Alzheimer’s biology expands beyond the amyloid–tau cascade

Recent work supports a multifactorial, stage-dependent model involving peripheral immune signaling, neuronal hyperactivity, ERBB4/mTOR-linked glial synapse elimination, systemic and vascular contributors, circadian biology, and cognitive resilience. The cDC1–CD8+ pathway and ERBB4 findings remain primarily preclinical; direct validation, human relevance, causality, and therapeutic safety are unresolved, while negative lithium trials underscore the difficulty of translating mechanistic rationale into clinical benefit.