Article

APOE genotype and MRI markers of cerebrovascular disease

Department of Epidemiology (L.H.K.), GSPH, University of Pittsburgh, Pittsburgh, PA
Neurology (Impact Factor: 8.3). 07/2013; 81(3):292-300. DOI: 10.1212/WNL.0b013e31829bfda4
Source: PubMed

ABSTRACT We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.
We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n = 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis.
APOE ε4 carrier status and APOE ε44 genotype were associated with increasing white matter hyperintensity burden (sample size-weighted z score meta-analysis [meta]-p = 0.0034 and 0.0030) and presence of cerebral microbleeds (meta odds ratio [OR] = 1.24, 95% confidence interval [CI] [1.07, 1.43], p = 0.004, and 1.87 [1.26, 2.78], p = 0.002), especially lobar. APOE ε2 carrier status was associated with increasing white matter hyperintensity load (z score meta-p = 0.00053) and risk of brain infarct (meta OR = 1.41[1.09, 1.81], p = 0.008).
APOE ε4 and APOE ε2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE ε4 with an increased burden of CVD could be partly contributing to the relationship between APOE ε4 and AD, APOE ε2 was associated with MRI markers of CVD in the opposite direction compared to AD.

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    • "Although the precise mechanisms are still not well understood, we have previously discussed evidence that aberrant lipid metabolism may play a role in AD risk. We and others have found that the APOE ε4 allele is associated with decreased cognition, gray matter volume in memory areas (the hippocampus ), white matter tract integrity, and increased magnetic resonance imaging markers for cardiovascular disease [136] [137] [138]. Furthermore, decreases in cerebral glucose metabolism are a known biomarker for AD [139], and cognitively-normal, middle-aged APOE ε4 carriers have AD-like changes in cerebral glucose metabolism [140] [141], with a possible gene-dose effect [142]. "
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    • "The ε4 allele of APOE is the " risk " variant for several phenotypes compared with ε3 ( " neutral " ), and ε2 (generally considered " protective " , although less consistently). These phenotypes include risk of Alzheimer's disease (AD) (Corder et al., 1994), less successful cognitive aging (Deary et al., 2004; Wisdom et al., 2011), differences in brain structure (e.g., atrophy; Biffi et al., 2010), and functional connectivity (Trachtenberg et al., 2012); vascular pathologies such as hyperlipidemia, coronary heart disease and stroke (Lahoz et al., 2001), and brain microbleeds (Schilling et al., 2013). It is not clear to what extent associations between APOE variants and worse cognitive aging in cross-sectional and longitudinal studies reflect preclinical " prodromal " AD (Bretsky et al., 2003; Deary et al., 2004). "
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