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

Abstract

Objective: To interrogate a poly-T variant (rs10524523, 9523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE e3/3 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 TOMM409523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE e3/3 carriers with different 9523 genotypes.Results: The 1,170 APOE e3/3 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 9523 variant were linked to APOE e3/3; 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 5 0.002). The same association was observed for episodic memory (p , 0.001) and semantic memory (p 5 0.003) but not for working memory, perceptual speed, or visuospatial ability. Conclusions:Our data reveal an association of APOE e3/3-TOMM409523 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.

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

“…Specifically, global cognition declined more rapidly in individuals who were homozygous for APOE ε3 and for the short poly-T in intron 6 of TOMM40 than in individuals who carried at least one copy of the VL-poly T[86]. Previously, we showed that TOMM40 mRNA expression was greater in brain samples from cognitively normal APOE ε3/ε3 individuals who were homozygous for the VL-poly T than in those who were homozygous for the short TOMM40 poly-T allele [46].…”

Sex differences in Alzheimer’s disease and common neuropathologies of aging

“…The APOE genotypes were determined by sequencing rs429358 (codon 112) and rs7412 (codon 158) at exon 4 of the APOE gene [65]. …”

Neuropathologic features of TOMM40 '523 variant on late‐life cognitive decline

“…Prior to examining their association with neuropathology, we first confirm that both ‘523-L carriers in LD with ε4, and the ε3/3 homozygotes with ‘523-S/S, exhibit faster decline in the current sample which represents a subset of autopsied individuals used in our prior report[12]. As expected, the results from a linear mixed model (Table 3 Model A) found that compared with ε3/3 homozygotes with ‘523-S/VL or -VL/VL genotype, 523-L carriers declined faster in cognition (Estimate=−0.059, Standard Error [SE]=0.009, p <0.001).…”

“…By contrast, three major ‘523 genotypes are present in APOE ε3/3 homozygotes, namely ‘523-S/S, ‘523-S/VL and ‘523-VL/VL. An earlier study found that age at AD onset varies across these three genotypes[11], and we recently reported that ‘523-S/S carriers exhibit faster decline in late life cognition compared with ‘523-S/VL or ‘523-VL/VL carriers[12]. These findings suggest that the ‘523 effect is not fully attributable to the LD with APOE variants.…”