Hypothesis: Modulation of microglial phenotype in Alzheimer's disease drives neurodegeneration

Abstract The pathophysiology of Alzheimer's disease (AD) remains to be elucidated. The amyloid hypothesis holds explanatory power but has limitations. This article suggests that amyloid deposition and increased permeability of the blood–brain barrier are independent early events in the disease process, which together fashion a distinct microglial activation phenotype. Downstream events including, phagocytosis of synapses and persistent glutamate signaling through N‐methyl‐D‐aspartate receptors drive neurodegeneration and tau pathology. This hypothesis draws on several strands of evidence and aims to illuminate several of the unexplained temporal and spatial features of AD.