What resolves this contention: APOE4 drives AD pathology through gain-of-toxic-…

What resolves this contention: APOE4 drives AD pathology through gain-of-toxic-function: early apoE4 overexpression strongly increases plaque load, apoE4 particles are abnormally large, and APOE4 has broad detrimental effects on tau, microglia, and astrocyte reactivity beyond amyloid-β vs. APOE4 effects may partly reflect loss-of-function: apoE4 has reduced half-life, constitutes only 30–40% of total apoE in heterozygous mice, and ASO-mediated APOE suppression reduces plaques, suggesting reducing apoE (including apoE4) is beneficial / APOE ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease, with pathogenic mechanisms now understood to extend beyond amyloid-β to include tau neurodegeneration, microglia and astrocyte responses, and blood-brain barrier disruption. / In targeted replacement APOE3/4 mice, apoE4 constitutes only 30–40% of total apoE levels due to enhanced degradation and re