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Longitudinal modeling of cognitive aging and the TOMM40 effect.

ABSTRACT: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two.There were significant effects overall for both TOMM40 (linear effect, P = .04; quadratic effect, P = .03) and APOE (linear effect, P = .06; quadratic effect, P = .008), with no significant interaction (P = .63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P = .009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P = .006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other.

SUBMITTER: Caselli RJ

PROVIDER: S-EPMC3483561 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Longitudinal modeling of cognitive aging and the TOMM40 effect.

Caselli Richard J RJ Dueck Amylou C AC Huentelman Matthew J MJ Lutz Michael W MW Saunders Ann M AM Reiman Eric M EM Roses Allen D AD

Alzheimer's & dementia : the journal of the Alzheimer's Association 20121101 6

<h4>Background</h4>TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical l ...[more]

PMID: 23102119

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Project description:A highly polymorphic T homopolymer was recently found to be associated with late-onset Alzheimer's disease risk and age of onset.To explore the effects of the polymorphic polyT tract (rs10524523, referred as '523') on cognitive performance in cognitively healthy elderly individuals.One hundred eighty-one participants were recruited from local independent-living retirement communities. Informed consent was obtained, and participants completed demographic questionnaires, a conventional paper-and-pencil neuropsychological battery, and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB). Saliva samples were collected for determination of the TOMM40 '523' (S, L, VL) and the apolipoprotein E (APOE) (?2, 3, 4) genotypes. From the initial sample of 181 individuals, 127 were eligible for the association analysis. Participants were divided into three groups based on '523' genotypes (S/S, S/L-S/VL, and L/L-L/VL-VL/VL). Generalized linear models were used to evaluate the association between the '523' genotypes and neuropsychological test performance. Analyses were adjusted for age, sex, education, depression, and APOE ?4 status. A planned subanalysis was undertaken to evaluate the association between '523' genotypes and test performance in a sample restricted to APOE ?3 homozygotes.The S homozygotes performed better, although not significantly, than the S/L-S/VL and the VL/L-L/VL-VL/VL genotype groups on measures associated with memory (CANTAB Paired Associates Learning, Verbal Recognition Memory free recall) and executive function (CANTAB measures of Intra-Extra Dimensional Set Shift). Follow-up analysis of APOE ?3 homozygotes only showed that the S/S group performed significantly better than the S/VL group on measures of episodic memory (CANTAB Paired Associates Learning and Verbal Recognition Memory free recall), attention (CANTAB Rapid Visual Information Processing latency), and executive function (Digit Symbol Substitution). The S/S group performed marginally better than the VL/VL group on Intra-Extra Dimensional Set Shift. None of the associations remained significant after applying a Bonferroni correction for multiple testing.Results suggest important APOE-independent associations between the TOMM40 '523' polymorphism and specific cognitive domains of memory and executive control that are preferentially affected in early-stage Alzheimer's disease.

Dataset Information

Longitudinal modeling of cognitive aging and the TOMM40 effect.

Publications

Longitudinal modeling of cognitive aging and the TOMM40 effect.

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