Do Classical Complement Activation and the Route of Administration of Anti-Amyloid Antibodies Contribute to Vascular Side Effects Known as Amyloid-Related Imaging Abnormalities?

Amyloid beta protein accumulates outside of neurons into plaques and within blood vessel walls inside the brain. Recently, two anti-amyloid antibodies, aducanumab (Biogen’s Aduhelm) and lecanemab (Eisai’s Leqembi), have received approval from the U.S. Food and Drug Administration (FDA) for the treatment of early-stage Alzheimer’s disease (AD). A third antibody, donanemab (Lilly), revealed promising Phase 3 results in July 2023 and is expected to also receive FDA approval in the near future. All three antibodies bind plaques and vascular amyloid, although to varying degrees. We hypothesize that plaque-binding antibodies infused intravenously through the blood first encounter vascular amyloid and bind it, leading to activation of a part of the immune system called the “classical complement cascade,” in which the first step is binding of the antibody/amyloid-bound immune complex to complement C1q. This sets off a series of events that eventually leads to the removal of the immune complex, recruitment of immune cells that secrete pro-inflammatory molecules and cause vascular degradation, and possibly even cell death, within and near the blood-brain barrier and brain blood vessels. Ultimately, this process may lead to brain swelling, otherwise known as edema, and later, after significant compromise of the blood vessel wall, microhemorrhages, small hemorrhages due to a weakening of the blood vessel wall—both of which have been observed in human clinical trials with the aforementioned anti-amyloid beta antibodies. While mostly asymptomatic and transient, there is a small fraction of AD patients that develop more severe and serious reactions. However, why this occurs is not well understood. We propose to determine whether plaque-binding anti-amyloid antibodies first bind to vascular amyloid and activate the classical complement cascade, setting off a local firestorm around amyloid-containing blood vessels that results in edema early and microhemorrhages after chronic treatment, and whether blocking complement activation by genetically manipulating the complement binding region on the antibody will prevent these vascular side effects. In addition, we will compare how the antibodies are delivered (e.g., intraperitoneal or subcutaneous injection or intravenous infusion) to see whether the route of delivery impacts the binding of the antibody to vascular and plaque amyloid, and the incidence and severity of the vascular side effects. Outcomes include biochemical and pathological analyses of amyloid, inflammation and immune cells in the brain, blood biomarkers and changes in gene expression, especially those related to vascular amyloid and microhemorrhages. These work will provide a better mechanistic understanding of anti-amyloid antibody-induced amyloid-related imaging abnormalities (ARIA) and may help identify novel therapeutic targets to mitigate the vascular side effects. As these antibodies roll out to the general population, there is a large unmet need to understand and reduce the risk of ARIA to protect patients and keep them safe.