Dataset Information

TOMM40 '523 Associations with Baseline and Longitudinal Cognition in APOE ?3 Homozygotes.

ABSTRACT: TOMM40 '523 is associated with Alzheimer's disease (AD), but APOE linkage disequilibrium confounds this association. In 170 APOE ?3 homozygotes, we evaluated relationships between short and very long TOMM40 alleles and longitudinal declines in three cognitive domains (attention, verbal memory, and executive function). We used factor analysis to create composite scores from 10 individual cognitive tests, and latent growth curve modeling adjusting for clinical status (normal, amnestic mild cognitive impairment, or AD) to summarize initial performance and change over three years. Relative to individuals with two very long TOMM40 alleles, APOE?3 homozygotes with one or two short alleles showed lower baseline cognitive performance regardless of clinical status. The number of short or very long TOMM40 alleles was not associated with longitudinal cognitive changes. In APOE?3 homozygotes from the University of Kansas Alzheimer's Disease Center cohort, an association between TOMM40 '523 and cognition is consistent with the possibility that TOMM40 influences cognition independent of APOE.

SUBMITTER: Watts A

PROVIDER: S-EPMC7206989 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

TOMM40 '523 Associations with Baseline and Longitudinal Cognition in APOE ɛ3 Homozygotes.

Watts Amber A Wilkins Heather M HM Michaelis Elias E Swerdlow Russell H RH

Journal of Alzheimer's disease : JAD 20190101 4

TOMM40 '523 is associated with Alzheimer's disease (AD), but APOE linkage disequilibrium confounds this association. In 170 APOE ɛ3 homozygotes, we evaluated relationships between short and very long TOMM40 alleles and longitudinal declines in three cognitive domains (attention, verbal memory, and executive function). We used factor analysis to create composite scores from 10 individual cognitive tests, and latent growth curve modeling adjusting for clinical status (normal, amnestic mild cogniti ...[more]

PMID: 31322569

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Project description:The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ?2/?3/?4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (? = -1.29, p = 3.97 × 10-9 ; ? = -1.38, p = 2.78 × 10-10 ; and ? = 0.58, p = 3.04 × 10-2 , respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (? = -0.63, p = 3.99 × 10-2 and ? = -0.94, p = 2.17 × 10-3 , respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (? = -1.68, p = 3.00 × 10-9 ), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (? = -4.11, p = 2.78 × 10-3 ). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, ? = 0.58, 95% confidence interval (CI) = -1.18, 2.35, p = 5.18 × 10-1 for 3,068 individuals aged ?30 years and ? = -4.28, CI = -5.65, -2.92, p = 7.71 × 10-10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ?4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.

Dataset Information

TOMM40 '523 Associations with Baseline and Longitudinal Cognition in APOE ?3 Homozygotes.

Publications

TOMM40 '523 Associations with Baseline and Longitudinal Cognition in APOE ɛ3 Homozygotes.

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