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

Neurology. 2017 Feb 14;88(7):661-668. doi: 10.1212/WNL.0000000000003614. Epub 2017 Jan 20.


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 ε3/3 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 ε3/3 carriers with different '523 genotypes.

Results: The 1,170 APOE 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 APOE 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 (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 ε3/3-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.

MeSH terms

  • Aged
  • Apolipoprotein E3 / genetics*
  • Cognition
  • Cognitive Dysfunction / genetics*
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genotyping Techniques
  • Homozygote*
  • Humans
  • Linear Models
  • Male
  • Membrane Transport Proteins / genetics*
  • Mental Status Schedule
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Neuropsychological Tests
  • United States
  • White People / genetics


  • Apolipoprotein E3
  • Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • TOMM40 protein, human