These failures underscored three key limitations of monospecific mAbs: (1) inability to address AD’s multifactorial pathology (Aβ, tau, neuroinflammation); (2) poor BBB penetration (0.1–0.3% of dose); and (3) high ARIA risks in APOE4 carriers [17,18]. This evidence concerns the gene APOE and Alzheimer disease.