We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD.

Despite most monoclonal antibodies against Aβ in Alzheimer’s failed to demonstrate efficacy, the newest antibodies showed statistically significant clinical effects. We conducted a systematic review and meta-analysis to assess the efficacy, target engagement, and safety of anti-Aβ antibodies in sporadic AD including phase III RCTs published up to November 28, 2023. Antibodies as a drug class, attenuated worsening on the clinical scales CDR-SB and ADAS-Cog by very small effect sizes and reduced amyloid on PET by a very large effect size. Reduction of amyloid on PET was moderately correlated with CDR-SB and ADAS-Cog reductions. However, antibodies increased risk of ARIA-E and ARIA-H by a very large and moderate effect size, respectively. In subgroup analyses by individual drug, Donanemab and Lecanemab induced the largest benefits. In subgroup analyses by binding affinity, antibodies without binding to monomers were associated with the most favorable effects. Despite statistical significance for improvement on clinical measures, antibody effects were below the threshold of clinically meaningful change during the period they were studied. However, the newest antibodies demonstrably interfere with the underlying ΑD pathophysiology and therefore their benefit could be cumulative over time leading to larger clinical effects in subsequent years. PROSPERO registration no. CRD42022381334.