<i>TOMM40</i>'523 variant and cognitive decline in older persons with <i>APOE</i> ε3/3 genotype.

Abstract

To interrogate a poly-T variant (rs10524523, '523) in <i>TOMM40</i>, a gene adjacent to the <i>APOE</i> gene on chromosome 19, in older persons with <i>APOE</i> ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD). Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. <i>APOE</i> and <i>TOMM40</i>'523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among <i>APOE</i> ε3/3 carriers with different '523 genotypes. The 1,170 <i>APOE</i> ε3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the '523 variant were linked to <i>APOE</i> ε3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with '523-S/S had faster decline in global cognition than participants with '523-S/VL or VL/VL (<i>p</i> = 0.002). The same association was observed for episodic memory (<i>p</i> < 0.001) and semantic memory (<i>p</i> = 0.003) but not for working memory, perceptual speed, or visuospatial ability. Our data reveal an association of <i>APOE</i> ε3/3-<i>TOMM40</i>'523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.