This study examined associations between polymorphisms in three genes, apolipoprotein E (APOE), angiotensin converting enzyme (ACE), and vitamin D receptor (VDR), and longitudinal change in brain volumes and white matter lesions (WML) as well as effect modification by cardiovascular factors and tibia lead concentrations. Two MRIs, an average of 5 years apart, were obtained for 317 former organolead workers and 45 population-based controls. Both regions-of-interest and voxel-wise analyses were conducted. APOE and genotypes were associated with less decline in white matter volumes. There was some evidence of interaction between genetic polymorphisms and cardiovascular risk factors (ACE and high-density lipoprotein; VDR and diabetes) on brain volume decline. The VDR FokI ff genotype was associated with an increase in WML (no association for APOE or ACE). This study expands our understanding of how genetic precursors of dementia and cardiovascular diseases are related to changes in brain structure. 1. Introduction Brain volume loss [1] and increase in white matter lesions (WML) [2] are common consequences of aging, and both are related to worse cognitive function and risk of dementia [3–6]. Little is currently known about the genetic determinants of age-related brain volume loss or increase in WML or how genes may modify the effect of other environmental risk factors for these outcomes. Certain genetic polymorphisms associated with a greater risk for neurodegenerative diseases such as Alzheimer’s disease (AD) in later life [7] are potential candidates. The apolipoprotein E (APOE) gene is the best-documented genetic risk factor for AD, with the ε4 allele significantly increasing the risk for AD [8–10] and cognitive decline [11]. The angiotensin converting enzyme (ACE) gene is associated with AD [12, 13] and WML [14]. Certain vitamin D receptor (VDR) gene polymorphisms have also been associated with increased risk of AD [15], cardiovascular disease, and diabetes [16, 17], and these, in turn, have been linked to WMLs [18, 19]. These genes are, therefore, strong candidates for evaluation of genetic determinants of brain volume loss and increased WML in living persons through the use of neuroimaging technology. Furthermore, because it is hypothesized that exposure to certain external agents may induce upregulation of neurodegenerative disease-associated genes [20], it is appropriate to also examine the effect of these genes in the light of gene by environment interaction. Specifically, well-known risk factors for neurodegenerative disease, including
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