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

Objective: To interrogate a poly-T variant (rs10524523,'523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE epsilon 3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD). Methods: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. APOE and TOMM40'523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE epsilon 3/3 carriers with different '523 genotypes. Results: The 1,170 APOE epsilon 3/3 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 APOE epsilon 3/3; 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 (p = 0.002). The same association was observed for episodic memory (p < 0.001) and semantic memory (p = 0.003) but not for working memory, perceptual speed, or visuospatial ability. Conclusions: Our data reveal an association of APOE epsilon 3/3-TOMM40'523 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.