Cell-type-specific APOE4 cascade across the Alzheimer's disease continuum

Apolipoprotein E4 (APOE4) is the leading genetic risk factor and an increasingly recognized causal contributor to Alzheimer's disease (AD). AD progresses along a temporal, pathological, and clinical continuum spanning preclinical, prodromal, and dementia stages. Across this continuum, APOE4 exerts detrimental effects at distinct times and in different cell types, underscoring the need for a model defining not only how but also when and in which cells these effects occur. In this review, we synthesize current findings and propose a temporal model linking cell-type-specific APOE4 expression to AD progression. In this model, age-associated stress upregulates neuronal APOE4 expression, leading to early neuronal deficits characteristic of preclinical AD. Neuronal APOE4-induced damage subsequently triggers a harmful glial response that, alongside glial APOE4, amplifies neurodegeneration and accelerates the onset of prodromal and dementia AD. This model highlights the temporal and cellular dynamics of APOE4 effects and suggests stage- and cell-type-specific therapeutics targeting APOE4-driven mechanisms across the AD continuum.