Dosing regimens for early alzheimer's disease

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, e.g., Alzheimer's disease. The invention also relates to a method for preventing or reducing amyloid plaques in the brain of a primary prevention subject. Certain aspects of the invention involve methods, doses, or dosing regimens that decrease the risk, frequency, severity, or occurrence of ARIA in subjects.

Description

DOSING REGIMENS FOR EARLY ALZHEIMER’S DISEASE REFERENCE 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 “31235.xml” created September 19, 2025, that is 14,256 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 (Aβ) plaques in patients with Alzheimer's disease (AD), including early AD, using an anti-N3pG antibody. Additionally, it involves methods, dosages, or dosing regimens intended for preventing or treating conditions where the subject is at risk of developing cerebral amyloid beta (Aβ) plaques or the subject has amyloid beta plaques, e.g., primary prevention of AD or early AD. The invention also covers methods, dosages, or dosing regimens designed to lower the risk, frequency, severity, or occurrence of amyloid-related imaging abnormalities (ARIA). BACKGROUND OF THE INVENTION

[0003] A treatment for Alzheimer's disease (AD) represents one of society's most critical unmet needs. The formation of amyloid-β peptide into brain amyloid plaques marks an early and essential step in Alzheimer's disease progression, leading to neurodegeneration and eventually clinical symptoms such as cognitive and functional impairment.

[0004] 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 γ-secretase to release the Aβ peptide, which comprises peptides ranging from 37-49 amino acid residues. Aβ 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 Aβ peptides, some undergoing N-terminal truncations and modifications like an N-terminal pyroglutamate residue (pGlu). N3pG Aβ (also called N3pG Aβ, N3pE Aβ, Aβ pE3-42, or Aβ p3-42) is a truncated form found only in amyloid plaques, lacking the first two amino acid residues at the N-terminus andhaving a pyroglutamate derived from glutamic acid at the third position. Although a minor component, N3pG Aβ peptide aggressively aggregates and accumulates early.

[0005] Antibody administration against Aβ, including N3pG Aβ antibody, has been shown to disrupt Aβ aggregates and clear plaques in animal models. Antibodies to N3pG Aβ exist in the art. For instance, U.S. Patent No. 10,647,759 discloses anti-N3pG Aβ antibodies and methods of treating diseases like AD with these antibodies. Remternetug, disclosed in U.S. Patent No. 10,647,759 targets the pyroglutamate modification of the third amino acid of amyloid beta (N3pG Aβ) specific to brain amyloid plaques.

[0006] Remternetug’s treatment strategy involves targeting and removing N3pG Aβ in AD patients with existing brain amyloid load, based on the amyloid hypothesis of AD which posits that Aβ production and deposition is an early necessary event in AD pathogenesis. However, sometimes, anti-Aβ antibody administration leads to adverse effects like amyloid-related imaging abnormalities (ARIA), vasogenic edema, microhemorrhages, infusion-related reactions, and immunogenicity. The exact cause of adverse events 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 cerebral edema in some instances.

[0007] ARIA is the most common side effect of this class of drugs. ARIA is usually asymptomatic and can be detected using brain magnetic resonance imaging (MRI). ARIA can lead to symptoms such as headache, confusion, dizziness, visual disturbances, nausea, and seizures. The causes of ARIA are not well understood and can depend on a variety of factors, such as, stage of Alzheimer’s, targeted population, rate of clearance of amyloid plaques.

[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 efficacy of the treatment. Thus, there remains a need for improved doses, dosing regimens, or methods to treat subjects without exacerbating / increasing adverse events and / or with increased efficacy in reducing the amyloid plaques in a patient’s brain. SUMMARY OF THE INVENTION

[0009] The antibodies of the present disclosure bind selectively to N3pG Aβ found primarily in deposited Aβ plaque in human subjects. The prevalence of the N3pG Aβ peptide in deposited parenchymal plaque is very low relative to other Aβ peptide species (~1 to 2%) where the majorityis full-length Aβ1-42. Thus, the total number of binding sites for the antibodies of the present disclosure relative to other plaque binding Aβ antibodies is dramatically lower. Biochemical analysis of CAA, the amyloid depositing along CNS blood vessels, demonstrated a similar low prevalence of N3pG peptides (~2%).

[0010] The present disclosure is related to anti-N3pG Aβ antibodies that exhibit a surprisingly fast rate of amyloid clearance upon administration to a human subject in need thereof without causing or increasing problematic adverse events. 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- N3pG Aβ antibodies and their dosing protocols detailed in this disclosure promote rapid amyloid clearance in the brain while minimizing the risk, occurrence, and / or severity of ARIA.

[0011] In one embodiment, the anti-N3pG Aβ antibody of the present disclosure is remternetug (LY3372993). It is an IgG1 mAb directed at the pyroglutamate modification of the third amino acid of the amyloid-beta peptide (N3pG Aβ) that is present only in brain amyloid plaques. The mechanism of action of remternetug is to target and remove deposited amyloid plaque, a key pathological hallmark of AD, via microglial-mediated clearance.

[0012] Remternetug has a relatively long half-life, reduced risk of immunogenicity, and robust amyloid plaque clearance that allows flexibility in dosing regimens. Such flexibility is not achievable with other anti-amyloid antibodies, such as donanemab. Remternetug can be given less frequently (longer window between doses) while achieving robust amyloid plaque clearance. Additionally, remternetug can be given subcutaneously without compromising its efficacy or exacerbating adverse effects.

[0013] One aspect of the present invention is related to a method of reducing amyloid beta (Aβ) plaques in the brain of a human subject suffering from Alzheimer’s Disease (AD) comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks;wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the dose of the antibody is administered subcutaneously. In some embodiments, the subject is suffering from early AD.

[0014] Another aspect of the present invention is related to 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 (Aβ) plaques, or the subject is suffering from Alzheimer’s disease comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii ), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the dose of the antibody is administered subcutaneously. In some embodiments, the subject is suffering from early AD.

[0015] Yet 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 total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVRconsists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the dose of the antibody is administered subcutaneously. In some embodiments, the subject is suffering from early AD.

[0016] Yet another aspect of the present invention is related to a method of slowing disease progression, cognitive decline, or functional decline in a human subject suffering from Alzheimer’s disease, comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the dose of the antibody is administered subcutaneously. In some embodiments, the subject is suffering from early AD.

[0017] Yet another aspect of the present invention is related to a method of reducing cerebral amyloid beta (Aβ) plaques in the brain of a primary prevention subject comprising administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or about once every 3 months), ii) once about every 26 weeks (or about once every 6 months), or iii) once about every 52 weeks (or about once every year); wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7.

[0018] Yet another aspect of the present invention is related to a method of treating or preventing cerebral amyloid plaque in the brain of a primary prevention subject comprising administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or about once every 3 months), ii) once about every 26 weeks (or about once every 6 months), or iii) once about every 52 weeks (orabout once every year); wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 shows the non-titration-based schema (blinded study) for study LAKC. Superscript “a”: V601 occurs up to 30 days prior to V1. V1 occurs up to 49 days prior to V2 (randomization). Sponsor may strictly control screening visit tolerance toward end of study enrollment. Superscript “b”: per sponsor decision, all participants in the 400 mg QW SC arm will have the dose adjusted to 800 mg SC Q4W or placebo following a minimum 4-week treatment pause. Superscript “c”: upon unblinding of the study, participants receiving placebo SC or placebo IV in the extension period will stop receiving placebo and will proceed to the follow-up period. Superscript “d”: Visits 802 and 803 apply only to participants receiving placebo SC in the extension.

[0020] Figure 2 shows the non-titration-based schema (open label) for study LAKC. Abbreviations: SC = subcutaneous; QW = every week; Q4W = every 4 weeks. Superscript “a”: Visit 1 (V1) occurs up to 49 days prior to V2 (randomization). The sponsor may strictly control screening visit tolerance toward the end of study enrollment. Per sponsor decision, all participants in the 400 mg QW SC arm will have the dose adjusted to 800 mg SC Q4W or placebo following a minimum 4-week treatment pause.

[0021] Figure 3 shows the study scheme for the titration-based treatment groups of LAKC showing the four titration-based arms of the study. In the figure, SC stands for subcutaneous. Superscript “a”: Visit 1 occurs up to 49 days before the start of study intervention at Visit 2. The sponsor may strictly control the screening visit tolerance toward the end of study enrollment. Superscript “b”: Visit 801 occurs 20 weeks after the last dose.

[0022] Figure 4 shows the schema (open label) for study LAKC Addendum 6, which enrolled participants with a low level of baseline amyloid plaque. Remternetug contingent 600 mg SC dosing regimen was initiated and fully enrolled. Abbreviations: SC = subcutaneous. Superscript “a”: a Visit 1 occurs up to 49 days before the start of study intervention at Visit 2. The sponsormay strictly control the screening visit tolerance toward the end of study enrollment. Superscript “b”. Schedule the follow-up visit (Visit 801) only if the participant discontinues early and the ED visit occurs ≤20 weeks from the participant’s last dose of study intervention. If a participant completes Visit 6 (Week 36), Visit 801 is not required.

[0023] Figure 5 shows Kaplan-Meier plot of onset of first ARIA-E by safety MRI Open-label safety population SC LAKC (open-label period): data cutoff date is 26 March 2024. Abbreviations: ARIA-E=amyloid-related imaging abnormality-edema / effusion; LY=LY3372993 (remternetug); MRI = magnetic resonance imaging; PBO = placebo; SC=subcutaneous; SC QW=LY 400 SC QW; SC Q4W=LY 800 SC Q4W; SC Ti1 = SC Titration 1; SC Ti2 = SC Titration 2; SC Ti3 = SC Titration 3; SC Ti4 = SC Titration 4; QW = once every week; Q4W = once every 4 weeks. Notes: The SC QW dosing regimen was stopped. For participants who were already assigned to the 400mg SC QW dosing regimen, the dose and frequency were adjusted to 800 mg SC Q4W (or PBO for double-blind cohort) following a minimum 4-week treatment pause.

[0024] Figure 6 shows the observed LSM mean % change from baseline in Study LAKC with open-label SC dosing regimens (data cutoff date: 26 March 2024). Abbreviations: APOE ɛ4=apolipoprotein subtype E ɛ4; CL=centiloid; LS = least square; MMRM = mixed model for repeated measure; PBO = placebo; QW = once every week; Q4W = once every 4 weeks; Q8W = once every 8 weeks; SC = subcutaneous; TRT = treatment group. MMRM model was adjusted for: baseline CL value, treatment, time, time-by-treatment, and APOE ɛ4 carrier status. Error bars represent standard error. Notes: The SC QW dosing regimen was stopped. For participants who were already assigned to the 400 mg SC QW dosing regimen, the dose and frequency were adjusted to 800 mg SC Q4W (or PBO for double-blind cohort) following a minimum 4-week treatment pause.

[0025] Figure 7 shows the study schema for LAKI. In the figure, LY stands for remternetug; Q4W = every 4 weeks; Q8W = every 8 weeks; V = visit; W = week. Superscript “a”: visit 601 and visit 1. Superscript “b”: if remternetug meets success factors defined by sponsor, then qualifying participants who were randomized to placebo and complete the Double-Blind Observation Period may have access to remternetug. Superscript “c”: randomization (enrollment, that is, assignment to treatment) occurs at V2. Superscript “d”: Double-Blind Observation Period continues until the minimum number of participants are enrolled and the target number of events for the primaryendpoint is achieved, up to approximately 234 weeks. Superscript “e”: visit 801 (follow-up) occurs at least 20 weeks after a participant’s last dose of study intervention. If at the time of study completion or early discontinuation more than 20 weeks have passed since the participant’s last dose of study intervention, Visit 801 is not required.

[0026] Figure 8 shows the predicted pharmacokinetic (PK) / serum concentrations of remternetug (µg / mL) vs. placebo over time (up to 260 weeks) in the top row, and the predicted Aβ removal in centiloids of remternetug vs. placebo over time (up to 260 weeks) in the second row, for different dosing regimens and frequencies, from an analysis of Study LAKC for a primary prevention population. The far-left top panel depicts the placebo PK as a flat line (no drug administration) over 260 weeks. The far-left bottom panel depicts the predicted PD response in Aβ accumulation in a primary prevention population over 260 weeks, with an average increase approaching an increase of approximately 5 centiloids (CL) / year from baseline, without drug treatment. Top row column “a” represents predicted remternetug serum concentrations (µg / mL) after a first dose of 320 mg, subsequent 640 mg of a second dose at 26 weeks, and subsequent 960 mg of remternetug as the third dose, at intervals of 52 weeks, out to 208 weeks. Top row column “b” represents predicted remternetug serum concentrations (µg / mL) after a first dose of 320 mg, a second dose of 640 mg at 24 weeks, subsequent 640 mg dose at 52 weeks, subsequent dose of 960 mg at 78 weeks, with additional dosing every 52 weeks out to 234 weeks. Top row column “c” represents predicted remternetug serum concentrations (µg / mL) after a first dose of 320 mg, with additional dosing of 640 mg remternetug every 26 weeks, out to 234 weeks. Top row column “d” represents the predicted remternetug serum concentrations (µg / mL) after a first dose of 500 mg, a subsequent second dose of 500 mg at week 26, subsequent third dose of 1000 mg at week 52, and subsequent dosing of 1000 mg every 52 weeks, out to 208 weeks. Top row column “e” represents the predicted remternetug serum concentrations (µg / mL) after a first dose of 500 mg, a subsequent second dose of 500 mg at week 26, subsequent third dose of 500 mg at week 52, and subsequent dosing of 1000 mg every 52 weeks, out to 234 weeks. Top row column “f” represents the predicted remternetug serum concentrations (µg / mL) after a first dose of 500 mg remternetug, a subsequent second dose of 500 mg at week 26, a subsequent third dose of 500 mg at week 52, and subsequent dosing of 700 mg every 26 weeks, out to week 208. The bottom row for columns “a” to “f” depict the predicted Aβ removal in centiloids (CL) over the corresponding time points according to thedosing and frequencies described above. The grey area indicates a 90% prediction interval around the projected slowing / prevention of cerebral Aβ plaque accumulation levels (in CL) for each of the doses and frequencies described.

[0027] Figure 9 shows the analysis of the predicted proportion of individuals below the threshold of amyloid plaque positivity (e.g., 24. 1 CL) as determined by amyloid PET, at various doses (as described for Figure 8 above, i.e., doses “a,” “b,” “c,” “d,” “e,” and “f,” vs. placebo) in a primary prevention population of AD over 260 weeks, from study LAKC. The dashed line in Figure 9 indicates a 90% cutoff level of individuals below the threshold of amyloid positivity. The grey area indicates a 95% confidence interval. This figure demonstrates that individuals in a primary prevention population will maintain at an Aβ plaque level below the threshold of amyloid positivity (24.1 CL) relative to placebo, out to 260 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0028] The present disclosure is related to anti-N3pG Aβ antibodies that exhibit a surprisingly fast rate of amyloid clearance without causing or increasing problematic adverse events upon administration to a human subject suffering from diseases related to accumulation of amyloid plaques in the brain. In one embodiment, the anti-N3pG Aβ antibody of the present disclosure is remternetug (LY3372993). It is an IgG1 monoclonal antibody (mAb) directed at the pyroglutamate modification of the third amino acid of the amyloid-beta peptide (N3pG Aβ) that is present only in brain amyloid plaques. The mechanism of action of remternetug is to target and remove deposited amyloid plaque, a key pathological hallmark of AD, via microglial-mediated clearance.

[0029] Remternetug has a relatively long half-life, reduced risk of immunogenicity, and robust amyloid plaque clearance that allows flexibility in dosing regimens. Such flexibility is not achievable with other anti-amyloid antibodies, such as, donanemab. Remternetug can be given less frequently (longer window between doses) while achieving robust and fast amyloid plaque clearance. In some embodiments, remternetug can be administered subcutaneously (SC). SC doses can be administered either every 4 weeks or every 8 weeks. Such intervals allow time for adverse events, e.g., asymptomatic ARIA to resolve without interrupting dosing.

[0030] The dosing regimens described here provide for fast and robust amyloid clearance, mitigate risk of adverse events, and reduce healthcare burden by allowing for less frequent dosing and / orreduced number of doses. As remternetug’s doses can be administered subcutaneously and less frequently, a dosing regimen can be administered easily, potentially increasing compliance, and adherence to therapy. Another advantage of remternetug is that it can administered in low doses and / or less frequently to achieve rapid and complete amyloid plaque clearance. Remternetug can achieve very high levels and rates of amyloid plaque clearance which represents a best-in-class treatment option.

[0031] In some embodiments, the methods, doses, and dosing regimens of the present invention are related to human subjects who have a disease characterized by Aβ plaques in the brain. This disease can be early Alzheimer’s disease (early AD), preclinical AD, mild cognitive impairment (MCI), clinical AD, or prodromal AD. In one embodiment, the patient is suffering from early AD (i.e., stages 1, 2, and 3 of AD according to FDA) or stage 4 of AD. In some embodiments, the patient is suffering from preclinical AD. In some embodiments, the patient is suffering from MCI. In some embodiments, the patient is suffering from clinical AD. In some embodiments, the patient is suffering from prodromal AD. In one embodiment, the patient is suffering from stage 4 AD (i.e., stage 4 of AD according to FDA).

[0032] In some embodiments, the methods, doses, or dosing regimens identified in the present disclosure result in the treatment or prevention of Alzheimer’s disease. In some embodiments, the methods, doses, or dosing regimens identified in the present disclosure causes: i) reduction of Aβ plaques in the brain of the human subject; ii) slowing of cognitive decline in the human subject; iii) slowing of functional decline in the human subject; iv) slowing of disease progression in the human subject; or v) prevention of accumulation of amyloid beta plaques in the brain of the human subject.

[0033] In some embodiments, the methods, doses, or dosing regimens identified in the present disclosure result in the treatment or prevention of early Alzheimer’s disease. In some embodiments, the methods, doses, or dosing regimens identified in the present disclosure causes: i) reduction of Aβ plaques in the brain of the human subject suffering from early AD; ii) slowing of cognitive decline in the human subject suffering from early AD; iii) slowing of functional decline in the human subject suffering from early AD; or iv) slowing of disease progression in the human subject suffering from early AD.

[0034] In some aspects, the methods, doses, or dosing regimens of the present disclosure are related to reducing Aβ plaques or Aβ load, preventing memory loss, and slowing or preventingcognitive or functional decline in a patient having a disease characterized by Aβ plaques. Some aspects of the present disclosure are related to a method of treating or preventing a disease characterized by Aβ plaques in a human subject comprising administering to the subject an anti- N3pG Aβ antibody to reduce Aβ plaques. Such treatment results in decrease or reduction in the amyloid deposits, amyloid beta plaques, or Aβ load in brain of the patient. 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 217 levels in a patient. 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 Aβ 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 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 beta plaques in the brain of a human subject who have one or two alleles of APOE4.

[0035] In certain embodiments, the methods, doses, or dosing regimens described herein pertain to treating or preventing amyloid beta plaque or its accumulation in the brains of human subjects aged 65 or older. In some embodiments, the subjects aged 65 or older lack one or both APOE4 alleles.

[0036] The anti-N3pG Aβ antibodies described in various aspects of the present disclosure include: • an anti-N3pG Aβ antibody comprising: light chain complementarity determining region 1 (LCDR1) having an amino acid sequence of SEQ ID NO: 4, light chain complementarity determining region 2 (LCDR2) having an amino acid sequence of SEQ ID NO: 5, and light chain complementarity determining region 3 (LCDR3) having an amino acid sequence of SEQ ID NO: 6 or an amino acid sequence havingat least 95% homology to LCDR1 of SEQ ID NO: 4, an amino acid sequence having at least 95% homology to LCDR2 of SEQ ID NO: 5, and an amino acid sequence having at least 95% homology to LCDR3 of SEQ ID NO: 6; • an anti-N3pG Aβ antibody comprising: heavy chain complementarity determining region 1 (HCDR1) having an amino acid sequence of SEQ ID NO: 1, heavy chain complementarity determining region 2 (HCDR2) having an amino acid sequence of SEQ ID NO: 2, and heavy chain complementarity determining region 3 (HCDR3) having an amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 95% homology to HCDR1 of SEQ ID NO: 1, an amino acid sequence having at least 95% homology to HCDR2 of SEQ ID NO: 2, and an amino acid sequence having at least 95% homology to HCDR3 of SEQ ID NO: 3; • an anti-N3pG Aβ antibody comprising: LCDR1 having an amino acid sequence of SEQ ID NO: 4, LCDR2 having an amino acid sequence of SEQ ID NO: 5, LCDR3 having an amino acid sequence of SEQ ID NO: 6, HCDR1 having an amino acid sequence of SEQ ID NO: 1, HCDR2 having an amino acid sequence of SEQ ID NO: 2, and HCDR3 having an amino acid sequence of SEQ ID NO: 3 or amino acid sequence having at least 95% homology to LCDR1 of SEQ ID NO: 4, amino acid sequence having at least 95% homology to LCDR2 of SEQ ID NO: 5, amino acid sequence having at least 95% homology to LCDR3 of SEQ ID NO: 7, amino acid sequence having at least 95% homology to HCDR1 of SEQ ID NO: 8, amino acid sequence having at least 95% homology to HCDR2 of SEQ ID NO: 9, and amino acid sequence having at least 95% homology to HCDR3 of SEQ ID NO: 10; • an anti-N3pG Aβ 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: 4, LCDR2 is SEQ ID NO: 5, LCDR3 is SEQ ID NO: 6, HCDR1 is SEQ ID NO: 1, HCDR2 is SEQ ID NO: 2, and HCDR3 is SEQ ID NO: 3 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: 4, LCDR2 having at least 95% homology to SEQ ID NO: 5, LCDR3 having at least 95%homology to SEQ ID NO: 6, HCDR1 having at least 95% homology to SEQ ID NO: 1, HCDR2 having at least 95% homology to SEQ ID NO: 2, and HCDR3 having at least 95% homology to SEQ ID NO: 3. • an N3pG Aβ antibody comprising a light chain (LC) comprising: the amino acid sequence of SEQ ID NO: 10 or amino acid sequence having at least 95% homology to SEQ ID NO: 10; • an N3pG Aβ antibody comprising a heavy chain (HC) comprising: the amino acid sequence of SEQ ID NO: 9 or amino acid sequence having at least 95% homology to SEQ ID NO: 9; • an anti-N3pG Aβ antibody comprising a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9 or wherein the LC comprises amino acid sequence having at least 95% homology to SEQ ID NO: 10 and the HC comprises amino acid sequence having at least 95% homology to SEQ ID NO: 9; • an anti-N3pG Aβ antibody comprising two light chains and two heavy chains, wherein the LC comprises amino acid sequence of SEQ ID NO: 10 or amino acid sequence having at least 95% homology to SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9 or amino acid sequence having at least 95% homology to SEQ ID NO: 9. • an N3pG Aβ antibody comprising a LCVR comprising the amino acid sequence of SEQ ID NO: 8 or amino acid sequence having at least 95% homology to SEQ ID NO: 8; • an N3pG Aβ antibody comprising a HCVR comprising the amino acid sequence of SEQ ID NO: 7 or amino acid sequence having at least 95% homology to SEQ ID NO: 7. • an N3pG Aβ antibody comprising a LCVR and a HCVR wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 8 or amino acid sequence having at least 95% homology to SEQ ID NO: 8; and the HCVR comprises the amino acid sequence of SEQ ID NO: 7 or amino acid sequence having at least 95% homology to SEQ ID NO: 7.

[0037] In an embodiment, the anti-N3pG Aβ antibody of the present disclosure is remternetug. Remternetug is a monoclonal antibody directed at the N3pG Aβ that is present only in deposited amyloid plaques. Remternetug includes two light chains and two heavy chains, wherein the LC comprises amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. Remternetug is an IgG1 monoclonal antibody consisting of 2 identical light chain polypeptides composed of 214 amino acids each and 2 identical heavy chain polypeptides composed of 451 amino acids each. Each heavy chain contains a single, N-linked glycosylation site at Asn302. Remternetug binds specifically to the aggregated N3pG Aβ peptide with high affinity (apparent dissociation constant approximately 45.7 nM). Remternetug selectively targets deposited plaque in the AD brain and has been engineered to maximize high effector function, including, target engagement, and microglia-mediated phagocytosis of the plaque.

[0038] In some embodiments, the antibody of the present disclosure comprises a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the antibody of the present disclosure comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9.

[0039] One aspect of the present invention is related to a method of reducing cerebral amyloid beta (Aβ) plaques in the brain of a primary prevention subject comprising administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months), ii) once about every 26 weeks (or once about every 6 months), iii) once about every 52 weeks (or once about every year), or iv) or any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7.

[0040] In some aspects, the present invention is related to an anti-N3pG Aβ antibody for use in reducing cerebral amyloid beta plaques in the brain of a primary prevention subject comprising: administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti- N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months), ii) once about every 26 weeks (or once about every 6 months), iii) once about every 52weeks (or once about every year), or iv) or any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7.

[0041] In some aspects, the present invention is related to use of an anti-N3pG Aβ antibody in the manufacture of a medicament for reducing cerebral amyloid beta (Aβ) plaques in the brain of a primary prevention subject comprising: administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months), ii) once about every 26 weeks (or once about every 6 months), iii) once about every 52 weeks (or once about every year), or iv) or any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7.

[0042] Another aspect of the present invention is related to a method of treating or preventing cerebral amyloid plaque in the brain of a primary prevention subject comprising administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months), ii) once about every 26 weeks (or once about every 6 months), iii) once about every 52 weeks (or once about every year), or iv) or any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7.

[0043] In some aspects, the present invention is related to an anti-N3pG Aβ antibody for use in treating or preventing cerebral amyloid beta plaques in the brain of a primary prevention subject comprising: administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months), ii) once about every 26 weeks (or once about every 6 months), iii) once about every 52 weeks (or once about every year), or iv) or any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7.

[0044] In some aspects, the present invention is related to use of an anti-N3pG Aβ antibody in the manufacture of a medicament for treating or preventing cerebral amyloid beta plaques in the brain of a primary prevention subject comprising: administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months), ii) once about every 26 weeks (or once about every 6 months), iii) once about every 52 weeks (or once about every year), or iv) or any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7.

[0045] In some embodiments, the methods described in the present disclosure i) minimizes amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events in the subject; ii) treats or prevents Alzheimer’s Disease (AD) in the subject; iii) prevents progression to preclinical AD or symptomatic AD in the subject; iv) maintains the subject below amyloid positivity level (below ~24.1 centiloids as measured by PET); v) slows AD disease progression, cognitive decline, or functional decline in the subject; and / or vi) reduces cerebral amyloid plaque level in the subject.

[0046] In some embodiments, the antibody is administered subcutaneously to primary prevention subjects or to subjects described in this disclosure.

[0047] In some embodiments, the primary prevention subject is administered one or more doses of the anti-N3pG Aβ antibody of about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 500 mg, about 640 mg, about 660, about 680 mg, about 700 mg, about 800 mg, about 960 mg, about 990 mg, about 1000 mg, about 1020 mg, or any combination thereof.

[0048] In some embodiments, the primary prevention subject is administered one or more doses of the anti-N3pG Aβ antibody of about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, or any combination thereof.

[0049] In some embodiments, the primary prevention subject is administered the one or more doses of the anti-N3pG Aβ antibody, as disclosed herein, at a frequency of: i) once about every 13 weeks (or once about every 3 months); ii) once about every 26 weeks (or once about every 6 months); iii) once about every 52 weeks (or once about every year); or iv) any combination thereof.

[0050] In some embodiments, the primary prevention subject is administered a titration dosing regimen wherein the titration dosing regimen is selected from Table 1. Table 1: Various Embodiments of Dosing regimens for administration to primary prevention subjects). Each dosing regimen includes a titration dosing regimen and a maintenance dosing regimen. Titration Dosing RegimenaMaintenance Dosing s0 00 0 0 0 0 0 0 00 0 0 0a Each empty box indicates no dose in the corresponding week “b” Each empty box indicates no dose in the corresponding week “c” Each row provides a dosing regimen that includes a titration dosing regimen and a maintenance dosing regimen “d” Start of titration dosing regimen “e” Start of maintenance dosing regimen

[0051] In some embodiments, the primary prevention subject is administered one or more maintenance doses. The maintenance dose or the maintenance dosing regimen: i) minimizes amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events in the subject; ii) treats or prevents Alzheimer’s Disease (AD) in the subject; iii) prevents progression to preclinical AD or symptomatic AD in the subject; iv) maintains the subject below amyloid positivity level (below ~24.1 centiloids as measured by PET); v) slows AD disease progression, cognitive decline, or functional decline in the subject; and / or vi) reduces cerebral amyloid plaque level in the subject.

[0052] In some embodiments, the primary prevention subject is administered a titration dosing regimen selected from Table 1 or a maintenance dosing regimen selected from Table 1. In some embodiments, the primary prevention subject is administered a titration dosing regimen selected from Table 1 and a maintenance dosing regimen selected from Table 1.

[0053] In some embodiments, the primary prevention subject is administered a maintenance dosing regimen wherein the maintenance dosing regimen is selected from Table 1. In some embodiments, the maintenance dosing regimen: i) minimizes amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events in the subject; ii) treats or prevents Alzheimer’s Disease (AD) in the subject; iii) prevents progression to preclinical AD or symptomatic AD in the subject; iv) maintains the subject below amyloid positivity level (below ~24.1 centiloids as measured by PET); v) slows AD disease progression, cognitive decline, or functional decline in the subject; and / or vi) reduces cerebral amyloid plaque level in the subject.

[0054] In some embodiments, the maintenance dosing regimen is administered to the primary prevention subject indefinitely. In some embodiments, the maintenance dosing regimen is administered to the primary prevention subject for 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 20 years, or 30 years.

[0055] In some embodiments, the primary prevention subject is administered a dosing regimen (which includes both the titration dosing regimen and the maintenance dosing regimen) as follows: i) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; and then 960 mg dose at week 52 (or a year) after start of the dosing regimen and every 52 weeks (or every year) thereafter; ii) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; and then 640 mg dose at week 52 (or a year) after start of the dosing regimen and every 26 weeks (or every 6 months) thereafter; iii) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; then 640 mg dose at week 52 (or a year) after start of the dosing regimen; then a 960 mg dose at week 78 (or year and half) after start of the dosing regimen and every 52 weeks (or every year) thereafter; or iv) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; then 640 mg dose at week 52 (or a year) after start of the dosing regimen; then a 640 mg dose at week 78 (or year and half) after start of the dosing regimen; and then a 960 mg dose every 52 weeks (or every year).

[0056] In some embodiments, the methods of the present disclosure include a step of evaluating the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events: i) before the administration of each titration dose; ii) after the administration of each titration dose; iii) before the administration of each maintenance dose; or iv) after the administration of each maintenance dose. In some embodiments, 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.

[0057] According to the methods of the present disclosure, if the primary prevention subject has ARIA or is displaying symptoms consistent with ARIA: i) the administration of the anti-N3pG Aβ antibody may be stopped, and corticosteroids may be administered to the subject; ii) the administration the anti-N3pG Aβ antibody may be temporarily withheld until resolution of ARIA symptoms or radiographic stabilization on MRI; or iii) the administration the anti-N3pG Aβ antibody may be discontinued.

[0058] In some embodiments, the administration of the antibody of the present disclosure does not result in ARIA events in the primary prevention subject or results in reduction in the risk, severity, frequency, or number of events of ARIA. In some embodiments, the administration of the antibody of the present disclosure does not result in serious ARIA or symptomatic ARIA.

[0059] In some embodiments, the primary prevention subject is administered an anti-N3pG Aβ antibody that includes a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the primary prevention subject of the present disclosure is administered an anti- N3pG Aβ antibody that includes two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9.

[0060] One aspect of the present invention is related to a method of reducing amyloid beta (Aβ) plaques in the brain of a human subject suffering from Alzheimer’s Disease (AD) comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0061] In some aspects, the present invention is related to an anti-N3pG Aβ antibody for use in reducing amyloid beta (Aβ) plaques in the brain of a human subject suffering from Alzheimer’s Disease (AD) comprising: i) administering to the subject a total of two doses of 400 mg of an anti- N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks afteradministration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0062] In some aspects, the present invention is related to use of an anti-N3pG Aβ antibody in the manufacture of a medicament for reducing amyloid beta (Aβ) plaques in the brain of a human subject suffering from Alzheimer’s Disease (AD) comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0063] Another aspect of the present invention is related to 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 (Aβ) plaques, or the subject is suffering from Alzheimer’s disease comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ antibody comprises a light chainvariable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0064] In some aspects, the present invention is related to an anti-N3pG Aβ antibody for use in reducing amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events comprising: i) administering to the subject a total of two doses of 400 mg of an anti- N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0065] In some aspects, the present invention is related to use of an anti-N3pG Aβ antibody in the manufacture of a medicament for reducing amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0066] Yet 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 total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0067] In some aspects, the present invention is related to an anti-N3pG Aβ antibody for use in treating or preventing Alzheimer’s Disease (AD) in a human subject comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti- N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0068] In some aspects, the present invention is related to use of an anti-N3pG Aβ antibody in the manufacture of a medicament for treating or preventing Alzheimer’s Disease (AD) in a human subject comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to thesubject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0069] Yet another aspect of the present invention is related to a method of slowing disease progression, cognitive decline, or functional decline in a human subject suffering from Alzheimer’s disease, comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0070] In some aspects, the present invention is related to an anti-N3pG Aβ antibody for use in slowing disease progression, cognitive decline, or functional decline in a human subject suffering from Alzheimer’s disease comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ antibody comprises a light chainvariable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0071] In some aspects, the present invention is related to use of an anti-N3pG Aβ antibody in the manufacture of a medicament for slowing disease progression, cognitive decline, or functional decline in a human subject suffering from Alzheimer’s disease comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti- N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, the subject is suffering from early AD.

[0072] The anti-N3pG Aβ 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 embodiments, the anti-N3pG Aβ antibody is administered subcutaneously to a subject as disclosed herein. In some embodiments, the anti- N3pG Aβ antibody is administered subcutaneously to a subject for the treatment or prevention of early AD.

[0073] In some embodiments, the subject is administered 2 doses of the 800 mg dose of step ii) (as disclosed in various aspects of the present disclosure) at a frequency of one 800 mg dose every 8 weeks (Q8W). In some embodiments, the subject is administered 3 doses of the 800 mg dose of step ii) at a frequency of one 800 mg dose every 8 weeks (Q8W). In some embodiments, the subject is administered 4 doses of the 800 mg dose of step ii) at a frequency of one 800 mg dose every 8 weeks (Q8W). In some embodiments, the subject is administered 5 doses of the 800 mgdose of step ii) at a frequency of one 800 mg dose every 8 weeks (Q8W). In some embodiments, the subject is administered 7 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W). In some embodiments, the subject is administered 9 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W). In some embodiments, the subject is administered 11 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W). In some embodiments, the subject is administered 13 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W).

[0074] In some embodiments, the subject is administered a maintenance dose of the antibody of the present disclosure after the dosing regimen is stopped, e.g., after the total of one to thirteen doses of 800 mg of the antibody are administered to the subject (as described in step iii) of the various aspects of the present disclosure). In some embodiments, the subject is administered the maintenance dose after the 800 mg dose (being administered at Q4W) of the antibody is stopped. For example, the subject is administered a maintenance dose of about 200 mg every three months, every six months, every year, every 13 weeks, every 26 weeks, or every 52 weeks. In some embodiments, the subject is administered a maintenance dose of about 400 mg every three months, every six months, every year, every 13 weeks, every 26 weeks, or every 52 weeks. In some embodiments, the subject is administered a maintenance dose of about 600 mg every three months, every six months, every year, every 13 weeks, every 26 weeks, or every 52 weeks. In some embodiments, the subject is administered a maintenance dose of about 800 mg every three months, every six months, every year, every 13 weeks, every 26 weeks, or every 52 weeks. In some embodiments, the subject is administered no maintenance dose. In some embodiments, the subject is administered a maintenance dose of about 200 mg every six months. In some embodiments, the subject is administered a maintenance dose of about 400 mg every six months. In some embodiments, the subject is administered a maintenance dose of about 600 mg every six months. In some embodiments, the subject is administered a maintenance dose of about 800 mg every six months.

[0075] In some embodiments, the methods or dosing regimens of the present disclosure include 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 each 400 mg dose in step i); c) after the administration of each 800 mg dose in step ii); or d) after the administration of each 800 mg dose in step iii).

[0076] In some embodiments, 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.

[0077] In some embodiments of the present disclosure, if the subject has ARIA or is displaying symptoms consistent with ARIA: i) the administration of the anti-N3pG Aβ antibody is stopped and / or corticosteroids are administered to the subject; ii) the administration the anti-N3pG Aβ antibody is temporarily withheld until resolution of ARIA symptoms or radiographic stabilization on MRI; or iii) the administration the anti-N3pG Aβ antibody is discontinued until resolution of ARIA symptoms or radiographic stabilization on MRI.

[0078] In some embodiments, the administration of the anti-N3pG Aβ antibody according to the methods, doses, or dosing regimens of the present disclosure does not a) result in ARIA events in the subject or b) results in reduction in the risk, severity, frequency, or number of events of ARIA. In some embodiments, the administration of the antibody does not result in serious ARIA or symptomatic ARIA.

[0079] According to some embodiments, administering of the anti-N3pG Aβ antibody reduces Aβ plaques by about 60 to about 95% as compared to baseline, wherein the Aβ plaques are measured by amyloid PET imaging scan. According to some embodiments, administering the anti-N3pG Aβ antibody results in LS Mean Change reduction in Aβ plaques by about 60% to about 95% from baseline, wherein the Aβ plaques are measured by amyloid PET imaging scan. According to some embodiments of the present disclosure, administering the anti-N3pG Aβ antibody results in the LS Mean Change reduction in Aβ plaques by about 60% to about 95% from baseline is after 76 weeks.

[0080] In some embodiments, the reduction of Aβ plaques in the brain of the human subject is determined by amyloid PET brain imaging or a diagnostic that detects Aβ or a biomarker for Aβ. 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 Aβ or a biomarker for Aβ. 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 byreference in its entirety); Florbetaben (Syed et al., “[18F]Florbetaben: A Review β-AmyloidPET Imaging in Cognitive Impairment,” CNS Drugs 29, 605–613 (2015), which is hereby incorporated by reference in its entirety); and Flutemetamol (Heurling et al., “Imaging β-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).

[0081] F 18 florbetapir can provide a qualitative and quantitative measurement of brain plaque load in patients, including patients with early AD, 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 β-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).

[0082] Amyloid imaging with radiolabeled PET compounds can also be used to determine if Aβ deposit in the brain of a human patient is reduced or increased (e.g., to calculate the percentage reduction in Aβ 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 Aβ 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 intheir entireties). In some embodiments, the change in brain amyloid plaque deposition from baseline is measured by F 18 florbetapir PET scan.

[0083] This disclosure encompasses the use of biomarkers indicative of diseases marked by Aβ plaques in the human brain, such as, Alzheimer’s disease. These biomarkers include, for instance, amyloid deposits, amyloid plaque, Aβ in CSF, Aβ 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 various 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. 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. Subjects may possess a genetic mutation leading to autosomal-dominant Alzheimer’s disease or may be 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.

[0084] In some embodiments of the disclosure, presence of abnormal brain pathology in a patient may be used as an inclusion criterion for clinical trials, testing, or for selection of patients for treatment with remternetug. In some specific embodiments, the patient selected for the clinical trial or for treatment with remternetug has abnormal brain pathology.

[0085] Exemplary tests for establishing the presence of abnormal brain pathology (and / or selection of patients for treatment with remternetug) include PET (positron emission tomography), CSF (cerebrospinal fluid) based testing, or certain blood-based tests.

[0086] Examples of CSF based tests that may be used for the purposes of the present invention include P-tau-181, amyloid beta 42 (Aβ42) (Palmqvist, S. et al., “Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Beta-amyloid 42: a Cross-validationStudy Against Amyloid Positron Emission Tomography. JAMA Neurol 71, 1282-1289 (2014), which is hereby incorporated by reference in its entirety)), or total tau.

[0087] Examples of blood-based tests that may be used for the purposes of the present invention include ratio of Aβ42 / Aβ40 or Aβ42 / Aβ38 (Janelidze et al., “CSF Abeta42 / Abeta40 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).

[0088] In some embodiments the presence of amyloid brain pathology may be established by methods such as, amyloid imaging with radiolabeled PET compounds or using a diagnostic that detects Aβ or a biomarker for Aβ. Exemplary methods that can be used in the present disclosure to establish abnormal brain pathology include, e.g., Florbetapir (Carpenter, et al., “The Use of the Exploratory IND in the Evaluation and Development of 18F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: A Review of One Company's Experience,” The 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 β-Amyloid PET Imaging in Cognitive Impairment,” CNS Drugs 29, 605–613 (2015), which is hereby incorporated by reference in its entirety); and Flutemetamol (Heurling et al., “Imaging β-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).

[0089] PET, cerebrospinal fluid, or plasma-based analysis of β-amyloid can also be used to measure the amyloid load / burden for the purposes of the present disclosure. For example, Aβ42 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 Aβ42 / Aβ40 or Aβ42 / Aβ38can be used as a biomarker for amyloid beta (Janelidze et al., “CSF Abeta42 / Abeta40and Abeta42 / Abeta38Ratios: Better Diagnostic Markers of Alzheimer Disease,” Ann. Clin. Transl. Neurol. 3, 154-165 (2016), which is hereby incorporated by reference in its entirety).

[0090] In a specific embodiment, the presence of abnormal brain pathology in a patient is established by using Phospho-tau-217 is measured on the Cobas® e801 analyzers using the electrochemiluminescence immunoassay (ECLIA) sandwich principle developed by RocheDiagnostics. An exemplary method for Roche’s ECLIA is as follows: The total duration of the assay is 18 minutes and contains 2 incubation steps. The first incubation step combines 60 µL of patient sample with a biotinylated monoclonal antibody specific for phosphorylation at threonine 217 (numbering based on Tau 4R2N) and a monoclonal Tau-specific antibody labeled with a ruthenium complex. These react to form a sandwich complex. The second incubation step combines streptavidin-coated microparticles with the sandwich complex and becomes bound to the solid phase via interactions of biotin and streptavidin. The reaction mixture is then aspirated into the Cobas e 801 measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell II M and an application of a voltage to the electrode then induces a chemiluminescent emission measured by a photomultiplier. Results are determined via a calibration curve, which is instrument-specifically generated by 2-point calibration, and a master curve provided via the reagent barcode or e-barcode.

[0091] In some embodiments, the testing with the above-described ECLIA may be used as a patient inclusion criterion for clinical trials, testing, or for selection of patients for treatment with remternetug. In some embodiments, the selected patient has P-tau (e.g., P-tau-217) levels between about 0.3 pg / ml to about 0.6 pg / ml (P-tau may be tested by Roche’s ECLIA or other known methods in the art). In some embodiments, the selected patient has P-tau-217 levels between about 0.32 pg / ml to about 0.4 pg / ml when tested by Roche’s ECLIA as described above. In some embodiments, the selected patient has P-tau-217 level of about 0.3 pg / ml when tested by Roche’s ECLIA as described above. In some embodiments, the selected patient has P-tau-217 level of about 0.4 pg / ml when tested by Roche’s ECLIA as described above. In some embodiments, the selected patient has P-tau-217 level of about 0.5 pg / ml when tested by Roche’s ECLIA as described above. In some embodiments, the selected patient has P-tau-217 level of about 0.6 pg / ml when tested by Roche’s ECLIA as described above. In some embodiments, the selected patient has P- tau-217 levels between about 0.3 pg / ml to about 0.6 pg / ml when tested by Roche’s ECLIA as described above. In some embodiments, deposited brain amyloid plaque or Aβ in CSF or plasma can be used to stratify subjects into groups and to identify which group of subjects is responsive to treatment / prevention of a disease (as described herein) using the antibodies, the dosing regimen, or the methods described herein.

[0092] 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 avariable 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 (2011)). Following the above method, the CDRs of the antibodies of the present disclosure were determined.

[0093] 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 IMGT®, 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%.

[0094] 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.

[0095] The term “prevention” means prophylactic administration of the antibody of the present disclosure to an asymptomatic subject or a subject in various stages of Alzheimer’s disease to prevent onset or slow progression of the disease.

[0096] The terms “disease characterized by deposition of Aβ” or a “disease characterized by Aβ plaques” are used interchangeably and refer to a disease that is pathologically characterized by Aβ plaques in the brain or in brain vasculature. This includes diseases such as stages of Alzheimer’s disease, Down syndrome, and cerebral amyloid angiopathy. A clinical diagnosis, staging or progression of Alzheimer’s disease can be readily determined by the attending 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).

[0097] As used herein, the term “early AD” includes stages 1, 2, and 3 of the FDA draft guidance titled, “Early Alzheimer’s Disease: Developing Drugs for Treatment,” (which is hereby incorporated by reference in its entirety; Internet link: fda.gov / regulatory-information / search-fda- guidance-documents / early-alzheimers-disease-developing-drugs-treatment; dated March 2024). According to the FDA guidance, stage 1 includes “patients with characteristic pathophysiological changes of AD but no evidence of clinical impact. These patients are truly asymptomatic with no subjective complaint, functional impairment, or detectable abnormalities on sensitive neuropsychological measures. The characteristic pathophysiological changes are typically demonstrated by assessment of various biomarker measures.” According to the FDA guidance, stage 2 includes “patients with characteristic pathophysiological changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures or subjective complaints of mild cognitive symptoms but no functional impairment. This may be considered a transitional stage in which slight cognitive symptoms first appear. The emergence of subtle functional impairment signals a transition to Stage 3.” According to the FDA guidance, stage 3 includes “patients with characteristic pathophysiological changes of AD, generally more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectablefunctional impairment. The functional impairment in this stage is not severe enough to warrant a diagnosis of overt dementia. This stage roughly corresponds with the syndrome of “mild cognitive impairment”; however, it is noted that the term “mild cognitive impairment” may also encompass patients in late Stage 2 or early Stage 4.”

[0098] As used herein, the term “about” means up to ±10%.

[0099] The terms “human subject,” “subject,” “individual,” and “patient” are used interchangeably in the present disclosure. In some embodiments, the subject has a disease characterized by Aβ deposits / plaques in the brain. The subject is part of the primary prevention population or has 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 AD patient. In some embodiments, the subject has prodromal AD and / or mild dementia due to AD. In some embodiments, the subject is part of the primary prevention population.

[0100] The phrases “slowing of decline” and “slowing disease progression” are used interchangeably in the present disclosure.

[0101] 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.

[0102] As used herein, “primary prevention” population includes individuals / subjects at risk of accumulating cerebral amyloid plaques in their brain and subsequently developing cognitive impairment and dementia due to AD. In some cases, primary prevention population includes subjects with risk factors for accumulating cerebral amyloid plaques including, but not limited to, age, genetic status (e.g., APOE4), and family history of AD. In most cases, a primary prevention population does not have evidence of clinical AD pathology or abnormal amyloid plaque pathology, defined by biomarkers collected from, but not limited to, plasma, CSF, or PET. In some cases, a primary prevention population may have minimal or negligible levels of cerebral amyloid plaques. An individual / subject who is a part of this “primary prevention” population is described herein as a “primary prevention subject” or “primary prevention individual.”

[0103] The term “maintenance dosing” or “maintenance dose” as used herein refers to a dose or dosing regimen that maintains the amyloid plaque levels below the amyloid positivitylevels. In some embodiments, below the amyloid positivity level refers to the subject having less than 24.1 centiloids of cerebral amyloid plaque as measured by PET. In some embodiments, below the amyloid positivity level refers to cerebral amyloid plaque levels that corresponds to a subject having less than 24.1 centiloids of cerebral amyloid plaque as measured by PET. In some embodiments, a subject is considered below the amyloid positivity level if the subject has a visually negative PET scan.

[0104] 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. EXAMPLES Example 1: A Clinical Study of Remternetug Versus Placebo (TRAILRUNNER-ALZ 1)

[0105] Study J1G-MC-LAKC (hereafter “Study LAKC”; TRAILRUNNER-ALZ1 NCT05463731, clinicaltrials.gov) was a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of remternetug in participants with early symptomatic AD, that is participants with MCI or mild AD. This patient population corresponded to Stages 3 through 4 of FDA draft guidance titled, “Early Alzheimer’s Disease: Developing Drugs for Treatment” (Internet link: fda.gov / regulatory-information / search-fda-guidance-documents / early- alzheimers-disease-developing-drugs-treatment; dated March 2024; which is hereby incorporated by reference in its entirety).

[0106] To date, two placebo-controlled cohorts investigating non-titration-based dosing regimens of SC remternetug have been investigated. The study schema for non-titration-based dosing in the placebo-controlled cohorts is shown in Figure 1.

[0107] In addition to the placebo-controlled cohorts, open-label safety addenda were enacted to investigate intravenous and subcutaneous (SC) remternetug, primarily to identify dosing regimens with optimal benefit-risk. LAKC placebo-controlled cohorts and Study LAKC Addenda 4 and 6 have informed on the dosing regimen to be investigated in Study LAKI.

[0108] Study LAKC Addenda 1 and 3 investigated intravenous remternetug, which has not directly informed on the dosing regimen for Study LAKI and thus are not described more fully hereafter.

[0109] Study LAKC Addendum 4 investigated non-titration-based dosing regimens of SC remternetug. The study schema for titration-based dosing is shown in Figure 2.

[0110] Study LAKC Addendum 5 investigated titration-based dosing regimens of SC remternetug. The inclusion criteria of LAKC Addendum 5 were specifically modified to enroll participants more representative of an early AD population (i.e., stages 1, 2, and 3 of AD according to FDA) relative to the placebo-controlled cohorts and LAKC Addendum 1, 3, and 4. Namely, participants with a MMSE score to 30 and lower levels of amyloid plaque were able to enroll into Study LAKC Addendum 5. The study schema for titration-based dosing is shown in Figure 3.

[0111] Addendum 6 of Study LAKC included participants with low levels of baseline amyloid plaque (i.e., 15CL to 37CL) treated with one of three SC dosing regimens. The study schema for Addendum 6 is shown in Figure 4. Methods

[0112] Non-titration-based dosing for Study LAKC are depicted in Figure 1 (Blinded) and Figure 2 (Open Label) (see PCT Application Publication No. WO 2024 / 107683 for additional details on the blinded and open label dosing; the publication is hereby incorporated by reference in its entirety).

[0113] Figure 1 shows the blinded non-titration-based dosing where the participants were divided between placebo and remternetug treatment into two cohorts in the primary study period at the following doses: a) Cohort 1: 400 mg SC QW for 36 doses; or b) Placebo given at the frequency described above; or c) Cohort 2: 800 mg SC Q4W for 13 doses; or d) Placebo given for 13 doses.

[0114] For Cohort 1 and for its corresponding placebo control, participants already randomized had their dose and frequency of study intervention adjusted to 800 mg SC Q4W or placebo, respectively, following a minimum 4-week treatment pause. Further enrollment into Cohort 1 and its corresponding placebo control was stopped.

[0115] Note that after 52 weeks, and a four week pause, an open label extension period began. Participants who received remternetug SC during the primary study period received placebo SC in the extension period. Participants who received placebo SC during the primary studyperiod received remternetug SC titration dosing regimen in the extension period at the following doses: • 100 mg every 8 weeks (Q8W) for 2 doses; • 8 weeks after the second 100 mg dose, participants received 400 mg Q8W for 2 doses; • 8 weeks after the second 400 mg dose, participants received 800 mg Q8W for 2 doses; • 8 weeks after the second 800 mg dose, participants received 800 mg every 4 weeks (Q4W) for up to 7 doses.

[0116] Figure 2 shows the open label non-titration-based dosing where the participants received the following doses: a) 400 mg SC QW for 36 doses; b) 800 mg SC QW for 13 doses.

[0117] For 400 mg SC QW dosing, participants already randomized had their dose and frequency of study intervention adjusted to 800 mg SC Q4W or placebo, respectively, following a minimum 4-week treatment pause.

[0118] In Study LAKC Addendum 5 and shown in Figure 3, titration-based treatment groups were defined as follows: a) For treatment group 1 (13 doses overall) participants received: • 100 mg Q8W for 2 doses; • 8 weeks after the second 100 mg dose, participants received 400 mg Q8W for 2 doses; • 8 weeks after the second 400 mg dose, participants received 800 mg Q8W for 2 doses; • 8 weeks after the second 800 mg dose, participants received 800 mg every 4 weeks (Q4W) for up to 7 doses. b) For treatment group 2 (14 doses overall) participants received: • 200 mg Q8W for 1 dose;• 8 weeks after the 200 mg dose, participants received 400 mg Q8W for 2 doses; • 8 weeks after the second 400 mg dose, participants received 800 mg Q8W for 2 doses; • 8 weeks after the second 800 mg dose, participants received 800 mg Q4W for up to 9 doses. c) For treatment group 3 (15 doses overall) participants received: • 400 mg Q8W for 2 doses; • 8 weeks after the second 400 mg dose, participants received 800 mg Q8W for 2 doses; • 8 weeks after the second 800 mg dose, participants received 800 mg Q4W for up to 11 doses. d) For treatment group 4 (13 doses overall) participants received: • 400 mg Q12W for 2 doses; • 12 weeks after the second 400 mg dose, participants received 800 mg Q8W for 2 doses; • 8 weeks after the second 800 mg dose, participants received 800 mg Q4W for up to 9 doses.

[0119] In Study LAKC Addendum 6 and shown in Figure 4, treatment groups are defined as follows: c) 200 mg SC every 16 weeks (Q16W) for 2 doses; or d) 400 mg SC Q16W for 2 doses; or e) 600 mg SC Q16W for 2 doses. Results

[0120] The planned SC dosing regimen of remternetug in participants with early AD in Study LAKI (described below) was informed by safety data from participants receiving blinded and open-label SC remternetug from Study LAKC, pharmacodynamic data from participantsreceiving open-label SC remternetug from Study LAKC, and PK data from participants receiving remternetug in Studies J1G-MC-LAKA (NCT03720548, clinicaltrials.gov), J1G-MC-LAKB (NCT04451408, clinicaltrial.gov) and J1G-MC-LAKC (NCT05463731, clinicaltrials.gov). These datasets are summarized hereafter. LAKC Safety Information on Participants Receiving SC Dosing:

[0121] A total of 685 participants in Study LAKC were given at least 1 subcutaneous dose of study intervention: a) 196 participants received double-blinded treatment (remternetug: placebo, 3:1), and b) 489 participants received open label remternetug. Note that 35 participants enrolled out of the 685 total participants were not included in this safety analysis because their baseline level of amyloid plaque pathology was distinctly lower than other participants enrolled in Study LAKC.

[0122] The exposures for the 650 participants in the SC dosing regimens are depicted in Table 2, which also describes ARIA events observed by MRI in the non-titration-based blinded study groups, non-titration-based open label study groups, and titration-based open label study groups.

[0123] In general, median exposures for participants in non-titration- and titration-based dosing regimens were approximately 57 and 18 weeks respectively. Participants receiving SC Titration 4 (starting dose of 400 mg Q12W) were recently enrolled with a median exposure of 3 weeks (prior to March 26, 2024). None of these SC Titration 4 participants had a scheduled MRI post-baseline at the time of this safety summary. Table 2: Overview of Adverse Events in Study LAKC Safety Population SC (Data Cutoff Date = 26 March 2024) 800 mg SC SC SC 400 mg 800 4W sbnd el )sbnd elimaging; N = number of participants in the analysis population, receiving open-label remternetug or double-blind study treatment; n = number of participants with at least 1 AE; PBO = placebo; QW = once every week; Q4W = once every 4 weeks; Q8W = once every 8 weeks; Q12W = once every 12 weeks; Remi = remternetug; SAE = serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse event.aThe SC QW dosing regimen was stopped. For participants who were already assigned to the SC QW dosing regimen, the dose and frequency were adjusted to 800 mg SC Q4W (or PBO for double-blind cohort) following a minimum 4-week treatment pause.bIncludes participants in SC Titration Treatment Group 4.cIdentified based on MRI or TEAE cluster output.dIncludes microhemorrhage and superficial siderosis.

[0124] Of participants receiving SC remternetug or placebo (N=650), 51.1% reported a TEAE (Table 2). Most common TEAEs (>5%) reported were ARIA-H (10%), ARIA-E (9.8%), headache (6.6%), and COVID-19 (5.1%).

[0125] Overall, 68 participants (10.5%) reported SAEs, and SAEs reported in 2 or more participants were ARIA-E (1.5%), syncope (0.6%), and ARIA-H (0.5%). Three treatment- emergent deaths (1 due to encephalopathy and subdural hematoma, 1 due to cardiac arrest, and 1due to cerebral arteriosclerosis) were reported. None were considered related to ARIA, macrohemorrhage, or study treatment by the investigators.

[0126] In all participants receiving remternetug and placebo, ARIA-E was identified by MRI and TEAE findings in 66 of 650 participants (10.2%) (Table 2). Although ARIA-E has been observed in the natural history of AD, it has been associated with amyloid-modifying therapies (Yaari R et al., “Amyloid-related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population with and Without Cerebral Amyloid,” J Prev Alzheimer’s Dis. 2022;9(4):617-624; which is hereby incorporated by reference in its entirety). Assuming all ARIA- E events occurred only in the estimated number of participants assigned to remternetug (N=601), the overall incidence was determined to be 11.0% for ARIA-E.

[0127] Kaplan-Meier plots were generated to demonstrate the observed initial onset of ARIA-E by safety MRI in participants receiving open-label remternetug SC (Figure 5). When comparing the first 16 weeks of exposure, the incidence of ARIA-E was unexpectedly and notably lower in the titration-based dosing groups compared to the 400 mg QW or 800 mg Q4W remternetug-treated groups. This difference reflected the lower and less frequent dosing in the titration arms during this period.

[0128] Symptomatic ARIA-E was reported in 26 of 650 (4.0%) participants (Table 2). Headache was the predominant symptom reported. Symptomatic ARIA-E events were generally observed in the first 16 weeks of treatment. ARIA-E as an SAE was reported in 11 of the 650 (1.7%) participants (1) and was the most reported SAE. Three of the 650 (0.5%) participants had ARIA-H as an SAE. All 3 participants co-reported serious ARIA-H with events of serious ARIA- E. SAEs of ARIA-E and ARIA-H were generally observed in the first 16 weeks of treatment. No participants receiving an open-label SC titration dosing regimen reported a serious ARIA event. In total, 3 of 650 participants (0.5%) receiving either remternetug or placebo SC had macrohemorrhage. Two participants were receiving double-blind treatment, and 1 participant received open-label remternetug (SC Titration 2). Participants with macrohemorrhage were managed with permanent discontinuation of study intervention.

[0129] Of participants receiving SC remternetug or placebo (N=650; 454 receiving open- label remternetug and 196 receiving blinded study treatment), 29 participants (4.5%) reported injection site reactions (ISRs). Events were either mild or moderate in severity, and none were considered serious. Events occurring in ≥0.5% participants were injection site erythema (n=12;1.8%), injection side reaction (ISR) (n=9; 1.4%), and injection site pain (n=3; 0.5%). Two participants (1 receiving blinded Q4W study intervention and 1 receiving SC Titration 1) reported a hypersensitivity event. Both events were considered moderate in severity and nonserious. Both events resolved without medication within 24 hours of occurrence. No anaphylaxis has been reported. Pharmacokinetic and Pharmacodynamic Information on Participants Receiving Remternetug

[0130] The PK profile for remternetug has been informed by all participants receiving SC and IV remternetug (Study J1G-MC-LAKC and J1G-MC-LAKA [NCT03720548] and J1G-MC- LAKB [NCT04451408], clinicaltrials.gov; and International Patent Application Publication No. WO 2024 / 107683; each of which are hereby incorporated by reference it its entirety). Remternetug serum exposures generally increased dose proportionally with terminal half-life of approximately 25 days consistent across dose groups. Remternetug PK was dose proportional at doses from 250 to 2800 mg IV. There were also dose-dependent increases in serum exposures following 400 and 800 mg SC dosing.

[0131] Preliminary population PK analyses were carried out using all observed data in AD participants (n=922 participants) where bioavailability was estimated at approximately 55% and mean absorption rate of remternetug following SC administration at 0.00675 h-1. Maximum plasma concentration was achieved approximately 7 days following SC administration. Central volume of distribution was 2.64 L with 35% interindividual variability, while peripheral volume of distribution was 2.36 L with 44% interindividual variability. Serum clearance was 0.0048 L / h, with 49% between-participant variability.

[0132] Figure 6 shows the observed mean % change from baseline over time following open-label SC dosing groups from Study LAKC. Time and dose / concentration-dependent amyloid plaque lowering were observed except SC Titration 1 (starting dose of 100 mg). Non-titration- based SC dosing regimens demonstrated more robust amyloid plaque lowering than titration-based SC dosing regimens in the initial weeks of treatment. The titration-based dosing regimens included a slow early titration with infrequent dosing until a time where ARIA risk has potentially been reduced (>16 weeks after initial dose). All 3 regimens eventually titrated up to 800 mg Q4W dosing, which exhibited robust amyloid plaque lowering.

[0133] PK / PD analysis of the data discussed above investigated the relationship between serum remternetug concentrations and amyloid plaque clearance (defined at levels <24.1 centiloids, CL, as measured using amyloid PET). It was found that, in the investigated dose range, a linear model best described the treatment effect on reduction of amyloid plaque level over time. Time to achieve amyloid plaque clearance (levels of <24.1 CL) was dependent on dose and baseline amyloid plaque level.

[0134] The mean percent coefficient of variation (CV%, between-participant variability) observed amyloid plaque baseline was 81.2 (44%) CL. An exposure-response model was used to fit the amyloid plaque data for SC and IV routes of administration over time. The model was parametrized in terms of natural degradation half-life of amyloid plaque, treatment effect, and baseline. The effect of remternetug PK was described using a linear model stimulating the degradation rate of plaque removal. The treatment effect represented by slope was also found to be correlated with the baseline amyloid plaque level. The exposure-amyloid plaque model suggested the following points: i) with an increase in exposure, there was a proportional increase in plaque removal rate; ii) time to achieve amyloid plaque clearance was dependent on baseline amyloid plaque level. The higher the baseline value, the more time was needed to achieve amyloid plaque clearance.

[0135] This model was used to guide SC dosing regimen selections and was continuously updated with emerging PK and PD data from open-label cohorts. There was very good correspondence between modeled and observed data in Study LAKC. The remternetug PK / PD model was used to simulate expected PK and amyloid plaque reduction following LAKI dosing regimen in early AD participants. It was assumed that PK and PD will continue to be dose proportional (as observed in Study LAKC), and remternetug-estimated treatment effect in early AD stages would be similar to that observed in LAKC study participants with symptomatic AD. Discussion

[0136] A titration-based SC dosing regimen was selected based on balancing the extent of amyloid plaque removal while reducing ARIA risk. Therefore, the LAKI study of Example 2 below in early AD will utilize SC Titration 3 from Study LAKC (defined as 400 mg Q8W × 2 doses, then 800 mg Q8W × 2 doses, then 800 mg Q4W × 11 doses).

[0137] The incidence and severity of ARIA-E observed with non-titration-based SC dosing indicated that a lower Cmax was not necessarily associated with a lower incidence of ARIA-E. Therefore, it was hypothesized that Cmax was not the predominant driver in ARIA-E with SC dosing. This hypothesis appeared to be consistent with observations from the CLARITY-AD study (NCT03887455, clinicaltrials.gov), where safety results of Lecanemab were compared between IV and SC dosing (Irizarry MC et al., “Preliminary Update on Lecanemab Safety in Clarity AD Open label Extension, Including Subcutaneous Formulation,” Poster presented at the 16th Clinical Trials on Alzheimer’s Disease (CTAD); October 24-27, 2023; Boston, MA; which is hereby incorporated by reference in its entirety).

[0138] Based on results from Study LAKC, it was hypothesized that 8-week dosing intervals early in treatment allowed sufficient time for potential asymptomatic ARIA to resolve and decreased the risk of symptomatic or serious ARIA. This hypothesis was supported by evidence that more frequent SC dosing (i.e., QW and Q4W remternetug) early in treatment was associated with higher ARIA-E incidence than less frequent SC dosing (i.e., Q8W remternetug) (Table 2 and Figure 5). More frequent dosing later in the titration-based dosing regimen, when ARIA development risk is lower, may enhance amyloid plaque clearance. SC Titration 3 (defined as 400 mg Q8W × 2 doses, then 800 mg Q8W × 2 doses, then 800 mg Q4W × 11 doses) balanced the approach of initial 8-week dosing intervals until a time where the ARIA risk has potentially been reduced (>16 weeks after initial dose) with more frequent dosing with a higher dosage to optimize amyloid plaque removal. It was noteworthy that in participants receiving SC Titration 3, ARIA-E and symptomatic ARIA-E incidences are 3.6% and 0.9%, respectively, and no serious ARIA-E events were reported.

[0139] With a median exposure of 18 weeks, participants randomized to SC Titration 3 have received 2 doses of 400 mg and 1 dose of 800 mg in Addendum 5 of Study LAKC. It is anticipated, based on this study, that the incidences of symptomatic and serious ARIA-E may remain relatively low, as participants continue with 800 mg doses and more frequent dosing. This was informed by the safety data from all participants receiving IV and SC remternetug, indicating that symptomatic and serious ARIA predominantly occurred in the first 16 weeks of dosing.

[0140] The risk of infusion-related reactions (IRRs) may be inherently avoided with SC administration of remternetug. IRRs have been observed with remternetug treatment, though they have generally been mild in severity, and none have been considered serious.

[0141] Additionally, hypersensitivity events observed with SC remternetug treatment have been mild to moderate in severity, and none were considered serious. No anaphylaxis has been observed.

[0142] The proposed dose titration regimen, initiating at 400 mg Q8W and increasing sequentially to a higher dosage and frequency over time, has been demonstrated to reduce early ARIA risk with remternetug to date. The dosing regimen is considered tolerable with injection site reactions (ISRs) being mild or moderate in severity and no anaphylaxis observed. The SC titration treatment regimen is hypothesized to result in approximately 84% of participants with early AD reaching amyloid plaque clearance by end of treatment.

[0143] The safety and PD data from symptomatic AD participants in Study LAKC (i.e., stages 3 and 4 of AD according to FDA) were considered representative of data from an early AD population (i.e., stages 1, 2, and 3 of AD according to FDA) due to the overlapping amyloid pathology characteristics of these 2 populations. Utilizing baseline data from the solanezumab Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease study (A4, NCT02008357, clinicaltrials.gov) that enrolled participants with preclinical AD (i.e., stages 1 and 2, and according to FDA). (Sperling RA et al., “Testing the Right Target and Right Drug at the Right Stage,” Sci Transl Med. 2011;3(111):111cm33, which is hereby incorporated by reference in its entirety), an analysis was conducted on participants who were P-tau-positive and had an MMSE score of ≥27. The mean baseline amyloid pathology was 86 CL. Comparatively, Study LAKC assessed titration-based SC dosing in participants with a mean baseline amyloid pathology of 80 CL and enrolled participants with MMSE scores up to 30. Therefore, the extent of amyloid pathology in participants receiving titration-based SC dosing was comparable to those intended to be enrolled in Study LAKI, which has entry criteria of P-tau positivity and an MMSE score of ≥27. Example 2: A Study of Remternetug Versus Placebo in Participants at Risk for Cognitive and Functional Decline due to Alzheimer’s Disease

[0144] The dosing regimen selected for Study LAKI (hereafter referred to as “the Study;” Protocol Number: J1G-MC-LAKI, TRAILRUNNER-ALZ 3, NCT06653153 at clinicaltrials.gov) was designed to maximize the benefit / risk by achieving robust amyloid plaque clearance with a titration-based approach to reduce potential ARIA risk and is based on the Study LAKC described in Example 1.

[0145] Study LAKI is a multicenter, randomized, double-blind, placebo-controlled, parallel-group treatment, Phase 3 study of remternetug for the treatment of participants with early AD. Study LAKI will evaluate the safety and efficacy of remternetug in participants who have early AD. The primary objective of the study is to assess whether treatment with remternetug delays the time to clinically meaningful progression as compared to placebo. For this purpose, clinically meaningful progression is defined as an increase from baseline at two consecutive time points either in Clinical Dementia Rating Sum of boxes score of 1 or greater or in Clinical Dementia Rating global score of 0.5 or greater.

[0146] The overall study duration depends on the length of time needed for events of clinical progression to occur. Thus, the study duration for each participant will vary. The maximum planned study duration of an individual is expected to be approximately up to 255 weeks.

[0147] Intended Patient Population: The Alzheimer’s Association updated the research framework developed by the National Institute on Aging and the Alzheimer’s Association, creating new diagnostic recommendations for AD (see, e.g., Jack CR Jr et. al., “Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease: Alzheimer’s Association Workgroup,” Alzheimer’s Dement. 2024;1-27; Dubois B et al., “Clinical Diagnosis of Alzheimer’s Disease: Recommendations of the International Working Group,” Lancet Neurol.2021;20(6):484-496; and “Early Alzheimer’s Disease: Developing Drugs for Treatment,” at Internet link: fda.gov / media / 110903 / download; each of which is hereby incorporate by reference in its entirety). This update outlines clinical staging of Alzheimer’s disease, with Stage 1 being asymptomatic with biomarker evidence only, Stage 2 representing transitional decline with mild detectable change and minimal impact on daily function, and Stage 3 being associated with cognitive impairment and early functional impact. Stages 1 through 3 are consistent with the FDA’s guidance for drug development in early AD. Stages 4 through 6 reflect dementia with mild-to-severe functional impairment.

[0148] The study schema is shown in Figure 7. The study has these periods: a) Prescreening / Screening: This period includes Visit 601 and Visit 1; b) Double-blind Treatment: This period starts with Visit 2 and continues for approximately 78 weeks; c) Double-Blind Observation: This period starts at the end of Double-Blind Treatment period and continues until the target number of events for the primary endpoint is achieved or until the study is ended at the sponsor’s discretion; d) Open-Label Extension (only for participants who previously receivedplacebo): This period will be conducted at the sponsor’s discretion, contingent on the availability of confirmatory efficacy results. If started, this period may continue for approximately 78^weeks; e) Follow-up (Visit 801): This period occurs at least 20 weeks after a participant’s last dose of study intervention. If, at the time of study completion or early discontinuation more than 20 weeks have passed since the participant’s last dose of study intervention, Visit 801 is not required.

[0149] Participants who meet study entry criteria will be randomized in a 1:1 ratio to one of these double-blind treatment groups: • Remternetug, given at a total of up to 15 time points: o 400^mg at randomization (Week 0), ks • P

[0150] Prescreening and Screening Periods: The prescreening and screening periods consist of Visit 601 and Visit 1. The study will be explained to the participant and study partner. Written informed consent must be obtained before any study procedures are conducted.

[0151] Participants must meet all inclusion and exclusion criteria prior to entering the Double-Blind Treatment Period. Individuals must meet all the following inclusion criteria during screening to participate in the Double-Blind Treatment Period. Plasma phosphorylated tau (P-tau), an investigational in vitro diagnostic device (immunoassay) for identifying the presence of abnormal brain amyloid pathology, will be used to determine a participant’s eligibility for Study LAKI. Plasma P-tau is an accepted method and core AD biomarker for assessing AD pathology (see, e.g., Jack et al. 2024; Palmqvist et al. 2020) and will be used in this study for the purpose of participant eligibility. The inclusion criteria are as follows: a) Have a phosphorylated tau (P-tau) result consistent with the presence of abnormal amyloid brain pathology (e.g., using Roche’s ECLIA as described above);b) Can give, and have given, signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. c) Are from 55 to 80 years of age, inclusive, at the time of signing the ICF. d) Have venous access sufficient to allow the protocol-required blood sampling. e) Have adequate literacy, vision, and hearing for neuropsychological testing in the opinion of the investigator at the time of screening. f) Are reliable, willing, and able to make themselves available for the duration of the study and are willing to follow study procedures, including use of electronic devices to complete study-related questionnaires and video calls. g) Have at least 1 reliable study partner who meets all these criteria: attained the legal age for consent to study participation; has given their own written informed consent and can comply with the requirements listed in the ICF and in this protocol; is in frequent contact with the study participant and familiar with the participant’s overall function and behavior, such as day-to-day activities and cognitive abilities; is available to provide oversight for at-home SC injections and is willing and able to administer the injections, if needed; and is available to complete the study assessments required of the study partner. h) Have, at screening, a plasma P-tau result consistent with the presence of abnormal brain amyloid pathology. i) Have, at screening, an MMSE score ≥27. j) Have, at screening, an FAQ score an <6. k) If currently receiving medications as symptomatic treatment for AD (for example, cholinesterase inhibitors), dose has been stable for at least 30 days before Visit 1 and dose is planned to remain stable for the duration of the study.

[0152] Individuals are excluded from participation in the Double-Blind Treatment Period if any one of the following criteria apply: a) Have dementia or significant other neurological disease that can affect cognition. b) Have current serious or unstable illnesses, including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in theinvestigator’s opinion, could interfere with the analyses in this study; or has a life expectancy of approximately ≤5 years. c) Have a history of cancer that, in the investigator’s opinion, has a high risk of recurrence and preventing completion of the study. d) Have any of the following: have answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” portion of the Columbia-suicide severity rating scale (C-SSRS) and the ideation occurred within the past month or have answered “yes” to any of the suicide-related behaviors on the “suicidal behavior” portion of the C- SSRS and the behavior occurred within the past month. e) Have a history of clinically significant multiple or severe drug allergies, significant atopy, or severe posttreatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and / or exfoliative dermatitis). Laboratory tests, vital signs, physical examinations, and imaging. f) Have any clinically important abnormality at screening / baseline, as determined by investigator, in vital signs, electrocardiogram (ECG), clinical laboratory test results, physical examination, or MRI that could be detrimental to the participant or could compromise the study. g) Have 1 or more of these laboratory test results at screening: alanine transaminase (ALT) ≥2.5 times Upper Level of Normal (ULN); aspartate aminotransferase AST ≥2.5 times ULN; total bilirubin (TBL) ≥1.5 times ULN; alkaline phosphatase (ALP) ≥2 times ULN. (Note: Participants with TBL ≥1.5 times ULN are not excluded if they meet all of the following criteria for Gilbert syndrome: bilirubin is predominantly indirect (unconjugated) at screening (direct bilirubin within normal limits); liver disease is absent; ALT, AST, and ALP are all ≤1 times ULN at screening; and hemoglobin is not significantly decreased at screening). h) Have any contraindications for MRI, including claustrophobia or the presence of contraindicated metal (ferromagnetic) implants / cardiac pacemaker incompatible with MRI or without access to an MRI facility that accepts patients with pacemakers.i) Have a centrally read MRI demonstrating presence of ARIA-E, >1 cerebral microhemorrhages, any superficial siderosis, any macrohemorrhage, or severe white matter disease at screening.

[0153] Prior or current therapies. j) Have had prior treatment with a passive anti-amyloid immunotherapy < 5 half- lives. k) Have received active immunization against Aβ in any other study. l) Have known allergies to remternetug, related compounds, or any components of the formulation, as described in the IB. m) Are currently enrolled in any other medical research (interventional or observational) judged not to be scientifically or medically compatible with this study. n) Have participated, within the last 30 days prior to screening, in a clinical trial involving a study intervention judged not to be scientifically or medically compatible with Study LAKI. If the previous study intervention is scientifically or medically incompatible with Study LAKI, then at least 3 months or 5 half-lives (whichever is longer) should have passed before the participant is screened in Study LAKI. Recent participation in an observational study may be permitted upon review of the observational study protocol and upon approval by the sponsor. o) Have previously been randomly assigned to treatment and completed or withdrawn from this study or received remternetug in this or any prior investigational study. p) Are of childbearing potential q) Are pregnant or breastfeeding, or plan to become pregnant or to breastfeed during the study. r) Are site personnel directly involved with this study or are members of their immediate family. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted. s) Are Lilly employees directly involved in this study or have study partners who are Lilly employees directly involved in this study.

[0154] Double-Blind Treatment Period: The Double-Blind Treatment period begins at Visit 2 (randomization / baseline). At Visit 2, all remaining study visits after randomization shouldbe scheduled as close as possible to the target date relative to first injection. Participants who meet entry criteria will be randomized to receive either remternetug or placebo at a total of up to 15 time points during this period.

[0155] Double-Blind Observation Period: The Double-Blind Observation period begins at Visit 11 (Week 78). In this period, participants will receive neither remternetug nor placebo, unless a dose interruption occurs, and dosing is extended into the double-blind observation period. Participants will have routine visits approximately every 26 weeks for clinical and safety assessments during this period. Participants will continue in this period until target number of events for the primary endpoint is achieved, up to approximately 234 weeks since the first dose, at the sponsor’s discretion. Investigators will be notified when participants have reached their final observation visit or the sponsor ends the study.

[0156] Open-Label Extension Period (Placebo Group Only): Activation of the Open-Label Extension period is dependent on confirmatory results of remternetug efficacy at sponsor’s discretion. If this period is activated, participants who meet all the following criteria will receive remternetug: a) Participant received placebo in the Double-Blind Treatment Period. b) Participant is active in the Double-Blind Observation period when the target number of primary outcome events is observed. c) Participant provides informed consent for the Open-Label Extension Period. d) Participant is not excluded from the Open-Label Extension Period, according to the relevant criteria specified for the Open-Label Extension Period below.

[0157] Individuals are excluded from participation in the Open Label Extension Period if any one of the following criteria apply: a) Are study participants who develop superficial siderosis before the start of Open Label Extension Period. b) Are study participants who develop an illness before the start of Open Label Extension Period that is unstable or serious or that, in the judgment of the investigator, precludes treatment with remternetug.

[0158] For qualifying participants, remternetug will be given at a total of up to 15 time points: a) 400^mg at Visit 101 (Week 0 in this period),b) 400^mg at Visit 102 (Week 8 in this period), c) 800^mg at Visit 103 (Week 16 in this period), d) 800^mg at Visit 104 (Week 24 in this period), e) 800^mg at Visit 105 (Week 32 in this period), and f) 800^mg at every fourth week thereafter, up to and including 72 weeks after^Week 0 of this period (Weeks 36, 40, 44, 48, 52, 56, 60, 64, 68, 72 in this period).

[0159] Follow-up Period: This period occurs at least 20 weeks after a participant’s last dose of study intervention; 20 weeks corresponds to at least five half-lives of remternetug. If, at the time of study completion or early discontinuation more than 20 weeks have passed since the participant’s last dose of study intervention, the Follow-up Period is not required.

[0160] Sample Size Determination for Study: Participants in the Study will be followed until the target number of primary outcome events is observed. Therefore, the total duration of study participation for each participant will vary. Up to approximately 1400 participants will be enrolled in the trial. The sample size was chosen to achieve approximately 350 clinical progression events within a trial duration of approximately 5 years after the first patient has been randomized. Assuming a hazard ratio of 0.725, a total of 350 events leads to approximately 85% power to show superiority of remternetug over placebo at a 1-sided 0.025 alpha level. The additional assumptions used to calculate the sample size were an annualized placebo event rate of 12% to 15%, and an annualized participant dropout rate of approximately 10%. Example 3: Selection of Dosing Regimen of Remternetug for Primary Prevention of AD

[0161] Intervention using remternetug in the context of primary prevention aims to eliminate existing deposited plaque, if present, and inhibit significant future meaningful plaque accumulation. With consistent but infrequent administration of low doses of remternetug, ongoing amyloid plaque buildup may be arrested or potentially reversed, thereby reducing progression to amyloid-positive status ( >24.1 Cl) and mitigating subsequent pathological changes that contribute to the onset of clinical symptoms associated with Alzheimer's disease (AD).

[0162] However, there are challenges in determining the suitability of remternetug for primary prevention in AD. Specifically: (1) it is previously unestablished whether any amyloid- targeting therapy, including remternetug, could effectively remove amyloid plaques during the earliest stages of their deposition; and (2) it remains uncertain if an appropriate dosing regimen ofremternetug could adequately prevent amyloid accumulation with infrequent dosing while also minimizing the risk of amyloid-related imaging abnormalities (ARIA).

[0163] Administration of remternetug facilitates removal of accumulated cerebral amyloid plaque through microglial-mediated phagocytosis. Prior research has demonstrated that the Aβp3- 42 peptide appears early in the amyloid deposition process (Saido et al., “Dominant and Differential Deposition of Distinct β-amyloid Peptide Species, AβN3(pE), in Senile Plaques,” Neuron. 1995;14(2):457-466 and Iwatsubo et al., “Full-length Amyloid-β(1-42(43)) and Amino- terminally Modified and Truncated Amyloid-β42(43) Deposit in Diffuse Plaques,” Am J Pathol. 1996;149(6):1823-1830, each of which are hereby incorporated by reference in their entireties). Remternetug may clear amyloid plaques at the initial stages or at very low levels of amyloid burden, such as in primary prevention settings.

[0164] Due to limited pharmacodynamic data for amyloid-targeting therapies like remternetug in primary prevention populations, remternetug was evaluated in individuals with low amyloid levels (15 to 37 CL at screening, N=52) in an addendum to the ongoing Phase 3 study, TRAILRUNNER-ALZ1 (LAKC). The findings indicated that remternetug can reduce cerebral amyloid plaque in this population in a dose-proportional manner, providing information relevant to determining an appropriate dosing regimen for preventing amyloid accumulation in primary prevention settings.

[0165] After addressing the aforementioned challenges, the remternetug dosing regimen for the primary prevention of AD is selected in consideration of the following factors: • Safety and tolerability data from Phase 1 and 3 clinical studies investigating remternetug in participants with AD, • Dosing no more frequent than six months upon titration to the highest dosage. • PK / PD analyses of all available data across a wide dose range.

[0166] In Addendum 6 of Study LAKC, participants with low amyloid levels (15 to 37 centiloids (CL) at screening; N = 52) were enrolled. No cases of ARIA-E were observed among those treated with subcutaneous (SC) remternetug at dosages up to 1000 mg. Based on these results, the likelihood of developing ARIA-E in a primary prevention patient population (asymptomatic individuals with no to minimal amyloid) treated with remternetug is considered to be very low.

[0167] Dose titration, initiating at a low dosage and increasing to higher dosages over time, was demonstrated to mitigate ARIA risk with remternetug in subjects with symptomatic AD. Accordingly, to mitigate any potential risk of ARIA-E, the dosing regimen of remternetug in Primary Prevention of AD may be titrated.

[0168] The development of ARIA across amyloid targeted therapies was observed at the beginning of remternetug treatment in subjects with early symptomatic AD. Moreover, it was observed that 3 month and greater dosing intervals may allow time for any potential asymptomatic ARIA to resolve prior to the subsequent dose. Thus, the dosing regimen was designed such that remternetug is dosed no more frequently than every 3 months during titration and no more frequently than every 6 months upon chronic / maintenance dosing for primary prevention of AD, as this population is not expected to have clinical, cognitive, or functional impairments due to AD. An approximately 25 day terminal half-life makes remternetug treatment ideal for such a dosing regimen.

[0169] Design Features: Based on internal analyses of Alzheimer’s Disease Neuroimaging Initiative (ADNI) and LAKC data, the dosing regimens are designed such that they will remove approximately 6 centiloids (CL) of amyloid per year. The dosing regimens may be designed such that they provide enough amyloid plaque removal to maintain amyloid plaque levels below a threshold of amyloid PET positivity (24.1 CL). Over the course of remternetug treatment being studied in Study LAKJ, it is predicted that at least 9 out of every 10 participants receiving remternetug will be below this threshold (i.e., at least 90% of subjects will be below about 24.1 CL) of amyloid PET positivity. Dose Justification Considerations: Pharmacokinetics (PK) and Pharmacodynamics (PD)

[0170] The dosing regimens for primary prevention population have been designed in view of the PK studies of all participants receiving subcutaneous (SC) and intravenous (IV) remternetug in Studies LAKB and LAKC. It was found that remternetug PK is dose proportional at doses from 250 to 2800 mg IV. There also are dose-dependent increases in serum exposures following 100 to 1000 mg SC dosing.

[0171] Preliminary PK studies of the AD population were carried out using all observed Phase 1 and 3 data (n = 922 participants with amyloid >24.1 CL) where bioavailability was estimated at approximately 60% and mean absorption rate of remternetug following SC administration at 0.007 h-1. Maximum plasma concentration is achieved approximately 7 daysfollowing SC administration. Central volume of distribution was 2.64 L with 35% inter-individual variability, while the peripheral volume of distribution was 2.36 L with 45% inter-individual variability. Serum CL was 0.005 L / h, with 49% between-participant variability. These studies informed the dosing frequency and the dosage for remternetug in primary prevention population.

[0172] Mean (coefficient of variation, CV%, between-participant variability) observed amyloid plaque levels at baseline was 81.2 (44%) CL in a population of AD trial participants (N=922). Longitudinal amyloid plaque level data was used in exposure-response analyses for SC and IV routes of administration over time. These analyses utilized natural degradation half-life of amyloid plaque levels, treatment effect, and baseline. The effect of remternetug PK was determined using linear analysis for degradation rate of amyloid plaque (Figure 8) and it was found that the treatment effect correlated with the baseline amyloid plaque level. The exposure amyloid plaque analyses suggest the following for participants with AD: • With an increase in exposure, there was a proportional increase in plaque removal rate. • Time to achieve amyloid plaque clearance was dependent on baseline amyloid plaque level. The higher the baseline value, the more time was needed to achieve amyloid plaque clearance.

[0173] Given the paucity of PK / PD data in amyloid targeting therapies in a primary prevention population, the PK / PD of remternetug were tested with three SC dosing regimens in a low amyloid (15 to 37 CL at screening) population (N= 52) in Addendum 6 of LAKC. The three dosing regimens with increasing dosages are as follows (where n is the number of participants): • 200 mg SC at Week 0, 16, and 400 mg SC at Week 36: n = 16 • 400 mg SC at Week 0, 16, and 800 mg SC at Week 36: n = 18, and • 600 mg SC at Week 0, 16, and 1000 mg SC at Week 36: n = 18.

[0174] Participants were randomized to these 3 dosing regimens (1:1:1) and had amyloid PET imaging at baseline and Week 56. Observed centiloid values at these time points are presented in Table 3. As expected, dose dependent CL change from baseline at Week 56 was observed. Table 3: Observed CL changes by PET in Study LAKC (Addendum 6) Dosing Regimen, Baseline Week 56 Week 56 Change from SC PET (CL) PET (CL) Baseline (CL)

[0175] The PK / PD data, together with data on the correlation between amyloid plaque and plasma P-tau-217 (using an assay for plasma P-tau-217), were used in designing the dosing regimens for primary prevention AD patients (see Figure 8). Specifically, the analyses mentioned above, including: 1) the PK and PD dose proportionality in Study LAKC Addendum 6 population, 2) the estimated treatment effect of remternetug in participants with low amyloid load at baseline, and 3) amyloid plaque baseline distribution using the plasma P-tau-217 assay for participant selection and screening, were used to produce dosing regimens for the primary prevention population. These dosing regimens are designed to achieve: 1) greater than 6 CL per year reduction, and / or 2) maintain amyloid plaque levels below a threshold of amyloid PET positivity (24.1 CL). The dosing regimens are expected to maintain amyloid plaque levels below a threshold of amyloid PET positivity (24.1 CL) in at least ~90% of individuals treated with remternetug. Over the course of 4 years of remternetug treatment, it is anticipated that greater than 90% of eligible participants receiving remternetug will be below the threshold of amyloid positivity while corresponding eligible untreated participants will accrue amyloid (See Figure 9).

[0176] Taken together, the data and analyses described above leads to possible doses and frequencies (see Table 4) for the use of remternetug in primary prevention of AD to: 1) maintain amyloid levels or 2) slow or arrest progression into amyloid positivity (i.e., >24.1 CL). Table 4. Possible doses and frequencies for the use of remternetug as treatment in a population for primary prevention of AD (i.e., individuals / candidates / subjects for primary prevention of AD). Titration Dosing RegimenaMaintenance Dosing RegimenbYear 1 Year 2 Year 3 onwards aac emp y ox n ca es no ose n e correspon ng wee “c” Each row provides a dosing regimen that includes a titration dosing regimen and a maintenance dosing regimen “d” Start of titration dosing regimen “e” Start of maintenance dosing regimen Example 4: A Study of Remternetug Versus Placebo in Participants at Risk of Amyloid Plaque Accumulation and Subsequent Development of Cognitive Impairment due to AD

[0177] This example provides details of Study LAKJ (hereafter referred to as “LAKJ;” Protocol Number: J1G-MC-LAKJ, TRAILRUNNER-ALZ 4). The dosing regimen for this trial is designed to evaluate the efficacy and safety of remternetug for the primary prevention of Alzheimer’s disease. Primary prevention of AD requires identifying individuals at risk for amyloid plaque accumulation prior to reaching the threshold of amyloid positivity. The benefit of this study and the treatment of primary prevention population is that inhibiting meaningful amyloid accumulation in such patients may prevent the onset of Stage 1 AD and subsequent irreversible pathological changes. This is expected to impede / prevent cognitive and functional impairments associated with later stages of the disease. One of the challenges, however, is whether such primary prevention population can be treated with remternetug safely such that the treatmentresults in: lack of accumulation or reduction of amyloid plaques in the population of subjects as well as clinical benefit.

[0178] Intervention in the primary prevention population with remternetug is not expected to inhibit amyloid plaque formation but is intended to remove the deposits once formed and prevent meaningful accumulation. In other words, the dosing regimens described here for remternetug are expected to remove deposits once formed at a rate that is greater than the rate of deposition and accumulation of amyloid plaques. With regular but infrequent dosing of remternetug, the chronic accrual of amyloid plaque will be halted and / or reversed. This may prevent and / or reverse transition to amyloid positivity and the downstream pathological changes leading to the onset of clinical AD symptoms. Unlike secondary prevention (as in Study LAKI above), intervening prior to significant amyloid burden is hypothesized to result in a greater long-term clinical benefit with less risk.

[0179] Study LAKJ is a multicenter, randomized, double-blind, placebo-controlled, parallel-group treatment, Phase 3 study to evaluate the safety and efficacy of remternetug in cognitively unimpaired participants, who are cerebral amyloid negative as defined by plasma P- tau (e.g., P-tau-217, P-tau-181, or P-tau-231) and at-risk for cerebral amyloid accumulation as determined by, e.g., age and / or APOE ε4 genotype. The primary objective of Study LAKJ will assess whether treatment with remternetug, compared to placebo, results in more individuals being below the threshold of cerebral amyloid positivity measured by amyloid PET, preventing their transition to Stage 1 AD.

[0180] The primary objective of Study LAKJ is to assess the effect of remternetug versus placebo in participants who are amyloid-negative as measured by beta-amyloid PET scan (using, e.g., 18 F florbetapir or another suitable beta-amyloid PET imaging agent), with the primary endpoint being defined as the proportion of participants who are amyloid-negative as measured by beta-amyloid PET scan (i.e., less than 24.1 CL using, e.g., 18 F florbetapir or another suitable beta- amyloid PET imaging agent) at the end of the study.

[0181] Secondary objectives of Study LAKJ include the assessment of the effect of remternetug versus placebo on time to P-tau-217 positivity as measured by 2 consecutive positive plasma P-tau-217 tests as the secondary endpoint. Additionally, another secondary objective of LAKJ may assess the effect of remternetug versus placebo on the degree of beta-amyloid plaque reduction as measured by beta amyloid PET scan (using, e.g., 18 F florbetapir or another suitablebeta-amyloid PET imaging agent), with the endpoint being defined as the change in cerebral beta- amyloid plaque levels from baseline through the participant’s final visit as measured by beta- amyloid PET scan (using, e.g., 18 F florbetapir or another suitable beta-amyloid PET imaging agent).

[0182] Additional secondary analyses include assessing the safety of SC remternetug on spontaneously reported adverse events, ARIA, and hypersensitivity or injection site reactions.

[0183] Exploratory analyses of LAKJ may include, but are not limited to, assessing of the effect of remternetug versus placebo on measures of cognition in participants at risk for AD as measured by known cognitive testing well defined in the art (such as, e.g., the Montreal Cognitive Assessment).

[0184] Intended Patient Population: The target population (primary prevention) for Study LAKJ is individuals at an elevated risk of accumulating amyloid plaques and subsequently developing irreversible cognitive impairment and dementia due to AD. This population does not have evidence of clinical AD pathology or abnormal amyloid plaque pathology as defined by plasma P-tau at the start of treatment.

[0185] Study participants are cognitively unimpaired individuals who are amyloid negative by plasma P-tau and considered at-risk as determined by their age and APOE genotype. This study measures cerebral amyloid positivity in individuals at-risk for cerebral amyloid accumulation. For this purpose, amyloid positivity is defined as >24.1 CL by amyloid PET (using, e.g., 18 F-florbetapir or another suitable beta-amyloid PET imaging agent).

[0186] Study participants will receive subcutaneous remternetug or placebo. All randomized participants will undergo baseline, 2-year, 4-year, and 6-year amyloid PET imaging (using, e.g., 18 F-florbetapir or another suitable beta-amyloid PET imaging agent). Amyloid PET imaging, assessed at the end of the study period, serves as the primary endpoint by identifying the proportions of participants who are amyloid negative, comparing remternetug and placebo arms. This data will provide a thorough understanding of the potential effects of remternetug on preventing AD pathology. Additionally, longitudinal amyloid PET imaging enables detailed exploratory analyses including examining the relationship between amyloid PET and plasma P- tau (e.g., P-tau-217) measurements, and a spatial assessment of amyloid accumulation and natural disease progression in participants treated with placebo. These findings may provide deeper insights into the scientific field of the early pathophysiology of AD. Additionally, MRI brain scansmay be performed as routine monitoring for ARIA during this study. An unscheduled MRI may be obtained upon suspicion of ARIA.

[0187] Stratification: Participant randomization will be stratified by: • APOE ε4 status (homozygous / heterozygous / non-carrier); • Age (50 (or 55) to less than 60, 60 to less than 70, and 70 to 80 years); and • Amyloid plaque levels as assessed by PET (PET amyloid positive / PET amyloid negative). No more than approximately 40% of the entire study population will be APOE ε4 noncarriers (APOE ε3 / ε3; ε3 / ε2; ε2 / ε2).

[0188] The overall study duration is approximately 10 years, with a 6-year primary treatment period, with planned early efficacy interim analysis at 4 years, and a long-term extension period (LTE), concluding once the total study duration reaches approximately 10 years. The study has these periods: a) Prescreening / Screening: this period includes Visit 0 (Visit 601) and Visit 1; b) Double-blind Treatment: this period starts with Visit 2 and continues for approximately 4 years to 6 years; c) Long-term extension: this period starts at the end of Double-Blind Treatment period and may continue until the total study duration reaches approximately 10 years or the study is ended at the sponsor’s discretion; and d) Follow-up: this period occurs at least 20 weeks after a participant’s last dose of study intervention. Interim analyses may be performed at any time points, including at 4 years as stated above. The study will remain blinded until the last participant reaches the primary endpoint study duration, at which time all remaining study participants without MRI exclusion criteria will transition to a long-term extension period and receive remternetug, initiating treatment with the titration dose(s) followed by maintenance dosing. The long-term extension will provide long-term safety, biomarker, and cognitive effects of remternetug treatment and aid recruitment and retention throughout the main portion of the study. Efficacy may be compared to available external control groups.

[0189] Participants who meet study entry criteria will be randomized in a 1:1 ratio into one of the following double-blind treatment groups: • Remternetug, administered subcutaneously via a pre-filled syringe or preparation from a vial:o 320^mg at randomization (Week 0), then 640 mg 6 months after first dose / randomization (Week 26), and 960 mg (Week 52) every 12 months after the second dose for up to and including 6 years; or o 320 mg at randomization (Week 0), then 640 mg 6 months after the first dose / randomization (Week 26), and 640 mg (Week 52) every 6 months after the third dose for up to and including 6 years; or o 320^mg at randomization (Week 0), then 640 mg 6 months after first dose / randomization (Week 26), 640 mg 6 months after the second dose (Week 52), and 960 mg (Week 78) every 12 months after the third dose for up to and including 6 years; or o 320 mg at randomization (Week 0), then 640 mg 6 months after the first dose / randomization (Week 26), 640 mg 6 months thereafter for 2 additional doses (weeks 52 and 78), and 960 mg once per year (Q12M) thereafter, for up to and including 6 years; or • Placebo, given at matching time points.

[0190] Prescreening and Screening Periods: The prescreening and screening periods consist of Visit 601 and Visit 1. At these visits, the study will be explained to the participant and study partner and written informed consent obtained before any study procedures are conducted. Visit 601 includes biomarker and genetic sample collection. Visit 1 can commence only after the participant’s biomarker and genetic eligibility are confirmed.

[0191] Double-Blind Treatment periods: The double-blind treatment period begins at Visit 2 (randomization / baseline). At Visit 2, all remaining study visits after randomization should be scheduled as close as possible to the target date relative to the first injection. Participants who meet entry criteria will be randomized to receive either remternetug or placebo for the 6-year double- blind treatment period, with interim analysis at about 4 years.

[0192] Study participants are cognitively unimpaired individuals who are amyloid negative by plasma P-tau and considered at-risk as determined by their age and APOE genotype. This study will measure cerebral amyloid positivity in individuals at-risk for cerebral amyloid accumulation. For this purpose, amyloid positivity is defined as >24.1 CL by amyloid PET. Study participants will receive SC remternetug or placebo. All randomized participants will undergo baseline, 2-year, 4-year, and 6-year amyloid PET imaging. Amyloid PET imaging, assessed at the end of the study period, serves as the primary endpoint by identifying the proportions ofparticipants who are amyloid negative, comparing remternetug and placebo arms. This data will provide a thorough understanding of the potential effects of remternetug on preventing AD pathology.

[0193] Additionally, longitudinal amyloid PET imaging enables detailed exploratory analyses including examining the relationship between amyloid PET and plasma P-tau-217 measurements, and a spatial assessment of amyloid accumulation and natural disease progression in participants treated with placebo. These findings may provide deeper insights into the scientific field of the early pathophysiology of AD.

[0194] Participants must meet all inclusion and exclusion criteria prior to entering the Double-Blind Treatment Period. Plasma phosphorylated tau (P-tau), an investigational in vitro diagnostic device (immunoassay) for identifying the presence of abnormal brain amyloid pathology, will be used to determine a participant’s eligibility for Study LAKI. Plasma P-tau is an accepted method and core AD biomarker for assessing AD pathology (see, e.g., Jack Jr, et. al., “Comparison of Plasma Biomarkers and Amyloid PET for Predicting Memory Decline in Cognitively Unimpaired Individuals,” Alzheimer’s & Dementia 20.3 (2024): 2143-2154 and Palmqvist, Sebastian, et al., “Discriminative Accuracy of Plasma Phospho-tau-217 for Alzheimer Disease vs Other Neurodegenerative Disorders,” JAMA 324.8 (2020): 772-781, which are each hereby incorporated by reference in their entireties) and will be used in this study for the purpose of participant eligibility.

[0195] Some inclusion criteria are described below, while not exhaustive and not limited to the following: l) Participant must be from 50 (or 55) to 80 years of age, inclusive; m) In general, an individual may take part in the study if they • are cognitively unimpaired by self-report; • are o 50 to 80 years of age and have at least 1 APOE ε4 allele (homozygotes, heterozygotes), or o 60 (or 65) to 80 years of age have no APOE ε4 alleles (noncarriers); andn) are P-tau negative, that is, have a plasma P-tau result inconsistent with the presence of abnormal brain amyloid pathology. Can give, and have given, signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol; o) Have venous access sufficient to allow the protocol-required blood sampling; p) Have adequate literacy, vision, and hearing for neuropsychological testing in the opinion of the investigator at the time of screening; and q) Are reliable, willing, and able to make themselves available for the duration of the study and are willing to follow study procedures, including use of electronic devices to complete study-related questionnaires and video calls.

[0196] Participants are excluded from the study if any of the following criteria apply. Some exclusion criteria are described below, while not exhaustive and not limited to the following: a) Have seen a doctor about memory concerns; b) Have a history or diagnosis of cognitive impairment, or significant other neurodegenerative disease that can affect cognition; c) Have received active immunization against Aβ in any other study; d) Have known allergies to remternetug, related compounds, or any components of the formulation; or e) Have a centrally read screening MRI demonstrating significant cerebral abnormalities including, but not limited to, the presence of ARIA-E, any macrohemorrhage, or severe white matter disease at screening.

[0197] Long-Term Extension Periods: The 4-year extension period begins after the initial double-blind period and continues until the study duration reaches 10 years in length. Participants who were initially randomized to placebo in the double-blind treatment period will begin to receive remternetug in the long-term extension period. Participants initially randomized to remternetug in the double-blind treatment period will continue to receive remternetug during the long-term extension period. To maintain blinding for the double-blind treatment period, treatment in the long- term extension period will remain blinded until all participants have either completed the double- blind treatment period or discontinued. Participants are eligible to be included in the long-term extension period of the study if the criteria described above in the double-blinded treatment periodsapply. Individuals are excluded from participation in the long-term extension study if they are excluded from double-blind treatment periods, or if they: a) Have centrally-read MRI evidence, prior to entering the long-term extension period, demonstrating significant cerebral abnormalities including, but not limited to any macrohemorrhage, or severe white matter disease; or b) Are study participants who develop an illness before the start of long-term extension period that is unstable or serious, or that, in the judgment of the investigator, precludes treatment with remternetug.

[0198] Follow-up Period: Participants who have received at least 1 dose of the study intervention will have a follow-up visit (Visit 801). This visit is to occur at least 20 weeks from the last dose of study intervention.

[0199] Dose modification is not permitted in any portion of the study. Permanent or temporary discontinuation from LAKJ may occur, for example but not limited to, upon significant adverse events associated with treatment-emergent-ARIA-E and / or ARIA-H or a macrohemorrhage, the participant’s request, or the investigator’s discretion.

[0200] Permitted Concomitant Therapies: Symptomatic ARIA-E may be treated with oral or intravenous steroids at the discretion of the investigator or treating physician. Any medication used to treat symptomatic ARIA-E will be documented as a concomitant therapy.

[0201] Sample Size Determination for Study: Approximately 800-1200 participants will be enrolled in Study LAKJ. Approximately 720-1080 participants will be included in the primary analysis population (below the indeterminate P-tau-217 range). The sample size is chosen to detect a difference in the proportion of PET-negative participants within a treatment duration of 6 years of those receiving remternetug vs. those receiving placebo. Assuming a relative risk reduction for amyloid positivity of 0.7, a total of 720-1080 participants will provide >80% power to show superiority of remternetug over placebo at a 1-sided 0.025 alpha level. A 70% relative risk reduction will prevent the initial and necessary first stage of AD (evidence of amyloid pathology with minimal-to-no symptoms) and ultimately prevent downstream clinical symptoms in a large proportion of the participants treated (see, e.g., Jack CR Jr et al., “Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease: Alzheimer’s Association Workgroup. Alzheimer’s Dement. 2024 Aug;20(8):5143-5169, which is hereby incorporated by reference in its entirety). Numerous observational studies have followed the natural history of AD progression in the general agingpopulation and in autosomal- dominant AD populations (see, e.g., Jansen WJ, Janssen O, Tijms BM, et al., “Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum,” JAMA Neurol. 2022;79(3):228-243, which is hereby incorporated by reference in its entirety). Such studies have demonstrated that abnormal amyloid accumulation is an early and necessary step leading to abnormal tau phosphorylation and tau aggregation and ultimately neurodegeneration and AD clinical syndrome, with cognitively normal amyloid-positive individuals having a 2.6-times greater risk of dementia due to AD than amyloid-negative individuals (Roberts, Rosebud O., et al., “Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-based Setting,” JAMA Neurology 75.8 (2018): 970-979, which is hereby incorporated by reference in its entirety). No more than 40% of the entire study population will be APOE ε4 noncarriers (APOE ε3 / ε3; ε3 / ε2; ε2 / ε2). The additional assumptions used to calculate the sample size are an annualizedevent rate of 2% to 6%, and with an annualized participant dropout rate of approximately 10%.

[0202] Participant Study Withdrawal (temporarily or permanently): A participant may be permanently or temporarily discontinued from study intervention, for example but not limited to the following: participant’s request, Investigator’s discretion, adverse or clinically significant new medical condition(s), significant adverse event associated with ARIA, or development of macrohemorrhage. Complete or permanent withdrawal from Study LAKJ is projected to be uncommon. Additionally, in events of temporary discontinuation due to ARIA, the participants may be monitored with serial MRIs every 4 to 6 weeks to monitor resolution and / or stabilization of ARIA. Reinitiating study intervention may occur if a participant has resolution of non-serious ARIA-E, stabilization of non-serious ARIA-H, and the resolution of any associated symptoms, at the discretion of the Investigator.

[0203] Efficacy Assessments / Projected Clinical Outcome Measurements: Amyloid burden (as assessed using amyloid PET) over time will be compared in remternetug- and placebo-treated participants. Each visit that includes clinical outcome assessments comprise of: rater-administered assessments, and / or self-administered assessments proctored by study personnel or site staff, and / or self-administered assessments completed independently. Site staff may administer the respective assessments using an eCOA tablet. Clinical outcomes assessments for each participant may be performed at approximately the same time on each day, whenever possible, to reduce potential variability.EXEMPLARY EMBODIMENTS 1. A method of reducing amyloid beta (Aβ) plaques in the brain of a human subject suffering from Alzheimer’s Disease (AD) comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. 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 (Aβ) plaques, or the subject is suffering from Alzheimer’s disease comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks;wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. 3. A method of treating or preventing Alzheimer’s Disease (AD) in a human subject comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. 4. A method of slowing disease progression, cognitive decline, or functional decline in a human subject suffering from Alzheimer’s disease, comprising: i) administering to the subject a total of two doses of 400 mg of an anti-N3pG Aβ antibody, wherein each dose is administered at a frequency of one 400 mg dose every 8 weeks (Q8W); ii) eight weeks after administration of the last 400 mg dose of step i), administering to the subject a total of two to five doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 8 weeks (Q8W); and iii) four weeks after administration of the last 800 mg dose of step ii), administering to the subject a total of one to thirteen doses of 800 mg of the antibody, wherein each dose is administered at a frequency of one 800 mg dose every 4 weeks;wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. 5. The method of any one of embodiments 1 to 4, wherein the subject has early AD, preclinical AD, mild cognitive impairment (MCI), clinical AD, or prodromal AD. 6. The method of any one of embodiments 1 to 4, wherein the human subject has early AD (stages 1, 2, and 3 of AD according to FDA). 7. The method of any one of embodiments 1 to 4, wherein the human subject has preclinical AD. 8. The method of any one of embodiments 1 to 4, wherein the human subject has mild cognitive impairment (MCI). 9. The method of any one of embodiments 1 to 8, wherein the antibody is administered subcutaneously. 10. The method of any one of embodiments 1-4, wherein the subject is administered 2 doses of the 800 mg dose of step ii) at a frequency of one 800 mg dose every 8 weeks (Q8W). 11. The method of any one of embodiments 1-4, wherein the subject is administered 3 doses of the 800 mg dose of step ii) at a frequency of one 800 mg dose every 8 weeks (Q8W). 12. The method of any one of embodiments 1-4, wherein the subject is administered 4 doses of the 800 mg dose of step ii) at a frequency of one 800 mg dose every 8 weeks (Q8W). 13. The method of any one of embodiments 1-4, wherein the subject is administered 5 doses of the 800 mg dose of step ii) at a frequency of one 800 mg dose every 8 weeks (Q8W). 14. The method of any one of embodiments 1-4, wherein the subject is administered 7 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W). 15. The method of any one of embodiments 1-4, wherein the subject is administered 9 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W). 16. The method of any one of embodiments 1-4, wherein the subject is administered 11 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W).17. The method of any one of embodiments 1-4, wherein the subject is administered 13 doses of the 800 mg dose of step iii) at a frequency of one 800 mg dose every 4 weeks (Q4W). 18. The method of any one of embodiments above, wherein the administration of the anti- N3pG Aβ antibody causes i) reduction of Aβ plaques in the brain of the human subject; ii) slowing of disease progression; iii) slowing of cognitive decline in the human subject; or iii) slowing of functional decline in the human subject. 19. The method of embodiment 17, wherein the reduction of Aβ plaques in the brain of the human subject is determined by amyloid PET brain imaging or a diagnostic that detects Aβ or a biomarker for Aβ. 20. The method of any one of embodiments 1 to 18, 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 each 400 mg dose in step i); c) after the administration of each 800 mg dose in step ii); or d) after the administration of each 800 mg dose in step iii). 21. The method of embodiment 20, 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. 22. The method of embodiment 20 or 21, wherein if the subject has ARIA or is displaying symptoms consistent with ARIA: i) the administration of the anti-N3pG Aβ antibody is stopped and / or corticosteroids are administered to the subject or ii) the administration the anti-N3pG Aβ antibody is temporarily withheld with or without subsequent administration of corticosteroids until resolution of ARIA symptoms or radiographic stabilization on MRI.23. The method of any one of embodiments 1 to 22, wherein the administration of the anti- N3pG Aβ antibody does not result in ARIA events in the subject or results in reduction in the risk, severity, frequency, or number of events of ARIA. 24. The method of any one of embodiments 1 to 22, wherein the administration of the antibody does not result in serious ARIA or symptomatic ARIA. 25. The method of any one of embodiments 1 to 24, wherein administering the anti-N3pG Aβ antibody reduces Aβ plaques by about 60 to about 95% as compared to baseline, wherein the Aβ plaques are measured by amyloid PET imaging scan. 26. The method of any one of embodiments 1 to 24, wherein administering the anti-N3pG Aβ antibody results in LS Mean Change reduction in Aβ plaques by about 60% to about 95% from baseline, wherein the Aβ plaques are measured by amyloid PET imaging scan. 27. The method of embodiment 26, wherein administering the anti-N3pG Aβ antibody results in the LS Mean Change reduction in Aβ plaques by about 60% to about 95% from baseline is after 76 weeks. 28. The method of any one of embodiments 1 to 27, wherein the anti-N3pG Aβ antibody comprises a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 29. The method of any one of embodiments above, wherein the anti-N3pG Aβ antibody comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. 30. The method of any one of embodiments above, wherein the subject is administered a maintenance dose. 31. The method of embodiment 30, wherein the subject is administered a maintenance dose of: a) about 200 mg every six months; b) about 400 mg every six months; c) about 600 mg every six months; or d) about 800 mg every six months.The method of embodiment 30, wherein the subject is administered a maintenance dose of: a) about 200 mg every year; b) about 400 mg every year; c) about 600 mg every year; or d) about 800 mg every year. The method of embodiment 30, wherein the subject is administered a maintenance dose of: a) about 200 mg every 26 weeks or every 52 weeks; b) about 400 mg every 26 weeks or every 52 weeks; c) about 600 mg every 26 weeks or every 52 weeks; or d) about 800 mg every 26 weeks or every 52 weeks.SEQUENCES Remternetug, HCDR1 (SEQ ID NO: 1) AASGFTFSSYPMS Remternetug, HCDR2 (SEQ ID NO: 2) AISGSGGSTYYADSVKG Remternetug, HCDR3 (SEQ ID NO: 3) AREGGSGSYYNGFDY Remternetug, LCDR1 (SEQ ID NO: 4) RASQSLGNWLA Remternetug, LCDR2 (SEQ ID NO: 5) YQASTLES Antibody 1, LCDR3 (SEQ ID NO: 6) QHYKGSFWT Remternetug, HCVR (SEQ ID NO: 7) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGGSTY TDIQMTQSPSTLSASVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLESGVP SRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIKEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGGSTY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYYNGFDYWGQGTV S P P Te p ed o p ess g e e e ug ea y C a (S Q O ) gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcacctttagcag ctatcctatgagctgggtccgccaggctccagggaaggggctggagtgggtctcagctattagtggtagtggtggtagcacatactacgca gactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagccgaggacacg gccgtatattactgtgcgagagaggggggctcagggagttattataacggctttgattattggggccagggaaccctggtcaccgtctcctca gcctccaccaagggcccatcggtcttcccgctagcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaa ggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagc aacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcc acgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagc cctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggac gagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggca gccggagaacaactacaagaccacgccccccgtgctggactccgacggctccttcttcctctatagcaagctcaccgtggacaagagcag gtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt Exemplified DNA for Expressing Remternetug Light Chain (SEQ ID NO: 12) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtcttggtaac tggttggcctggtatcagcagaaaccagggaaagcccctaaactcctgatctatcaggcgtctactttagaatctggggtcccatcaagattc agcggcagtggatctgggacagagttcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacattataaaggtt ctttttggacgttcggccaagggaccaaggtggaaatcaaacggaccgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagtaat ag gc

Claims

CLAIMS We claim:

1. A method of reducing cerebral amyloid beta (Aβ) plaques in the brain of a primary prevention subject comprising administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months); ii) once about every 26 weeks (or once about every 6 months); iii) once about every 52 weeks (or once about every year); or iv) any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO:

7.

2. A method of treating or preventing cerebral amyloid plaque in the brain of a primary prevention subject comprising administering to the subject one or more doses of from about 320 mg to about 1020 mg of an anti-N3pG Aβ antibody at a frequency of about: i) once about every 13 weeks (or once about every 3 months); ii) once about every 26 weeks (or once about every 6 months); or iii) once about every 52 weeks (or once about every year); or iv) any combination thereof; wherein the anti-N3pG Aβ 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: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO:

7.

3. The method of any one of claims 1-2, wherein the method: i) minimizes amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events in the subject; ii) treats or prevents Alzheimer’s Disease (AD) in the subject;iii) prevents progression to preclinical AD or symptomatic AD in the subject; iv) maintains the subject below amyloid positivity level (below ~24.1 centiloids as measured by PET); v) slows AD disease progression, cognitive decline, or functional decline in the subject; and / or vi) reduces cerebral amyloid plaque level in the subject.

4. The method of any one of claims 1-3, wherein the antibody is administered subcutaneously.

5. The method of any one of claims 1-4, wherein the subject is administered one or more doses of about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 500 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about 800 mg, about 960 mg, about 990 mg, about 1000 mg, about 1020 mg, or any combination thereof.

6. The method of claim 5, wherein the subject is administered the one or more doses at a frequency of: i) once about every 13 weeks (or once about every 3 months); ii) once about every 26 weeks (or once about every 6 months); or iii) once about every 52 weeks (or once about every year).

7. The method of any one of claims 1-6, wherein the subject is administered a titration dosing regimen wherein the titration dosing regimen is selected from Table 1.

8. The method of any one of claims 1-7, further comprising administering one or more maintenance doses to the subject.

9. The method of claim 8, wherein the one or more maintenance doses: i) minimize ARIA risk, ARIA frequency, ARIA severity, or ARIA events in the subject; ii) treat or prevent Alzheimer’s Disease in the subject; iii) prevent progression to preclinical AD or symptomatic AD in the subject;iv) maintain the subject below amyloid positivity level (below ~24.1 centiloids as measured by PET); v) slow AD disease progression, cognitive decline, or functional decline in the subject; and / or vi) reduce cerebral amyloid plaque level in the subject.

10. The method of any one of claims 1-7, further comprising administering a maintenance dosing regimen to the subject wherein the maintenance dosing regimen is selected from Table 1.

11. The method of claim 10, wherein the maintenance dosing regimen: i) minimizes amyloid-related imaging abnormality (ARIA) risk, ARIA frequency, ARIA severity, or ARIA events in the subject; ii) treats or prevents Alzheimer’s Disease (AD) in the subject; iii) prevents progression to preclinical AD or symptomatic AD in the subject; iv) maintains the subject below amyloid positivity level (below ~24.1 centiloids as measured by PET); iv) slows AD disease progression, cognitive decline, or functional decline in the subject; and / or v) reduces cerebral amyloid plaque level in the subject.

12. The method of claim 10 or 11, wherein the subject is administered a dosing regimen, including the titration dosing regimen and the maintenance dosing regimen, wherein the dosing regimen is selected from Table 1.

13. The method of claim 12 wherein the subject is administered a dosing regimen as follows: i) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; and then 960 mg dose at week 52 (or a year) after start of the dosing regimen and every 52 weeks (or every year) thereafter; ii) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; and then 640 mg dose at week 52 (or a year) after start of the dosing regimen and every 26 weeks (or every 6 months) thereafter;iii) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; then 640 mg dose at week 52 (or a year) after start of the dosing regimen; then a 960 mg dose at week 78 (or year and half) after start of the dosing regimen and every 52 weeks (or every year) thereafter; or iv) a dose of 320 mg at week 0 (start of dosing regimen); then a 640 mg dose at week 26 (or 6 months) after start of dosing regimen; then a 640 mg dose at week 52 (or a year) after start of the dosing regimen; then a 640 mg dose at week 78 (or year and half) after start of the dosing regimen; and then a 960 mg dose every 52 weeks (or every year).

14. The method of any one of claims 1-13, wherein the reduction of Aβ plaques in the brain of the subject is determined by amyloid PET brain imaging or a diagnostic that detects Aβ or a biomarker for Aβ.

15. The method of any one of claims 1 to 14, further comprising a step of evaluating the subject for ARIA risk, ARIA frequency, ARIA severity, or ARIA events: i) before the administration of each titration dose; ii) after the administration of each titration dose; iii) before the administration of each maintenance dose; or iv) after the administration of each maintenance dose.

16. The method of claim 15, 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.

17. The method of claim 16, wherein if the subject has ARIA or is displaying symptoms consistent with ARIA: i) the administration of the anti-N3pG Aβ antibody is stopped, and corticosteroids are administered to the subject; ii) the administration the anti-N3pG Aβ antibody is temporarily withheld until resolution of ARIA symptoms or radiographic stabilization on MRI; oriii) the administration the anti-N3pG Aβ antibody is discontinued.

18. The method of claim 1 or 2, wherein the administration of the antibody does not result in ARIA events in the subject.

19. The method of claim 1 or 2, wherein the administration of the antibody does not result in serious ARIA or symptomatic ARIA.

20. The method of any one of claims 1-19, wherein the anti-N3pG Aβ antibody comprises a LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO:

9.

21. The method of any one of claims 1-20, wherein the anti-N3pG Aβ antibody comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9.

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