Protective Strategies to Reduce Amyloid Related Imaging Abnormalities (ARIA) After Anti-Amyloid Beta Immunotherapy (R01 - Clinical Trial Not Allowed)

Funding Opportunity Description Goal 1 of the National Plan to Address Alzheimer’s Disease is to prevent and effectively treat Alzheimer's disease (AD) and Alzheimer’s disease-related dementias (ADRD). ADRD are defined as Frontotemporal Dementia (FTD), Vascular Contributions to Cognitive Impairment and Dementia (VCID), Lewy Body Dementias (LBD), and Multiple Etiology Dementias (MED). Starting in 2012, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held research summits to assess the needs and set AD/ADRD research implementation milestones. The NINDS ADRD Summit 2022 resulted in ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. One priority is to establish and refine experimental models and technologies to identify disease-relevant mechanisms underlying VCID. As beta-amyloid is central to AD pathology, beta-amyloid is being pursued as a therapeutic target, including through passive immunotherapy against beta-amyloid. Because of the translational potential of passive anti-beta-amyloid immunotherapy on the ADRD disease processes, understanding the effect of this therapy on the blood-brain barrier and brain blood vessels in the intact living brain is critically important. In September 2023 NINDS sponsored a workshop to address Amyloid-Related Imaging Abnormalities (ARIA) as a side effect of anti-beta-amyloid immunotherapy with the goals to identify scientific gaps and opportunities (Home - NINDS Anti-Beta and ARIA). Therefore, this NOFO invites basic disease-related applications that use age-appropriate beta-amyloid animal models to understand genetic-, cellular-, and molecular mechanisms of adverse responses that occur at and/or proximal to the BBB due to passive anti-beta-amyloid immunotherapy. Two anti-beta amyloid antibodies, aducanumab and lecanemab, have received approval by the FDA for the treatment of mild to moderate Alzheimer’s disease (AD), and Phase 3 trials for several additional antibodies are currently underway. Aducanumab received accelerated approval in 2021 and lecanemab received full, traditional approval by the FDA in 2023. During the clinical trials for these anti-beta amyloid immunotherapies, however, MRI abnormalities were reported as an adverse treatment effect, termed “amyloid-related imaging abnormalities” (ARIA). Some patients experienced severe side effects, including leaky blood-brain barrier, edema, and brain hemorrhage. There are two subtypes of ARIA: ARIA showing edema and effusion (ARIA-E) and ARIA showing microhemorrhages and superficial siderosis (ARIA-H). ARIA-E is likely due to changes in water flux at the BBB, while ARIA-H is likely due to damage to the walls of small arterioles. ARIA is associated with areas of dynamic changes in Aβ localization, especially clearance from vessel walls, and presents an issue with clinical applications of anti-beta amyloid immunotherapies. Age, the presence of cerebrovascular disease, and APOE carrier status increase the risk of ARIA-effusion (E) and ARIA-hemorrhage (H). A better understanding of the mechanisms underlying the vulnerability of ApoE4 carrier status and other risk factors to the adverse side effects of anti-beta amyloid passive immunotherapy could help develop protective strategies to reduce severe and potentially fatal adverse events from passive immunotherapy. Therefore, it is critical to better understand the benefits and risks associated with this therapy and strategies to improve efficacy and safety. The purpose of this NOFO is to understand genetic, cellular, and molecular factors that result in the initial response of the BBB to passive anti-beta-amyloid immunotherapy, with the goal of protecting the BBB.