ABSTRACT Background Apolipoprotein ε4 ( APOE ε4) is a potent genetic risk factor for Alzheimer's disease (AD). However, its role in cerebral small vessel disease (CSVD) remains unclear. Given the clinical and pathological similarities between CSVD and AD, this study aimed to investigate the associations of APOE ε4 gene dosage with cognitive function and dyslipidemia in CSVD patients, and to explore whether lipid disturbances mediate the effect of APOE ε4 on white matter hyperintensity (WMH) burden and cognitive impairment. Methods The study was a retrospective study. A total of 717 inpatients with CSVD admitted to the Department of Neurology, Wuhan No.1 Hospital, from January 2023 to January 2025 were enrolled. Associations among APOE ε4 gene dosage, cognitive function, lipid metabolism, and WMH were analyzed. Results The number of APOE ε4 alleles showed a significant negative correlation with MMSE and MoCA scores ( p < 0.001), and a dose‐dependent positive correlation with the risk of cognitive impairment and WMH severity, independent of traditional vascular risk factors. Lipid analysis indicated that APOE ε4 was an independent risk factor for elevated low‐density lipoprotein cholesterol (LDL‐C), but had no significant associations with high‐density lipoprotein cholesterol (HDL‐C) or triglycerides (TG). Mediation analysis suggested that LDL‐C may mediate the indirect detrimental effect of APOE ε4 on cognitive function. Conclusion APOE ε4 gene dosage is an independent risk factor for cognitive decline and WMH in CSVD patients, independent of traditional vascular risk factors. APOE ε4 may indirectly impair cognitive function by elevating LDL‐C levels to exacerbate atherosclerosis and cerebrovascular injury.
Jin et al. (Wed,) studied this question.
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