Associations between APOE genotype and cerebral small-vessel disease: a longitudinal study

Objective: It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. Method: There were 135 healthy elderly (including epsilon 2, epsilon 4 allele carriers and epsilon 3 homozygotes) who had completed two years' follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimer's disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. Results: We found that APOE epsilon 4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE epsilon 4 carriers had significantly decreased A beta(1-42) level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and epsilon 4 allele was related with declining trend of cognition. Conclusion: Our findings suggested APOE epsilon 4 allele was associated with increased A beta deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and epsilon 4 allele can exert long-term detrimental effects on individual's trajectory of cognition.