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Alzheimer's disease genes are associated with measures of cognitive ageing in the lothian birth cohorts of 1921 and 1936.

ABSTRACT: Alzheimer's disease patients have deficits in specific cognitive domains, and susceptibility genes for this disease may influence human cognition in nondemented individuals. To evaluate the role of Alzheimer's disease-linked genetic variation on cognition and normal cognitive ageing, we investigated two Scottish cohorts for which assessments in major cognitive domains are available: the Lothian Birth Cohort of 1921 and the Lothian Birth Cohort of 1936, consisting of 505 and 998 individuals, respectively. 158 SNPs from eleven genes were evaluated. Single SNP analyses did not reveal any statistical association after correction for multiple testing. One haplotype from TRAPPC6A was associated with nonverbal reasoning in both cohorts and combined data sets. This haplotype explains a small proportion of the phenotypic variability (1.8%). These findings warrant further investigation as biological modifiers of cognitive ageing.

SUBMITTER: Hamilton G

PROVIDER: S-EPMC3132531 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Alzheimer's disease genes are associated with measures of cognitive ageing in the lothian birth cohorts of 1921 and 1936.

Hamilton Gillian G Harris Sarah E SE Davies Gail G Liewald David C DC Tenesa Albert A Starr John M JM Porteous David D Deary Ian J IJ

International journal of Alzheimer's disease 20110612

Alzheimer's disease patients have deficits in specific cognitive domains, and susceptibility genes for this disease may influence human cognition in nondemented individuals. To evaluate the role of Alzheimer's disease-linked genetic variation on cognition and normal cognitive ageing, we investigated two Scottish cohorts for which assessments in major cognitive domains are available: the Lothian Birth Cohort of 1921 and the Lothian Birth Cohort of 1936, consisting of 505 and 998 individuals, resp ...[more]

PMID: 21766012

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Project description:BackgroundDNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples.ResultsHere, we showed an association between age and log10-transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N = 7010, β = 0.0091, p < 2 × 10-16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, β = 0.033, p = 7.9 × 10-4) and 1936 (N = 898, β = 0.0079, p = 0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, body mass index (BMI), smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log10-transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases, and it was not heritable (SNP-based heritability of 4.4%, p = 0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually or in the meta-analysis after correction for multiple testing (HRmeta = 1.12; 95% CImeta = [1.02; 1.21]; pmeta = 0.021).ConclusionsThese findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.

Project description:Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 ("523") variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640-650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 "risk" allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 "short" allele showed lower white matter integrity when compared with carriers of the "long" and "very-long" alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.

Project description:[Correction Notice: An Erratum for this article was reported online in Psychology and Aging on Mar 5 2020 (see record 2020-16850-001). This article should have been published under the terms of the Creative Commons Attribution License (CC BY 3.0). Therefore, the article was amended to list the authors as copyright holders, and information about the terms of the CC BY 3.0 was added to the author note. In addition, the article is now open access. All versions of this article have been corrected.] It is unclear how scores on self-report resilience scales relate to key ageing-related domains in older age and if they truly measure resilience. We examined antecedents and outcomes of age-76 Brief Resilience Scale (BRS) scores in participants of the Lothian Birth Cohort 1936 (n = 655). We found bivariate associations between age-76 BRS scores and ageing-relevant antecedent variables measured at least 3 years earlier, from domains of cognitive ability, physical fitness, and wellbeing and, additionally, sociodemographics and personality (absolute r's from .082 to .49). Biological health variables were not associated with BRS scores. Age-73 cognitive ability (largest β = 0.14), physical fitness (largest β = 0.084), and wellbeing variables (largest β = 0.26) made positive independent contributions to age-76 BRS scores in multivariate models. In a conservative model including all variables as covariates, corrected for multiple comparisons, only emotional stability (neuroticism) significantly independently contributed to BRS score (β = 0.33). An exploratory backward elimination model indicated more wellbeing and personality associates of BRS scores (βs from .087 to .32). We used latent difference score modeling to assess outcomes of BRS scores; we examined associations between age-76 BRS and change in latent factors of age-related domains between age 76 and 79. Whereas BRS scores were related cross-sectionally to levels of latent cognitive ability (r = .19), physical fitness (r = .20), and wellbeing (r = .60) factors, they were not related to declines in these domains. The independence of the BRS construct from established wellbeing and personality factors is unclear. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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Alzheimer's disease genes are associated with measures of cognitive ageing in the lothian birth cohorts of 1921 and 1936.

Publications

Alzheimer's disease genes are associated with measures of cognitive ageing in the lothian birth cohorts of 1921 and 1936.

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