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DNA methylation-based measures of accelerated biological ageing and the risk of dementia in the oldest-old: a study of the Lothian Birth Cohort 1921.

ABSTRACT: BACKGROUND:Previous studies have demonstrated an association between DNA methylation-based measures of accelerated ageing and age-related health outcomes and mortality. As a disease closely associated with advancing age, we hypothesized that DNA methylation-based measures of accelerated ageing might be associated with risk for dementia. This study therefore aimed to examine the association between four recognised measures of age acceleration and subsequent dementia. METHODS:Study subjects (n =?488) were members of the Lothian Birth Cohort 1921. Dementia case ascertainment used data from death certificates, electronic hospital records, and clinical reviews. Venous blood samples were taken at baseline, at age 79?years. DNA methylation and measures of epigenetic age were calculated in accordance with Horvath's epigenetic clock tutorial, using the online calculator (https://dnamage.genetics.ucla.edu/). From these values, four measures of accelerated ageing were calculated: extrinsic epigenetic age acceleration (EEAA), intrinsic epigenetic age acceleration (IEAA), AgeAccelPheno and AgeAccelGrim. Competing risk regression models - with death as a competing risk - were performed to examine the association between each measure of accelerated ageing and incident dementia. APOE ?4 status, sex, age, smoking status, history of cardiovascular disease, cerebrovascular disease, hypertension, and diabetes were included as covariates. RESULTS:None of the multivariate models revealed a positive association between increased epigenetic age acceleration and dementia risk. Across all included models, never-smoking increased risk for dementia (HR 1.69 [1.06, 2.71], p =?0.03), and having no APOE ?4 alleles reduced risk for dementia (HR 0.44 [0.29, 0.67], p

SUBMITTER: Sibbett RA

PROVIDER: S-EPMC7048023 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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DNA methylation-based measures of accelerated biological ageing and the risk of dementia in the oldest-old: a study of the Lothian Birth Cohort 1921.

Sibbett Ruth A RA Altschul Drew M DM Marioni Riccardo E RE Deary Ian J IJ Starr John M JM Russ Tom C TC

BMC psychiatry 20200228 1

<h4>Background</h4>Previous studies have demonstrated an association between DNA methylation-based measures of accelerated ageing and age-related health outcomes and mortality. As a disease closely associated with advancing age, we hypothesized that DNA methylation-based measures of accelerated ageing might be associated with risk for dementia. This study therefore aimed to examine the association between four recognised measures of age acceleration and subsequent dementia.<h4>Methods</h4>Study ...[more]

PMID: 32111184

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Project description:BackgroundPrevious studies have demonstrated that individual measures of fitness - such as reduced pulmonary function, slow walking speed and weak handgrip - are associated with an increased risk of dementia. Only a minority of participants included in these studies were aged over 80. The aim of this study was therefore to investigate the association between physical fitness and dementia in the oldest old.MethodsSubjects (n = 488) were enrolled in the Lothian Birth Cohort 1921 and aged 79 at baseline. Dementia cases arising after enrolment were determined using data from death certificates, electronic patient records and clinical reviews. Fitness measures included grip strength, forced expiratory volume in 1 s (FEV1) and walking speed over 6 m, measured at 79 years. Dementia risk associated with each fitness variable was initially determined by logistic regression analysis, followed by Cox regression analysis, where death was considered as a competing risk. APOE ε4 status, age, sex, height, childhood IQ, smoking, history of cardiovascular or cerebrovascular disease, hypertension and diabetes were included as additional variables. Cumulative incidence graphs were calculated using Aalen-Johansen Estimator.ResultsAlthough initial results indicated that greater FEV1 was associated with an increased risk of dementia (OR (odds ratio per unit increase) 1.93, p = 0.03, n = 416), taking into account the competing risk of mortality, none of the fitness measures were found to be associated with dementia; FEV1 (HR (hazard ratio per unit increase) 1.30, p = 0.37, n = 416), grip strength (HR 0.98, p = 0.35, n = 416), walking speed (HR 0.99, p = 0.90, n = 416). The presence of an APOE ɛ4 allele was however an important predictor for dementia (HR 2.85, p < 0.001, n = 416). Cumulative incidence graphs supported these findings, with an increased risk of dementia for APOE ɛ4 carriers compared with non-carriers. While increased FEV1 was associated with reduced risk of death, there was no reduction in risk for dementia.ConclusionsIn contrast to previous studies, this study found that lower fitness beyond age 79 was not a risk factor for subsequent dementia. This finding is not explained by those with poorer physical fitness, who would have been more likely to develop dementia, having died before onset of dementia symptoms.

Project description:BACKGROUND:DNA 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. RESULTS:Here, 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, ? = 0.0091, p < 2 × 10-16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, ? = 0.033, p = 7.9 × 10-4) and 1936 (N = 898, ? = 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). CONCLUSIONS:These 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:BACKGROUND:With increasing numbers of people surviving beyond eighty years, this section of the population demands attention to reduce the impact of dementia. In order to develop effective preventative strategies, it is essential to understand age-specific risk factor profiles for dementia: do risk factors for dementia in those in their sixties and seventies persist into oldest age? The aims of this study were to determine incident dementia and to investigate the risk profile for dementia from age 79 to 95 years in a well-characterised cohort. METHODS:Participants underwent intelligence testing at age 11 and were followed-up from at 79 years of age. Variables included: age, sex, age 11 IQ, APOE ?4, education, diabetes, hypertension, statin use, physical activity at leisure and in occupation, symptoms of depression, height, number of teeth, body mass index, blood pressure, cholesterol and HbA1c. Dementia cases were ascertained from death certificates, electronic patient records and clinical reviews. Logistic regression analysis determined the degree of risk for dementia associated with each variable. Analyses were completed both with and without the physical activity variables due to the significant number of missing data for these variables. RESULTS:Of the eligible cohort, n = 410 participants remained dementia-free and n = 110 had developed probable dementia. When logistic regression analyses contained all variables, complete data was available for n = 234 (n = 48 with dementia). Results demonstrated that positive APOE ?4 carrier status (OR: 2.15, 95% CI: 1.04, 4.42) and greater lifetime physical activity (OR: 1.14, 95% CI: 1.02, 1.28) increased the risk for dementia. A reduction in risk for dementia was seen for hypertension (OR: 0.47, 95% CI: 0.23, 0.98). When physical activity variables were excluded, the number with complete data increased to n = 377 (n = 80 with dementia). APOE ?4 remained significant (OR: 2.37; 95% CI: 1.37, 4.07), as did hypertension (OR: 0.55; 95% CI: 0.32, 0.93). CONCLUSIONS:Dementia incidence was consistent with expected rates. The risk profile for dementia in this cohort of participants aged 79-95 confirmed previous findings that risk factors differ for those over 79 years. Further evidence is recommended in order that the risk profile for this age group can be accurately determined.

Project description:The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-?, tau, TDP-43 and ?-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-?, tau, TDP-43 and ?-synuclein pathologies as well as hippocampal sclerosis. Amyloid-? and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-? area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while ?-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-? continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-? pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-? plaques, more abundant neocortical amyloid-? deposition and hippocampal sclerosis with its attendant TDP-43 pathology.

Dataset Information

DNA methylation-based measures of accelerated biological ageing and the risk of dementia in the oldest-old: a study of the Lothian Birth Cohort 1921.

Publications

DNA methylation-based measures of accelerated biological ageing and the risk of dementia in the oldest-old: a study of the Lothian Birth Cohort 1921.

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