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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.

Project description:ObjectivesFactors that are responsible for age-related neurologic deterioration of noncognitive and cognitive processes may have a shared cause. We sought to examine the temporal, directional associations of handgrip strength and cognitive function in a national sample of aging Americans.DesignLongitudinal panel.SettingEnhanced interviews that included physical, biological, and psychosocial measures were completed in person. Core interviews were often conducted over the telephone.ParticipantsThe analytic sample included 14,775 Americans aged at least 50 years who participated in at least 2 waves of the 2006-2016 waves of the Health and Retirement Study.MeasuresHandgrip strength was measured with a hand-held dynamometer. Participants were considered cognitively intact, mildly impaired, or severely impaired according to the Telephone Interview of Cognitive Status questionnaire. Separate lagged general estimating equations analyzed the directional associations of handgrip strength and cognitive function.ResultsThe overall time to follow-up was 2.1 ± 0.4 years. Every 5 kg higher handgrip strength was associated with 0.97 [95% confidence interval (CI) 0.93, 0.99] lower odds for both future cognitive impairment and worse cognitive impairment. Those who were not weak had 0.54 (CI 0.43, 0.69) lower odds for future cognitive impairment and 0.57 (CI 0.46, 0.72) lower odds for future worse cognitive impairment. Conversely, any (β = -1.09; CI -1.54, -0.64), mild (β = -0.85; CI -1.34, -0.36), and severe cognitive impairment (β = -2.34; CI -3.25, -1.42) predicted decreased handgrip strength. Further, the presence of any, mild, and severe cognitive impairment was associated with 1.82 (CI 1.48, 2.24), 1.65 (CI 1.31, 2.08), and 2.53 (CI 1.74, 3.67) greater odds for future weakness, respectively.Conclusions/implicationsStrength capacity and cognitive function may parallel each other, whereby losses of functioning in 1 factor may forecast losses of functioning in the other. Handgrip strength could be used for assessing cognitive status in aging Americans and strength capacity should be monitored in those with cognitive impairment.

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Longitudinal modeling of cognitive aging and the TOMM40 effect.

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Longitudinal modeling of cognitive aging and the TOMM40 effect.

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