A genome-wide search for genetic variants influencing the brain's white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At ∼73 years of age, members of the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract-averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, g(FA), derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome-wide search was performed with g(FA) on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 × 10(-8)). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 (p = 1.65 × 10(-6)), which is related to tumor suppression and hemostasis, and another in LOC388630 (p = 5.08 × 10(-6)), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to g(FA).

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.