Abstract
Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 (“523”) variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640–650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 “risk” allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 “short” allele showed lower white matter integrity when compared with carriers of the “long” and “very-long” alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.
Highlights
The apolipoprotein E (APOE) gene is located on chromosome 19q13.2 and is 3.7 kilobases (KB) long
The present study aims to investigate the effects of APOE and the outer membrane of 40 (TOMM40) genotypes on brain white matter integrity as assessed using quantitative tractography in a large, age-homogenous sample of relatively healthy older people
This left 675 participants, of which 642 and 652 participants had successful genotyping for APOE and TOMM40, respectively
Summary
The apolipoprotein E (APOE) gene is located on chromosome 19q13.2 and is 3.7 kilobases (KB) long. The ε4 allele of APOE is the “risk” variant for several phenotypes compared with ε3 (“neutral”), and ε2 (generally considered “protective”, 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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