blood-based biomarker assay and will assess the effect of donanemab treatment versus placebo on clinical progression of the patient to mild cognitive impairment (MCI). Study AACM will be made up of 4 Study Periods (SP) as shown in Figure 5. Participants will be followed until the target number of primary outcome events is observed, so the total duration of study participation will vary for each participant. The estimated duration for each study period is shown below:• Study Period I - Screening: up to 12 weeks before randomization• Study Period II - Double-blind treatment: approximately 32 weeks (up to 9 doses Q4W)• Study Period III - Double-blind observation: estimated to be up to 300 weeks• Study Period IV - Treatment Extension (Study Period II Placebo Group Only): approximately 174 weeks

[0157] Participants who meet entry criteria will be randomized in a 1:1 ratio to either of the following Study Period II treatment groups: donanemab 700 mg IV Q4W for first 3 doses, and 1400 mg IV Q4W for the next 6 doses; or placebo for 9 doses.Table 10: Study AACM Objectives and EndpointsAbbreviations: AD = Alzheimer’s Disease; ADA = anti-drug antibody; AEs = adverse events; ARIA = amyloid-related imaging abnormalities; BPS-0 = Behavioral Pattern Separation- Object test; CBB = Cogstate Brief Battery; CDR = Clinical Dementia Rating; CDR-GS = CDR-Global Score; CDR-SB = CDR-Sum of Boxes; CFI = Cognitive Function Index; CP AL = Continuous Paired Associate Learning; C-SSRS = Columbia Suicide-Severity Rating Scale; FNAME = Face Name Association Test; iDSSTm = International Daily Symbol Substitution Test-Medicines; ISLT = International Shopping List Test; MoCA = Montreal Cognitive Assessment; MRI = magnetic resonance imaging; PK = pharmacokinetic; SAP = statistical analysis plan.

[0158] Study Period I - Screening: The screening period comprises Visit 1 where the study will be explained to the participant and study partner and informed consent will be obtained.

[0159] Study Period II - Double-Blind Treatment: The treatment period is a double-blind treatment phase beginning at Visit 2 (randomization / baseline). At Visit 2, all remaining procedures should be scheduled as close as possible to the target date, relative to date of first infusion. Participants who meet entry criteria will be enrolled and randomized to receive 1 dose every 4 weeks for a total of up to 9 infusions of treatment with donanemab or placebo. During this double-blind period, participants will receive IV donanemab or IV placebo Q4W. Participants are intended to receive 9 doses of study intervention.

[0160] Study Period III - Double-Blind Observation: The observation period is a doubleblind observation phase beginning at Visit 12. Participants are anticipated to not receive study intervention during this period. Participants will participate in routine visits approximately every 26 weeks to collect clinical and safety assessments. Participants will continue in Study Phase III until the target number of events for the primary endpoint is achieved and the minimum number of participants enroll, up to a maximum of approximately 300 weeks.

[0161] Study Period IV - Treatment Extension (Study Period II Placebo Group Only):Participants who are active in SP III at the time the target number of primary outcome events is observed may be given the option to enter a treatment-extension period.Activation of SP IV is dependent on confirmatory results of donanemab efficacy at sponsor’s discretion. The treatment-extension period begins at Visit 101. Participantsassigned to receive placebo during SP II and who enter SP IV will receive an open-label initial treatment regimen of donanemab for up to 9 doses of donanemab:• 350 mg IV Q4W x 1 dose• 700 mg IV Q4W x 1 dose• 1050 mg IV Q4W x 1 dose, and• 1400 mg IV Q4W x 6 doses.

[0162] After the ninth dose of donanemab, participants will be re-randomized 1 : 1 to receive a double-blind maintenance treatment of either donanemab 3 doses of 1400 mg IV Q52W or placebo. The dosing scheme for A ACM is shown in Figure 5. The overall dosing scheme / treatment interventions for Study A ACM is shown in Table 12.

[0163] Justification for Dose: To reduce participant burden, a once-every-four- weeks (Q4W) dosing schedule was selected over a biweekly (Q2W) regimen. The 1400 mg Q4 week dosing was selected as the highest dose regimen for robust amyloid plaque lowering. Safety data from Study I5T-MC-AACG (NCT NCT03367403, clinicaltrial.gov) showed that the 1400 mg dose of donanemab had an acceptable safety profile based on the ability to monitor and manage AEs and AEs of special interest including ARIA-E, ARIA-H and hypersensitivity reactions, and the overall frequency, severity, and seriousness of AEs at this dose level.

[0164] A titration schedule of 700 mg IV Q4W for the first 3 doses and then 1400 mg IV Q4W (standard titration schedule) was chosen to decrease the risk of ARIA-E. The number of doses (9 total) was selected to optimize amyloid plaque reduction and minimize participant burden in a preclinical population. In Study 15T-MC-AACG, at 24 weeks, plaque reduction was 68 centiloids (CL; see, e.g., Mintun MA, Lo AC, Evans CD, et al., “Donanemab in early Alzheimer’s Disease” N Engl J Med. 2021;384(18):1691-1704, which is hereby incorporated by reference in its entirety). The mean amyloid plaque level for the overall population in Study I5T-MC-AACG was 104 CL. In the preclinical AD population at baseline in Study H8A-MC-LZAZ (Anti- Amyloid Treatment in Asymptomatic Alzheimer’s Disease [A4], NCT 02008357, clinicaltrials.gov), the mean amyloid plaque level was 66 CL (Sperling RA, Donohue MC, Raman R, et al., “Association of factors with elevated amyloid burden in clinically normal older individuals,” JAMA Neurol 2020;77(6):735-745, which is hereby incorporated by reference in its entirety). It is anticipated that >70% of participants will achieve amyloidnegative status with this 32-week dosing paradigm.

[0165] The standard titration schedule (700 mg IV Q4W x 3, followed by 1400 mg IV Q4W) was changed to the modified titration regimen (350 mg IV Q4W x 1, 700 mg IV Q4W x 1, 1050 mg IV Q4W x 1, followed by 1400 mg IV Q4W) based on the results of Study AACQ, which demonstrated similar cumulative exposures and amyloid plaque reduction, with lower frequency of ARIA-E than standard titration.

[0166] By the end of the initial treatment regimen in Study AACM Study Period IV with modified titration as described above, it is anticipated that greater than 70% of participants will achieve amyloid plaque-negative status. Once amyloid is cleared with donanemab treatment, re-accumulation is estimated to be 2.8 CL / year (see, e.g., Shcherbinin et al., “Rapid amyloid clearance and efficacy: Results from TRAILBLAZER-ALZ 2, a phase 3 study of donanemab for treatment of early Alzheimer's disease,” Clinical Trials on Alzheimer’s Disease (CTAD) - 16th Annual Conference: October 24 - 27, 2023, which is hereby incorporated by reference in its entirety).

[0167] To continue evaluation of donanemab’s effect on amyloid reaccumulation after the initial treatment regimen, a maintenance treatment regimen of 1400 mg IV Q52W will be tested. Annual dosing was selected to minimize the burden of infusions and safety assessments. The 1400 mg IV dose was selected because PK / PD analyses suggest that it will continue to maintain amyloid levels below 24.1 CL in greater than 70% of treated participants.

[0168] End of Study: A participant is considered to have completed the study if he / she has completed all required phases of the study, including the last visit or the last scheduled procedure. The end of the study for the primary outcome occurs when the target number of primary outcome events is observed.

[0169] Inclusion Criteria / Exclusion Criteria: Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted in Study AACM. Participants are allowed to participant in Study AACM if, for example but not limited to, any of the following criteria are met:• 55 to 80 years of age inclusive, at the time of signing the informed consent.• A TICS-M score reflective of intact cognitive functioning.• Has a P-tau result consistent with the presence of amyloid pathology.• Have a reliable study partner who will provide written informed consent to participate and is in frequent contact with the participant. The study partner must be of legal age to consent for study participation and familiar with overall function and behavior, suchas day-to-day activities and cognitive abilities. The legal age of consent should be consistent with the local jurisdiction (usually 18 years or 21 years). A second study partner may serve as backup. The study partner must be available to conduct the functional scales. o If a study partner must withdraw from study participation, a replacement may be allowed at the investigator’s discretion. The replacement will need to sign a separate informed consent on the first visit that he or she accompanies the participant.• Have adequate literacy, vision, and hearing for neuropsychological testing in the opinion of the investigator at the time of screening.• Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.• Males and females will be eligible for this study. o Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. o Female participants:• Women not of childbearing potential may participate and include those who are: o infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation), congenital anomaly such as Mullerian agenesis; or o post-menopausal - defined as either:■ A woman 55 or older not on hormone therapy, who has had at least 12 months of spontaneous amenorrhea; or■ A woman at least 55 years of age with a diagnosis of menopause prior to starting hormone replacement therapy.Inclusion criteria: Treatment Extension (Study Period II Placebo Group Only)• Are actively participating in Study AACM at the time of conclusion of Study Period III.• Capable of giving signed informed consent.• Are study participants who are considered appropriate for treatment with donanemab, in the judgment of the investigator.Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply, including but not limited to:Medical Conditions• Mild cognitive impairment or dementia, or significant other neurodegenerative disease that can affect cognition.• Current serious or unstable illnesses including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator’ s opinion, could interfere with the analyses in this study; or has a life expectancy of approximately <5 years.• History of cancer with high risk of recurrence and preventing completion of the trial.• History of clinically significant multiple or severe drug allergies, or severe posttreatment hypersensitivity reactions (including but not limited to erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, and / or exfoliative dermatitis).Imaging, Vital Signs, Electrocardiograms and Laboratory Tests• Have any clinically important abnormality at screening on MRI or clinical laboratory test results that could be detrimental to the participant or study integrity, as determined by investigator.• Have any contraindications for MRI, including claustrophobia or the presence of contraindicated metal (ferromagnetic) implants / cardiac pacemaker.• Have a centrally read MRI demonstrating presence of ARIA-E, >4 cerebral microhemorrhages, more than 1 area of superficial siderosis, any macrohemorrhage or severe white matter disease at screening.• ALT >2.5X ULN of the performing laboratory, AST >2.5X ULN, TBL >1 5X ULN, or ALP >2X ULN at screening.• Note: Participants with TBL >1 ,5X ULN are not excluded if they meet all the following criteria for Gilbert’s syndrome: o Bilirubin is predominately indirect (unconjugated) at screening (direct bilirubin within normal limits). o Absence of liver disease. o ALT, AST, and ALP <1X ULN at screening. o Hemoglobin is not significantly decreased at screening.Prior / Concomitant Therapy• Have had prior treatment with a passive anti-amyloid immunotherapy <5 half-lives prior to randomization.• Have received active immunization against A|3 in any other study.• Have known allergies to donanemab, related compounds, or any components of the formulation.• Current or previous use of prescription medications used as treatment for MCI or AD.Prior / Concurrent Clinical Study Experience• Are currently enrolled in any other medical research (interventional or observational) judged not to be scientifically or medically compatible with this study.• Have participated, within the last 30 days, in a clinical trial involving a study intervention judged not to be scientifically or medically compatible with this study. If the previous study intervention is scientifically or medically incompatible with this study and has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed prior to screening (participation in observational studies may be permitted upon review of the observational study protocol and approval by the sponsor).• Have previously completed or withdrawn from this study or received donanemab in any prior investigational study. This exclusion criterion does not apply to participants who are allowed to rescreen before randomization in this study.Demographic Screening Restrictions• Screening of participants based on age may be restricted at the discretion of the sponsor.• The sponsor may extend screening of individuals from underrepresented groups to optimize the diversity of the study population.

[0170] Primary Endpoint(s) Analysis: The primary outcome is the time to clinical progression as measured by an increase in CDR-GS or an increase of at least 1 point in CDR-SB from baseline, sustained at 2 consecutive visits in participants with baseline CDR-GS 0. If a patient dies prior to observing clinical progression, the intercurrent event of death will be counted as a clinical progression event for the statistical analysis. Time to progression is defined as the time from first infusion until the progression event is observed. For statistical analyses, the time of the progression event will be defined as the date of the first of the two consecutive assessments at which the CDR increased frombaseline. Any additional adjudication to the primary outcome will be prespecified in the SAP prior to unblinding of clinical efficacy data. Note that interim analyses may be conducted for Study AACM. Interims potentially executed include futility, early efficacy, and sample size (the number of events) or study duration re-estimation, and will be conducted by an external Data Monitoring Committee. Investigators will receive information about interim results only if they need to know for the safety of their participants or changes to the protocol. For interims that stop the trial early, participants will proceed to their early termination visit.

[0171] The primary efficacy analysis model is a Cox proportional-hazards model. The model includes terms for treatment, ApoE e4 allelic dose, and age as fixed effects. The primary efficacy analysis will be conducted when at least the prespecified number of events has been achieved, currently planned as approximately 350 events.

[0172] Secondary Endpoint(s) Analysis: MMRM analyses and NCS analyses will be conducted for the ISLT, CP AL, iDSSTm, Category Fluency, CBB, CDR-SB, CFI, MoCA, and the cognitive composite.

[0173] For the MMRM, the change from baseline score for these scales at each scheduled postbaseline visit during the treatment period will be the dependent variable. The model for the fixed effects will include the following terms: baseline score, treatment, visit, treatment-by- visit interaction, baseline-by-visit interaction, ApoE e4 allelic dose, and age at baseline. Visit will be considered a categorical variable. The null hypothesis is that the contrast between the donanemab group versus placebo equals 0. An unstructured covariance matrix will be used to model the within-subject variance-covariance errors. If the unstructured covariance structure matrix results in a lack of convergence, the following tests will be used in sequence:• heterogeneous Toeplitz covariance structure• heterogeneous autoregressive covariance structure• heterogeneous compound symmetry covariance structure• compound symmetry covariance structure

[0174] The Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. Due to the variable length of observation for each participant based on enrollment and the unknown duration of an events-based trial, the primary time point for treatment comparison will be determined at the end of the trial. The treatment group contrast in least-squares mean progression and its associated p-value and 95% confidenceinterval will be calculated for the treatment comparison of donanemab versus placebo using the MMRM model specified above.

[0175] In addition to the MMRM model, the mean for each treatment group over the entire double-blind duration of the study can be modeled using natural cubic splines (NCS, Chambers JM and Hastie TJ, “Statistical Models in S,” Wadsworth & Brooks / Cole; 1992, which is hereby incorporated by reference in its entirety). The NCS model provides a type of smoothing function to the data and can adequately estimate longitudinal trajectories under a variety of shapes (for example, linear and quadratic) for each treatment group. The degrees of freedom of the model can be prespecified to establish the level of smoothing of the data. The number and location of the “knots” is utilized to parse out different time periods where the data may transition from one shape to another to provide an adequate fit.

[0176] Maintenance Dosing Double-Blind Analysis: MMRM and NCS analysis will be conducted on the CDR-SB in the efficacy-evaluable maintenance treatment regimen population.

[0177] For the MMRM, the change from maintenance baseline score for the CDR-SB at each scheduled postbaseline visit during the maintenance period will be the dependent variable. The model for fixed effects may include terms for maintenance baseline score, treatment, visit, treatment-by-visit interaction, baseline-by- visit interaction, ApoE a4 allelic dose, amyloid levels, and age at baseline. Visit will be considered a categorical variable. The null hypothesis is that the contrast between the donanemab maintenance group versus placebo maintenance group at each visit is equal to 0. An unstructured covariance matrix will be used to model the within- subject variance covariance errors. If the unstructured covariance structure matrix results in lack of convergence, the following tests will be used in sequence:• heterogeneous Toeplitz covariance structure• heterogeneous autoregressive covariance structure• heterogeneous compound symmetry covariance structure• compound symmetry covariance structure

[0178] The Kenward- Roger approximation will be used to estimate the denominator degrees of freedom. The treatment group contrast in least-squares mean progression and its associated p- value and 95% confidence interval will be calculated for the maintenance treatment comparison of donanemab versus placebo using the MMRM model specified above.

[0179] Also, the mean for each treatment group over the double-blind maintenance period can be modeled using the natural cubic splines.

[0180] In addition, a slope analysis and / or predictive modeling may be conducted on the CDR-SB to predict the long-term benefit of maintenance dosing (for example, what is the predicted treatment difference after 10 years).

[0181] Evaluation of Immunogenicity: Participant samples will be analyzed using a 4-tiered approach. All samples will be assessed in Tier 1 (screening) for the possible presence of AD As. Samples found to produce a signal above or equal to the screening cut point will be assessed in Tier 2 to confirm specificity to donanemab (confirmation). Any samples confirmed as specific for anti-donanemab antibodies will be reported as “detected.” All samples below the screening cut point (Tier 1) or not confirmed (Tier 2) will be reported as “not detected.” Any “detected” sample in Tier 2 will be assessed in Tier 3 (titer assessment) and Tier 4 (neutralizing antibodies). Antidrug antibody titer values will be reported from Tier 3 titer assessment. Any samples above the Tier 4 assay cut point will be reported as “detected for neutralizing antibodies”; samples below the assay cut point in Tier 4 will be reported as “not detected for neutralizing antibodies.”

[0182] The frequency and percentage of participants with preexisting (baseline) AD As, AD As at any time after baseline, and TE AD As to donanemab will be tabulated. If no ADAs are detected at baseline, TE ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimal required dilution of the assay. For samples with ADAs detected at baseline, TE ADAs are defined as those with a 4-fold (2 dilutions) increase in titer compared to baseline. For the TE ADA participants, the distribution of maximum titers will be described. The frequency of neutralizing antibodies may also be tabulated. The relationship between the presence of antibodies to donanemab and PK, PD, safety, and / or efficacy assessment may be assessed.

[0183] Pharmacokinetic / Pharmacodynamic Analyses: Compartmental modeling of donanemab PK data using nonlinear mixed effects modeling or other appropriate software may be explored, and population estimates for clearance and central volume of distribution may be reported. Depending on the model selected, other PK parameters may also be reported. Exploratory graphical analyses of the effect of dose level or demographic factors on PK parameters may be conducted. If appropriate, data from other studies of donanemab may be used in this analysis.

[0184] The PK / PD relationships between serum donanemab concentration and the Standardized Uptake Value ratio (SUVr), cognitive endpoints, ARIA incidence rate, or other markers of PD activity may be explored graphically. The relationship between the presence of antibodies to donanemab and PK, PD, safety, and / or efficacy may be assessed graphically. To facilitate this modeling, and to ensure that exposure estimates from this study are available at the end of the trial, it is intended that the PK data will be locked after all participants complete Visit 16 (156 weeks of treatment), to allow PK modeling to begin before the end of the trial. No safety or efficacy data will be included in the 156- week PK lock. An Early PK Lock Plan will be developed and implemented prior to this lock, which will specify the safeguards to be taken to ensure the integrity of the study. Additional modeling may be performed based on the results of the graphical analyses.

[0185] Sample Size Determination: Up to approximately 2200 participants will be enrolled in the trial. The sample size was determined to achieve approximately 350 clinical progression events in baseline CDR-GS 0 participants. Assuming a hazard ratio of 0.725, a total of 350 events leads to 85% power to show superiority of donanemab over placebo at a 1 -sided 0.025 alpha level in the baseline CDR-GS 0 participants.

[0186] The overall sample size of up to approximately 2200 participants was chosen to ensure that the trial would achieve the desired number of clinical progression events within an overall trial duration of less than 5 years with high confidence. The assumptions used for this calculation were a uniform distribution of an annualized placebo event rate of 3.5% to 10% (Vos SJB, Xiong C, Visser PJ, et al., “Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study” Lancet Neurol 2013;12(10):957-65; Pankratz VS, Roberts RO, Mielke MM, et al., “Predicting the risk of mild cognitive impairment in the Mayo Clinic Study of Aging,” Neurology 2015;84( 14): 1433-42; both of which are hereby incorporated by reference in their entirety), a hazard ratio of 0.725, and an overall participant dropout rate of 20% at 3 years and 25% at 4 years.

[0187] Approximately 500-600 participants are anticipated to enter the treatment extension period. The assumptions of the placebo decline and the standard deviation of the change from baseline at Week 130, as well as the additional percent slowing of decline that may occur with the maintenance regimen relative to placebo, are unknown. Therefore, the power is provided under a wide range of hypothesized scenarios, an example of which is shown in Table 11. Additional assumptions used in the power calculations include: 20% of participants will drop out during the treatment extension period, a standard deviation of 1for the change from baseline to Week 130, and a two-sided 5% Type I error rate. A two- sample t-test was utilized for the calculations.Table 11. Example of Sample Size and Power on % Slowing of Progression in Study AACMTable 12. Study Interventions AdministeredAbbreviations: IMP = investigational medicinal product; IV = intravenous; N / A = not applicable; NIMP = non-investigational medicinal product; Q4W = every 4 weeks; Q52W = every 52 weeks.

[0188] Dose Modifications: Dose modification of study intervention during the double-blind treatment period (Study Period II) and the initial treatment regimen in Study Period IV is not permitted except for some instances of ARIA; if ARIA occurs during the titration period (that is, before the fourth infusion of study drug), dose modification can be considered at the discretion of the investigator or designee. Dose modifications are not permitted during the maintenance period.

[0189] Statistical Hypotheses: The primary objective is to assess the effect of donanemab versus placebo with respect to clinical progression in participants with preclinical AD as measured by a time to clinical progression. Key secondary hypotheses are that donanemab is superior to placebo with respect to clinical progression in participants with preclinical AD as measured by:• Cognitive composite• International Shopping List Test (ISLT)• Continuous Paired Associates Learning test (CP AL) for visuospatial memory• Individual Digit Symbol Substitution test (iDSSTm)• Category Fluency• Cogstate Brief Battery computer-based cognition test (CBB)• Clinical Dementia Rating-Sum of Boxes (CDR-SB)• Cognitive Flexible Inventory test (CFI), and• Montreal Cognitive Assessment (MoCA)SEQUENCESSEQ ID NO: 1 LCVRDIVMTQTPLSLSVTPGQPASISCKSSQSLLYSRGKTYLNWLLQKPGQSPQLLIYAVSKL DSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIKSEQ ID NO: 2 HCVRQVQLVQSGAEVKKPGSSVKVSCKASGYDFTRYYINWVRQAPGQGLEWMGWINPGS GNTKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGITVYWGQGTTVT vssSEQ ID NO: 3 LCDIVMTQTPLSLSVTPGQPASISCKSSQSLLYSRGKTYLNWLLQKPGQSPQLLIYAVSKLDSGVPDRFSGSGSGTDFTLK1SRVEAEDVGVYYCVQGTHYPFTFGQGTKLE1KRTVAA PS VFIFPPSDEQLKS GTAS VVCLLNNFYPREAKVQWKVDN ALQS GNS QES VTEQDS K DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 4 HCQVQLVQSGAEVKKPGSSVKVSCKASGYDFTRYYINWVRQAPGQGLEWMGWINPGSGNTKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGITVYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSEQ ID NO: 5 LCDR1KSSQSLLYSRGKTYLNSEQ ID NO: 6 LCDR2AVSKLDSSEQ ID NO: 7 LCDR3VQGTHYPFTSEQ ID NO: 8 HCDR1GYDFTRYYINSEQ ID NO: 9 HCDR2WINPGSGNTKYNEKFKGSEQ ID NO: 10 HCDR3EGITVY

Claims

1. CLAIMSWe claim:

1. A method of reducing amyloid beta (AP) plaques in the brain of a human subject suffering from Alzheimer’s disease (AD) comprising: administering to the subject a dose of about 350 mg of an anti-N3pG A antibody; four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose every 4 weeks; wherein the anti-N3pGlu AP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

2. A method of reducing amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events in a human subject wherein the subject’s brain has amyloid beta (AP) plaques, or the subject is suffering from Alzheimer’s disease comprising: administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG AP antibody at a frequency of one 1400 mg dose every 4 weeks;wherein the anti-N3pGlu A0 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

3. A method of treating or preventing Alzheimer’s disease (AD) in a human subject comprising: administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG A antibody; four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose every 4 weeks; wherein the anti-N3pGlu Ap antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

4. A method of slowing disease progression in a human subject suffering from Alzheimer’s disease, comprising: administering to the subject a dose of about 350 mg of an anti-N3pG Ap antibody; four weeks after administration of the 350 mg dose, administering to the subject a dose of about 700 mg of the anti-N3pG Ap antibody; four weeks after administration of the 700 mg dose, administering to the subject a dose of about 1050 mg of the anti-N3pG Ap antibody; and four weeks after the administration of the 1050 mg dose, administering to the subject one or more doses of about 1400 mg of the anti-N3pG Ap antibody at a frequency of one 1400 mg dose every 4 weeks;wherein the anti-N3pGlu A0 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2.

5. The method of any one of claims 1 to 4, wherein the human subject has high risk of ARIA.

6. The method of claim 5, wherein the human subject has at least one AP0E4 allele, has two AP0E4 alleles, has cerebral amyloid angiopathy (CAA), microhemorrhages, or superficial siderosis.

7. The method of any one of claims 1 to 6, wherein the rate of reduction of amyloid plaques in the human subject upon administration of the anti-N3pG Ap antibody is comparable to, matches, or exceeds that of subjects on standard dosing regimen of the anti- N3pG A antibody, wherein the standard dosing regimen comprises: administering to the subject three doses of 700 mg of the anti-N3pG Ap antibody at a frequency of once every 4 weeks; and four weeks after administration of the last 700 mg dose, administering to the subject one or more doses of 1400 mg of the anti-N3pG Ap antibody at a frequency of once every 4 weeks.

8. The method of claim 7, wherein the ARIA risk, ARIA severity, ARIA frequency, or number of ARIA events is reduced as compared to the standard dosing regimen.

9. The method of claim 7 or 8, wherein the duration of administration of the anti-N3pG Ap antibody to the patients on standard dosing regimen is 24 weeks, 52 weeks, 72 weeks, or 76 weeks.

10. The method of any one of claims 1 to 9, wherein the anti-N3pG A0 antibody is administered until AP plaques present in the subject’s brain are cleared (<24 CL), within normal range (visually negative), at minimal levels (<11 CL), or stop reducing (plateau).

11. The method of any one of claims 1 to 9, wherein the 1400 mg dose of the anti-N3pG A antibody is administered until Ap plaques present in the subject’s brain are cleared (<24 CL), within the normal range (visually negative), at minimal levels (<11 CL), or stop reducing (plateau).

12. The method of any one of claims 1 to 11 , wherein the anti-N3pG Ap antibody doses are administered over a period of no more than 24 weeks, 52 weeks, 72 weeks, or 76 weeks.

13. The method of any one of claims 1 to 12, further comprising a step of evaluating the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events: a) before or after the administration of each dose; b) after the administration of 350 mg dose; c) after the administration of 700 mg dose; d) after the administration of 1050 mg dose; or e) after the administration of 1400 mg dose.

14. The method of any one of claims 1 to 12, further comprising a step of evaluating the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events: a) before the administration of the 350 mg dose; b) after the administration of the 350 mg dose and before administering the 700 mg dose; c) after the administration of the 700 mg dose and before administering the 1050 mg dose;d) after the administration of the 1050 mg dose and before administering the 1400 mg dose; or e) after the administration of the 1400 mg dose.

15. The method of claim 13 or 14, wherein the step of evaluating the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events comprises: i) evaluating the subject’s brain’s magnetic resonance image (MRI); or ii) evaluating the subject after the subject displays symptoms consistent with ARIA.

16. The method of any one of claims 13 to 15, wherein if the subject has ARIA or is displaying symptoms consistent with ARIA: i) the administration of the anti-N3pG Ap antibody is stopped and / or corticosteroids are administered to the subject; ii) the administration the anti-N3pG A antibody is temporarily withheld until resolution of ARIA symptoms or radiographic stabilization on MRI; or iii) the administration the anti-N3pG Ap antibody is discontinued until resolution of ARIA symptoms or radiographic stabilization on MRI.

17. The method of claim 16, wherein the administration of the anti-N3pGlu Ap antibody is re-initiated after resolution of ARIA symptoms or radiographic stabilization on MRI.

18. The method of any one of claims 13 to 17, wherein ARIA is ARIA-E or ARIA-H.

19. The method of any one of claims 1 to 18, wherein administration of the anti-N3pGlu Ap antibody:a) slows disease progression by at least 15% as compared to being untreated estimated by Disease Progression Model (DPM), wherein disease progression is measured by iADRS or CDR-SB ; b) slows disease progression by at least 15% as compared to being untreated estimated by a mixed-model repeated-measures analysis (MMRM), wherein disease progression is measured by iADRS or CDR-SB; c) slows disease progression by at least 15% as compared to being untreated, wherein disease progression is measured by Integrated Alzheimer’s disease Rating Scale (iADRS); d) slows disease progression by at least 3 points as compared to being untreated, wherein disease progression is measured by Integrated Alzheimer’s disease Rating Scale (iADRS); e) slows disease progression by at least 20% as compared to being untreated, wherein the disease progression is measured by Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB); f) reduces the level of Af) plaque in the brain of the subject by at least 10%, 20%, 30%, 40%, 50%, or 60% as measured by amyloid PET imaging; or g) reduces plasma P-tau-217 by at least 5% from baseline.

20. The method of any one of claims 1 to 18, wherein administering the anti-N3pGlu Af> antibody reduces A[ plaques by about an average of about 50 centiloids (CL) to about 100 centiloids as compared to Ap plaques prior to administering the anti-N3pGlu A antibody, wherein the Ap plaques are measured by amyloid PET imaging scan.

21. The method of any one of claims 1 to 18, wherein administering the anti-N3pGlu Ap antibody results in LS Mean Change reduction in Ap plaques by about 40-60 centiloids from baseline over 24 weeks, wherein the Ap plaques are measured by amyloid PET imaging scan.

22. The method of any one of claims 1 to 18, wherein administering the anti-N3pGlu A0 antibody results in LS Mean Change reduction in AP plaques by about 56.3 centiloids from baseline over 24 weeks, wherein the A plaques are measured by amyloid PET imaging scan.

23. The method of any one of claims 1 to 18, wherein 24 weeks of administering the anti- N3pGlu Ap antibody reduces the Ap plaque by at least 60% to 70%.

24. The method of any one of claims 1 to 18, wherein 24 weeks of administering the anti- N3pGlu Ap antibody reduces the Ap plaque by at least 67.5%.

25. The method of any one of claims 1 to 24, wherein the anti-N3pGlu Ap antibody is administered intravenously or subcutaneously.

26. The method of any one of claims 1 to 25, wherein the subject has early symptomatic Alzheimer’s disease.

27. The method of any one of claims 1 to 25, wherein the subject has mild cognitive impairment or mild dementia stage of Alzheimer’s disease.

28. The method of any one of claims 1 to 25, wherein the subject has preclinical Alzheimer’s disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, or severe AD.

29. The method of claim 28, wherein the subject has preclinical AD and is administered 1 dose of about 350 mg, 1 dose of about 700 mg, 1 dose of about 1050 mg, and 6 doses of about 1400 mg of the antibody at the frequency of one dose every 4 weeks.

30. The method of any one of claims 1 to 29, wherein the level of Ap plaques in the brain of the subject is sustained at normal levels for at least 52 weeks after the administration of the anti-N3pGlu Ap antibody is stopped.

31. The method of any one of claims 1 to 29, wherein administering the anti-N3pGlu A0 antibody reduces the level of Af3 plaques in the brain of the subject to normal levels by 24 weeks.

32. The method of any one of claims 1 to 31, wherein the anti-N3pGlu Ap antibody comprises a light chain (LC) and a heavy chain (HC), wherein the LC comprises the amino acid sequence of SEQ ID NO: 3 and the HC comprises the amino acid sequence of SEQ ID NO: 4.

33. The method of claim 32, wherein the anti-N3pGlu A antibody comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 3 and the HC comprises the amino acid sequence of SEQ ID NO: 4.

34. The method of any one of claims above, wherein the subject is pretreated or concomitantly treated with a corticosteroid, antihistamine, or a non-steroidal antiinflammatory drug.

35. The method of claim 34, wherein the corticosteroid is dexamethasone, prednisone, or methyl prednisone.

36. The method of claim 34, wherein the corticosteroid is administered at a dose of 10 mg IV 30 minutes to one hour prior to the administration of the antibody.

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