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Does incipient dementia explain normal cognitive decline determinants? Lothian birth cohort 1921.

ABSTRACT: The presence of an apolipoprotein E (APOE) ε4 allele, lower physical fitness, smoking, and lower serum vitamin B-12 have been reported as contributing to poorer cognitive function in LBC1921 at age 79, after adjusting for childhood intelligence. Because incident dementia was not previously ascertained within LBC1921, it is possible that preclinical or unrecognized cases at age 79 influenced findings. Dementia cases arising over approximately 16 years of follow-up were determined by a consensus using evidence from electronic medical records, death certificates, and clinical reviews. The analyses from the original reports were repeated after the exclusion of those who had developed dementia. In a subsequent set of analyses, the authors considered the potential impact of terminal decline, excluding those participants who died within 4 years of baseline testing. Positive APOE ε4 status was found to be associated with poorer Logical Memory (Wechsler, 1987) at age 79 (F(1, 355) = 8.16, p = .005, ηp2 = 0.022; n = 359) and lower Moray House Test (Scottish Council for Research in Education, 1933) score at age 79 (F(1, 357) = 4.27, p = .04, ηp2 = 0.012; n = 363). Lower age 79 IQ was associated with smoking (F(2, 360) = 3.67, p = .026, ηp2 = 0.020; n = 367), lower vitamin B-12 (Sβ = 0.11, p = .014; n = 367), and poorer physical fitness (Sβ = 0.21, p < .001; n = 359). Only the relationship with physical fitness remained significant after excluding those who died within 4 years of baseline (Sβ = 0.203, p < .001; n = 310). Unrecognized dementia had little or no effect on determinants of lifetime cognitive ageing in LBC1921. Terminal decline may have accounted for the associations with age 11 to age 79 cognitive change. (PsycINFO Database Record

SUBMITTER: Sibbett RA

PROVIDER: S-EPMC6001941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:BackgroundWith 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.MethodsParticipants underwent intelligence testing at age 11 and were followed-up from at 79 years of age. Variables included: age, sex, age 11 IQ, APOE ɛ4, 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.ResultsOf 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 ɛ4 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 ɛ4 remained significant (OR: 2.37; 95% CI: 1.37, 4.07), as did hypertension (OR: 0.55; 95% CI: 0.32, 0.93).ConclusionsDementia 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: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 <?0.001). CONCLUSIONS:The present study did not demonstrate any consistent association between DNA methylation-based measures of accelerated ageing and dementia in subjects aged over 79?years. Further, larger studies - including separate analyses of dementia subtypes - are required to further investigate the potential association between DNA methylation-based measures of accelerated ageing and dementia.

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.

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Does incipient dementia explain normal cognitive decline determinants? Lothian birth cohort 1921.

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