Impaired amyloid-beta uptake and distinct transcriptomic profiles of monocytes in APOE4 carriers: The Chongqing Ageing and Dementia Study

Abstract

The ε4 allele of the apolipoprotein E gene (APOE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). However, its impact on monocyte-mediated amyloid-β (Aβ) clearance and associated immune dysfunction remains poorly understood. Through Aβ uptake assays in humans and mice coupled with transcriptomic profiling, we identified a significant and persistent monocytic Aβ uptake deficiency in APOE4 carriers. This deficit was quantitatively associated with poor cognitive function and elevated plasma Aβ levels. Mechanistically, RNA sequencing revealed that this impairment is driven by a stage-specific molecular transition: in cognitively normal individuals, APOE4 induces a functional mismatch characterized by proinflammatory priming and lipid metabolic dysregulation, whereas in AD patients, this evolves into profound immune exhaustion or transcriptional collapse of core immune and endocytosis pathways. These findings establish APOE4 as a systemic modulator of innate immune competence, suggesting that monocyte-targeted functional rejuvenation may be a potential therapeutic strategy for AD.