# Understanding and Mitigating Vascular Side-Effects Associated with Anti-Amyloid Immunotherapy > **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $831,601 ## Abstract PROJECT SUMMARY/ABSTRACT: Recent FDA accelerated approvals of two anti-amyloid antibody treatments, aducanumab and lecanemab, for early-stage Alzheimer’s disease (AD) provide the first disease-modifying treatments to date, albeit with modest- to-moderate slowing of cognitive decline, and potentially fatal vascular side effects known as Amyloid Related Imaging Abnormalities due to edema (ARIA-E) or microhemorrhages (ARIA-H) in a subset of patients, especially ApoE4 carriers. A recent press release reported efficacy and ARIA in a Phase 3 trial of donanemab, another antibody targeting aggregated amyloid- (A) protein. ARIA is mostly asymptomatic and transient but occasionally causes more severe cortical edema and hemorrhage, which makes understanding and mitigating ARIA an urgent unmet need as these antibodies move into the clinic. Strong but circumstantial evidence points to cerebral amyloid angiopathy (CAA), Aβ deposits within the brain vasculature, rather than amyloid plaques, as a cause of ARIA. Patients with CAA in addition to amyloid plaques are at higher risk of ARIA than patients with plaques but no CAA. Patients carrying an APOE ε4 allele, which predisposes to CAA and impairs Aβ clearance across the blood-brain barrier, are also at higher risk than patients with ε3 or ε2 alleles. We hypothesize that infused anti-amyloid antibodies first encounter and bind vascular amyloid and cause ARIA. Testing this hypothesis requires determining if antibodies that cause more ARIA (e.g., aducanemab) bind more vascular A, localize earlier and at higher concentrations to vascular A, and cause more immune activation toward vascular A than antibodies that cause less ARIA (e.g., lecanemab). APOE is likely to play a role as an anti-APOE antibody, HAE-4, has been reported to clear both vascular and plaque amyloid while restoring vascular function (Xiong et al., 2021). Complement fixation of the anti-A antibodies at sites of vascular amyloid may lead to activation of the complement cascade that results in a proinflammatory response, BBB leakage, edema and microhemorrhage. Therefore, we hypothesize that combining anti-amyloid antibodies with antibodies targeting poorly lipidated APOE associated with fibrillar amyloid or complement C1s to block complement activation will mitigate ARIA and perhaps improve efficacy. We propose the following three Aims: 1. We will compare four anti-amyloid antibodies (aducanemab, lecanemab, gantenerumab and donanemab) for their binding to plaque vs. vascular amyloid both biochemically and pathologically. 2. We will define the timing of ARIA and characterize vascular changes after 2, 4 and 8 weekly treatments with recombinant murine aducanemab, lecanemab and donanemab in aged 5XE4 mice. 3. We will combine the anti-amyloid antibody most prone to induce ARIA in Aim 2 with the HAE-4 anti-APOE antibody or an anti-C1s antibody to block the activation of the classical complement pathway to mitigate ARIA in aged 5XE4 mice. If successful,... ## Key facts - **NIH application ID:** 10848013 - **Project number:** 1R01NS136122-01 - **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL - **Principal Investigator:** CYNTHIA A LEMERE - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $831,601 - **Award type:** 1 - **Project period:** 2024-06-01 → 2029-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10848013 ## Citation > US National Institutes of Health, RePORTER application 10848013, Understanding and Mitigating Vascular Side-Effects Associated with Anti-Amyloid Immunotherapy (1R01NS136122-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10848013. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*