Emerging roles of apolipoprotein E4 in cerebral small vessel disease-related cognitive impairment: mechanistic insights and therapeutic perspectives

Cerebral small vessel disease (CSVD) is a major contributor to cognitive decline and vascular cognitive impairment in the elderly. However, the extent to which apolipoprotein E4 (ApoE4) contributes to sporadic, non-amyloid CSVD remains unclear. Previous literature has often inferred CSVD mechanisms from Alzheimer’s disease (AD) research, carrying the risk of overstating disease-specific causal relationships. Therefore, this narrative review re-evaluates the relationship between ApoE4 and CSVD using a CSVD-centric hierarchy of evidence. Population-based imaging and epidemiological data suggest that “APOE” ε4 may alter susceptibility to white matter injury and cognitive impairment; however, the effect sizes are generally small or context-dependent, and associations are influenced by factors such as age, hypertension, diabetes, total vascular risk burden, AD pathology, ancestry, sex, and “APOE” gene dosage. Evidence is stronger for cerebral amyloid angiopathy (CAA)—which involves mechanisms distinct from sporadic arteriolosclerotic CSVD—and thus warrants separate discussion. At the mechanistic level, direct evidence regarding CSVD supports endothelial dysfunction, BBB leakage, neurovascular unit (NVU) instability, and white matter injury as core pathological processes. Among the evidence specific to ApoE4, models involving impaired neurovascular regulation and chronic hypoperfusion are the most compelling; conversely, mechanisms such as the cyclophilin A–MMP-9 pathway, TREM2–ApoE signaling, insulin receptor trafficking, reelin-related synaptic effects, endoplasmic reticulum stress, and autophagy currently rely primarily on AD research or preclinical evidence. Two recently proposed specific hypotheses—the brain–heart–kidney axis hypothesis and the microglial lipid droplet model—offer valuable conceptual frameworks but should be viewed as testable theories rather than established mechanisms. To date, no ApoE4-targeted therapies have been proven effective for CSVD-related cognitive impairment future research should prioritize genotype-stratified longitudinal CSVD cohorts, standardized imaging studies, adjustment for Alzheimer’s disease (AD) biomarkers, analysis of interactions between vascular risk factors, studies on human white matter tissue, and the development of ApoE4 disease models that integrate chronic hypoperfusion and vascular comorbidities.