Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer disease brain
ImportanceAnti-amyloid immunotherapy is used to treat Alzheimer disease (AD) with moderate benefits and potentially serious side effects due to amyloid related imaging abnormality with effusions/edema (ARIA-E). Different anti-amyloid antibodies have different in vitro binding characteristics to different synthetic A{beta} aggregates, leading to the assumption that they bind different species in the human brain. Lecanemab is hypothesized to bind "protofibrils," but these are not well-characterized in human brain. It is also unknown how binding differences correlate with ARIA-E rates. The APOE {varepsilon}4 allele increases ARIA-E risk, but how it affects antibody binding characteristics is unknown. ObjectivesTo determine whether anti-amyloid antibodies bind different species of human brain A{beta} and whether these binding properties to human brain A{beta} explains ARIA-E rates. DesignCross-sectional study of 18 postmortem human brains. SettingSingle tertiary care hospital. ParticipantsDeceased patients with AD and cerebral amyloid angiopathy (CAA). Main Outcomes and MeasuresEquilibrium binding constants (KD) and total A{beta} binding (Bmax) of recombinant aducanumab, lecanemab, and donanemab equivalents to human brain soluble and insoluble amyloid plaque-enriched and CAA-enriched A{beta} aggregates. ResultsLecanemab did not bind with greater affinity to the soluble fraction of A{beta} compared to aducanumab. All three antibodies were bound essentially identical quantities of A{beta} across the 18 cases and fractions (Pearsons r 0.84 - 0.97). Antibody preference for plaque vs CAA A{beta} did not differ in soluble fractions but differed slightly in insoluble extracts. The APOE {varepsilon}4 allele led to a more soluble antibody-accessible A{beta} pool in a dose-dependent manner for all three antibodies. Conclusions and RelevanceThe lecanemab binding target in human brain is unlikely to be distinctly "protofibrillar" compared to other antibodies. Differences in antibody preference for plaque vs CAA A{beta} are unlikely to fully explain differences in ARIA-E rates. The APOE {varepsilon}4 allele may plausibly increase ARIA-E risk by making antibody-accessible A{beta} more soluble. These results have implications for improving the safety and efficacy of current and future anti-amyloid antibody therapies.