TOMM40 ‘523 VARIANT AND COGNITIVE DECLINE IN COMMUNITY BASED OLDER PERSONS WITH APOE E3/3 GENOTYPE

Abstract

The Apolipoprotein E (APOE) polymorphism is the best known genetic risk factor for late-onset Alzheimer’s disease (AD). Recent data suggest that a poly-T variant (‘523) in the adjacent TOMM40 gene represents a more informative signal in predicting age of AD onset. We interrogated the ‘523 variant in older persons with homozygous APOE ε3/3 genotype for associations with longitudinal cognitive decline. Data came from two cohort studies of aging and dementia in which participants underwent annual clinical evaluations for up to 21 years. The ‘523 genotypes were determined based on the length variation of the poly-T stretch of the rs10524523 polymorphism. Linear mixed models compared the rates of decline in global cognition and five cognitive domains by the ‘523 genotypes. All 1,170 APOE ε3/3 homozygotes were of European ancestry, free of dementia at baseline, and had an average age of 78.5 years. Three major genotypes at the ‘523 variant were linked to APOE ε3/3, 26.5% had 2 short poly-Ts (S/S), 48.9% had 1 short and 1 very long poly-Ts (S/VL) and 24.0% had 2 very long poly-Ts (VL/VL). Longitudinal data analyses show that subjects with ‘523-S/S had faster decline in global cognition than subjects with ‘523-S/VL (p=.002) or ‘523-VL/VL (p=.030). The same association was observed in episodic memory (p=.0004 for ‘523-S/VL and p=.010 for ‘523-VL/VL) and semantic memory (p=.002 for ‘523-S/VL and p=.050 for ‘523-VL/VL), but not significant (all ps>.05) in working memory, processing speed or visuospatial ability. Our data reveal an association of the APOE ε3/3-TOMM40 ‘523 haplotypes with cognitive decline in community based older persons, such that the VL poly-T at the TOMM40 ‘523 locus is related to less decline, primarily in episodic and semantic memory.