Association of Apolipoprotein E ɛ4 Allele with Enlarged Perivascular Spaces

Abstract

Objective Enlarged perivascular spaces have emerged as markers of cerebral small vessel disease and are linked to perivascular drainage dysfunction. The apolipoprotein E‐ɛ4 (APOE‐ɛ4) allele is the strongest genetic risk factor for cerebral amyloid angiopathy and Alzheimer's neuropathology, but the underlying mechanisms remain unclear. We studied the relationship between APOE‐ɛ4 and the topography and burden of enlarged perivascular spaces to elucidate underlying mechanisms between APOE‐ɛ4 and adverse clinical outcomes. Methods We included 3,564 Framingham Heart Study participants with available genotypes and magnetic resonance imaging. Enlarged perivascular spaces in the basal ganglia and centrum semiovale were rated using a validated scale. We related APOE‐ɛ4 allele presence to high burden of enlarged perivascular spaces in each region and a mixed score reflecting high burden in both regions using multivariable logistic regression. Exploratory analyses incorporated presence of cerebral microbleeds and assessed effect modification by hypertension. Results Mean age was 60.7 years (SD = 14.6), 1,644 (46.1%) were men, 1,486 (41.8%) were hypertensive, and 836 (23.5%) participants were APOE‐ɛ4 carriers. APOE‐ɛ4 was associated with high burden of enlarged perivascular spaces in the centrum semiovale (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.16, 1.81) and mixed regions (OR = 1.37, 95% CI = 1.11, 1.68). Associations were slightly stronger in hypertensive subjects. Interpretation The APOE‐ɛ4 allele plays a modest role in the burden of enlarged perivascular spaces in the centrum semiovale. Further studies are needed to clarify the underlying small vessel disease type in community‐dwelling individuals with predominant centrum semiovale enlarged perivascular spaces, which may be hypertensive angiopathy in our sample. ANN NEUROL 2022;92:23–31

Association of Different Combinations of ALDH2 rs671, APOE rs429358, rs7412 Polymorphisms with Hypertension in Middle-Aged and Elderly People: A Case–Control Study

“…60 APOE gene polymorphism is associated with small vessel disease, which may cause hypertensive vascular disease. 61 Lipid metabolism of the elderly people was more affected by APOE polymorphism than that of the middle-aged people, 62 age-dependent lipid changes were also observed in ApoE/LDLR −/− mice. 63 In addition, there is a significant relationship of the gene-gene and polymorphism-polymorphism interactions with hypertension.…”

Biomarkers involved in the pathogenesis of cerebral small-vessel disease

“…Apolipoprotein E (APOE) genotype, especially APOE-ε4, a genetic marker for sporadic CAA, has been used as a genetic risk factor for CAA and Alzheimer disease (AD). APOE-ε4 was found to be associated with a high burden of EPVS in the centrum semiovale ( 10 ). While the APOE-ε2 allele appears to be more prevalent in patients with CAA-associated intracerebral hemorrhage ( 11 ).…”

Association of enlarged perivascular spaces with cognitive function in dementia‐free older adults: A population‐based study

“…The burden of EPVS has been associated with older age, male sex, and apolipoprotein E ( APOE ) ε4 allele. 10 , 11 , 12 In addition, EPVS is correlated with white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and lacunes in older adults. 10 , 13 , 14 Given that other CSVD markers and demographic and genetic factors are closely related to cognitive function, 5 , 14 , 15 , 16 it is worth exploring whether the associations of EPVS load with domain‐specific cognitive function are present independent of other CSVD markers or vary by demographic factors and APOE genotype.…”