The triple-hit hypothesis of Alzheimer’s disease: blood–brain barrier breakdown, infection, and neuroimmune activation as a unified etiological framework

Studies of Alzheimer’s disease (AD) have long been dominated by the amyloid cascade hypothesis, although mounting evidence suggests that amyloid-β (Aβ) deposition might be a late downstream event, rather than the initiating trigger of AD. Here, I propose a unifying Triple-Hit Hypothesis in which AD develops through a sequential interaction among three causative processes that have been individually implicated before in the onset of Alzheimer’s disease: (1) early blood–brain barrier (BBB) breakdo