Abstract
Alzheimer’s disease (AD) risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE) is the strongest known genetic risk factor for AD, and a related gene, apolipoprotein J (APOJ), also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry (VBM) in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. Apolipoprotein E-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root.
Highlights
Multiple genetic polymorphisms have been shown to increase Alzheimer’s disease (AD) risk without guaranteeing its onset (Bertram et al, 2007)
Because pathogenesis of AD begins as early as two decades prior to the presentation of clinical symptoms (Bateman et al, 2012), it is plausible that a series of genetically-induced differences in brain structure— such as entorhinal cortex volume—could accumulate with aging to increase vulnerability to AD later in life
We assayed entorhinal cortex volume in a cohort of young adults to directly investigate whether apolipoprotein E (APOE) and apolipoprotein J (APOJ) genetic AD risk alters the structure of this region in early adulthood
Summary
Multiple genetic polymorphisms have been shown to increase Alzheimer’s disease (AD) risk without guaranteeing its onset (Bertram et al, 2007). Genome-wide association studies have repeatedly shown that the ε4 allele of the apolipoprotein E (APOE) gene is the strongest known genetic risk factor for AD, increasing risk by 200–300% and decreasing age of onset, in a dose-dependent manner (Farrer et al, 1997; Bertram et al, 2007; Harold et al, 2009; Fei and Jianhua, 2013). The putative functional similarities between the proteins these genes encode (Kounnas et al, 1995; Koch et al, 2001; Elliott et al, 2010; Leeb et al, 2014) prompted us to explore whether APOE and APOJ polymorphisms may have a cumulative effect, which would suggest the potential of a common pathway for these risk factors in a region critical for AD pathogenesis
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