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Abstract: Telomere shortening is a feature of cellular ageing common to a range of human tissues. Shorter telomeres are associated with an increased likelihood of mortality, including death from heart disease. We examined the association between telomere length and heart disease (present in 33%) in a well-characterised, narrow age cohort of older people (n =190, all born in 1921), and tested for any concomitant effects of medication use. Mean telomere length was significantly shorter in participants who reported heart disease (p =.001). Participants with ischemic changes on ECG had shorter telomere lengths (6.67 versus 7.65kb, p =.021) after adjusting for other ECG abnormalities. This finding adds to the growing body of evidence for an association between telomere shortening and ischemic heart disease. Telomere shortening in peripheral blood leukocytes is a promising index of ischemic heart disease risk in older people and deserves further investigation as a potential mechanism. [Copyright &y& Elsevier]

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997-2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between baseline cognitive test scores and long-term cognitive outcomes. On recruitment, significant sex differences within and between the ABC21 and ABC36 cohorts supported advantages in verbal ability and learning among the ABC36 women that were not significant in ABC21. Comorbid physical disorders were self-reported in both ABC21 and ABC36 but did not contribute to differences in terms of performance in cognitive tests. When used alone without other criteria, cognitive tests scores which fell below the -1.5 SD criterion for tests of progressive matrices, namely verbal learning, digit symbol and block design, did not support the concept that Mild Cognitive Impairment (MCI) is a stable class of acquired loss of function with significant links to the later emergence of a clinical dementia syndrome. This is consistent with many previous reports. Furthermore, because childhood IQ-type data were available, we showed that a lower cognitive performance at about 64 or 78 y than that predicted by IQ at 11 ± 0.5 y did not improve the prediction of progress to MCI or greater cognitive loss. We used binary logistic regression to explore how MCI might contribute to the prediction of later progress to a clinical dementia syndrome. In a fully adjusted model using ABC21 data, we found that non-amnestic MCI, along with factors such as female sex and depressive symptoms, contributed to the prediction of later dementia. A comparable model using ABC36 data did not do so. We propose that (1) MCI criteria restricted to cognitive test scores do not improve the temporal stability of MCI classifications; (2) pathways towards dementia may differ according to age at dementia onset and (3) the concept of MCI may require measures (not captured here) that underly self-reported subjective age-related cognitive decline.

Introduction: Various methods are available to measure hippocampal atrophy rate. We compared methods to predict Alzheimer's dementia., Methods: Participants with brain imaging at ages 69 and 73 years were identified from a previous study. Simple manual measures and computationally automated volumetry were performed. Receiver operating characteristics assessed the predictive ability of each method at baseline and on logit regression analysis of two serial scans., Results: Ten of 149 participants developed Alzheimer's dementia and had lower baseline volumes (3647 vs. 4194 mm 3 P  = .002), rates of volume loss (-126 vs. -36 mm 3 /y; P  = .001), and rates of loss in hippocampal fraction (-8.55 vs. -2.35 x 10 -5 /y; P  = .001). Baseline volume with a rate of change gave the highest area under the curve value of 0.96., Discussion: Automated volumetry measuring hippocampal size at age 69 years and subsequent rate of change predicts Alzheimer's dementia development.

Cognitive reserve is a hypothetical concept introduced to explain discrepancies between severity of clinical dementia syndromes and the extent of dementia pathology. We examined cognitive reserve in a research programme that followed up a non-clinical sample born in 1921 or 1936 and IQ-tested age 11 years in 1932 or 1947. Structural MRI exams were acquired in about 50% of the sample from whom a subsample were recruited into an additional fMRI study. Here, we summarise findings from seven inter-related studies. These support an understanding of cognitive reserve as a balance between positive life course activity-driven experiences and the negative effects of brain pathologies including cerebrovascular disease and total and regional brain volume loss. Hypothesised structural equation models illustrate the relative causal effects of these positive and negative contributions. Cognitive reserve is considered in the context of choice of interventions to prevent dementia and the opposing effects of cerebrovascular disease and Alzheimer like brain appearances., (Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.)

Purpose: To distinguish between contributions to dementia made by homocysteine, folate, B12 and antioxidant micronutrients., Methods: This is a follow-up study of a sample reported in 2002. Homocysteine was measured at baseline in 201 individuals born in 1921 and without dementia at age 77 years and followed up to age 88 years. Baseline macro- and micronutrient status was estimated from BMI, the MONICA food frequency questionnaire, plasma folate, B12 and, in a subgroup (N = 173), plasma antioxidant micronutrients. Time to dementia onset during follow-up was compared between participants grouped by homocysteine concentration using Cox regression. Model 1 adjusted for age, sex, childhood IQ, education, socioeconomic deprivation, presence of heart disease, hypertension, plasma folate and B12. In model 2 plasma, antioxidants were added to these covariables., Results: During a mean follow-up of about 5 years, there were 39 incident dementia cases among 201 participants. In model 1, being in the highest homocysteine group (>14 μmol/L) was associated with a 234 % increased risk (HR 3.34, 95 % CI 1.16-9.57) of any dementia. After inclusion of plasma antioxidants in model 2, there were 32 incident dementia cases from a subsample (N = 173). Homocysteine >14 μmol was associated with a 272 % increased dementia risk (HR = 3.72, 95 % CI 1.06-13.08)., Conclusions: High homocysteine increases the risk of dementia. The association between tHcy and dementia is independent of plasma folate, B12 and antioxidant micronutrient status.

The objectives of this study are to model the relative effects of positive (childhood intelligence) and negative (magnetic resonance imaging (MRI)-derived white matter hyperintensities (WMH)) predictors of late-life intelligence in two well-characterised normal cohorts aged 68 and 78 and to measure the influence of hypertension on WMH and lifelong cognitive change. The Scottish Mental Surveys of 1932 and 1947 tested the intelligence of almost all school children at age 11. One hundred and one participants born in 1921 and 233 participants born in 1936 had brain MRI, with measurement of WMH using Scheltens' scale, and tests of late-life fluid intelligence. Structural equation models of the effect of childhood intelligence and brain WMH on the general intelligence factor 'g' in late life in the two samples were constructed using AMOS 18. Similar models were constructed to test the effect of hypertension on WMH and lifelong cognitive change. Fluid intelligence scores were lower and WMH scores were higher in the older samples. Hypertensive participants in both samples had more WMH than normotensive participants. The positive influence of childhood intelligence on 'g' was greater in the younger sample. The negative effect of WMH on 'g' was linear and greater in the older sample due to greater WMH burden. The negative effect of hypertension on lifelong cognitive ageing was all mediated via MRI-derived brain WMH. The positive relationship between childhood and late-life intelligence decreases with age. The negative relationship between WMH and late-life intelligence is linear and increases with age.

There are well-established differences in dementia incidence between communities and within communities over time. In part, these differences may be attributable to local improvements in dementia diagnosis and classification. Nevertheless, there are grounds for cautious optimism that there have been slight, but significant, recent reductions in dementia incidence. Possible causes include public health measures to reduce mortality attributable to stroke and heart disease, improved nutrition, and greater personal wealth. A life-course approach to dementia pathophysiology may help to elucidate the nature and timing of interventions that might delay dementia onset., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate two psychometric properties of SF-36, namely unidimensionality and reliability., Methods: The data are from three cohorts in the HALCyon collaborative research programme into healthy ageing: Aberdeen Birth Cohort 1936 (n = 428), Hertfordshire Ageing Study (n = 358) and Hertfordshire Cohort Study (n = 3,216). The Mokken scaling model was applied to each sub-scale of SF-36 to evaluate unidimensionality as indicated by scalability. The lower bound for internal consistency reliability was determined by Cronbach's alpha., Results: All six sub-scales of SF-36, with the exception of general health (GH) and mental health (MH), demonstrated strong scalability (0.5 ≤ H < 1). The results were consistent across all 3 cohorts. Both GH and MH showed medium scalability (0.4 ≤ H <0.55), although individual items 'sick easier..', 'as healthy as..' and 'expect to get worse' of the GH sub-scale and 'nervous', 'happy' in the MH sub-scale had low scalability (H < 0.4) in the oldest cohort (aged 73-83). Cronbach's alphas for all sub-scales were between 0.70 and 0.92., Conclusions: The unidimensionality and reliability of the sub-scales of SF-36 are sufficient to make this a useful measure of health-related quality of life in older people. Caution is needed when interpreting the results for GH and MH in the oldest cohort due to the poor unidimensionality.

Objectives: To describe the discovery and development of the Aberdeen 1921 and 1936 birth cohort studies., Study Design: The Aberdeen birth cohort studies were started in 1998 when the Scottish Mental Survey archives of the Scottish Council for Research in Education were re-discovered and permissions granted to follow-up survivors born in 1921 or 1936 and then aged about 77 or 64 years and who had entered (or were about to enter) the age of greatest risk for Alzheimer's disease (AD)., Main Outcome Measures: Sources of attrition from the study, exposures to childhood adversity, nutritional, genetic and life style factors of possible relevance to extent of age-related cognitive decline and the timing of onset of dementia., Results: By 2010, the feasibility of following up more than 75% of Scottish Mental Survey survivors living in the Aberdeen area without dementia was well-established, dementia ascertainment to age about 88 years was completed in the 1921 birth cohort and was underway in the 1936 born cohort., Conclusion: These databases are available to other bone fide research groups wishing to test specific hypotheses that may either replicate their own findings or make best use of the data collected in the Aberdeen studies., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood., Methods and Findings: Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations., Conclusions: Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.

Background: Evidence for an inverse relation between dietary intake of n-3 polyunsaturated fatty acids (PUFAs) and age-related cognitive decline is inconsistent. This inconsistency may arise because the relation is present only in the absence of the apolipoprotein E epsilon4 (APOE epsilon4) allele., Objective: We aimed to determine the contribution of erythrocyte n-3 PUFA content to cognitive aging in the presence or absence of the APOE epsilon4 allele., Design: We followed up 120 volunteers, born in 1936, at approximate ages of 64, 66, and 68 y. Their intelligence quotient at 11 y old was available. At first follow-up, we determined APOE genotype and measured the PUFA composition of erythrocyte membranes. Six cognitive tests were administered at all follow-ups. We related cognitive performance at approximately 64 y old and cognitive changes from approximately 64 to approximately 68 y old to erythrocyte n-3 PUFA composition on recruitment and to APOE epsilon4 allele status., Results: Total n-3 PUFA and docosohexaenoic acid concentrations were associated with benefits for cognition at approximately 64 y old and from approximately 64 to approximately 68 y old. After adjustment for sex, APOE epsilon4 status, and intelligence quotient at 11 y old, the effects associated with total n-3 PUFA remained significant. Cognitive benefits were associated with higher erythrocyte n-3 PUFA content but were significant only in the absence of the APOE epsilon4 allele., Conclusions: These data are evidence of a gene x environment interaction for cognitive aging. They are relevant to the analysis of trials of n-3 PUFA supplements in cognitive aging and dementia prevention, and they support heterogeneity in cognitive aging and, possibly, in Alzheimer disease.

Background: The genetic basis of variation in human cognitive abilities is poorly understood. RIMS1 encodes a synapse active-zone protein with important roles in the maintenance of normal synaptic function: mice lacking this protein have greatly reduced learning ability and memory function., Objective: An established paradigm examining the structural and functional effects of mutations in genes expressed in the eye and the brain was used to study a kindred with an inherited retinal dystrophy due to RIMS1 mutation., Materials and Methods: Neuropsychological tests and high-resolution MRI brain scanning were undertaken in the kindred. In a population cohort, neuropsychological scores were associated with common variation in RIMS1. Additionally, RIMS1 was sequenced in top-scoring individuals. Evolution of RIMS1 was assessed, and its expression in developing human brain was studied., Results: Affected individuals showed significantly enhanced cognitive abilities across a range of domains. Analysis suggests that factors other than RIMS1 mutation were unlikely to explain enhanced cognition. No association with common variation and verbal IQ was found in the population cohort, and no other mutations in RIMS1 were detected in the highest scoring individuals from this cohort. RIMS1 protein is expressed in developing human brain, but RIMS1 does not seem to have been subjected to accelerated evolution in man., Conclusions: A possible role for RIMS1 in the enhancement of cognitive function at least in this kindred is suggested. Although further work is clearly required to explore these findings before a role for RIMS1 in human cognition can be formally accepted, the findings suggest that genetic mutation may enhance human cognition in some cases.

Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.

Hypertension is associated with cognitive impairment in older adults. The Hypertensive Old People in Edinburgh (HOPE) study reported improved scores in two psychometric tests in those subjects with the greatest fall in diastolic blood pressure during a 24-week randomised, double-blind trial of captopril versus bendrofluazide in 81 elderly hypertensive people with mild cognitive impairment. Three hundred and eighty-seven of the original sample of 603 older people with and without hypertension and/or cognitive impairment from which the trial subsample was drawn were available for adequate psychometric testing 4 years later. Blood pressure was related prospectively to Raven's Progressive Matrices (RPM), a measure of fluid intelligence, but not memory differences. RPM scores were obtained at baseline, 6 weeks, 12 weeks and at the end of the randomised controlled trial. For subjects on captopril mean scores at each time point adjusted for blood pressure change were 27.6 (95% CI 25.5-29.6), 27.2 (95% CI 25.1-29.2), 28.4 (95% CI 26.6-30.3) and 28.9 (95% CI 26.9-30.9), and for bendrofluazide 27.1 (95% CI 25.1-29.0), 28.9 (95% CI 26.9-30.9), 28.9 (95% CI 27.2-30.7) and 28.7 (95% CI 26.8-30.6). There was a significant improvement in scores for those on bendrofluazide compared with captopril at week 6 (F=8.10, p=0.006, partial eta2=0.11). There were no significant effects for either drug or blood pressure at any time point for tests of memory. Future trials of the effects of antihypertensive therapy on cognition should focus more on outcomes other than memory. Early differential effects of therapeutic agents may not be maintained.

We investigated whether smoking is a risk factor for relative cognitive decline from age 11 to 64 years. The potentially confounding effects of childhood IQ, occupational status, level of education, presence of heart disease, hypertension, and lung function were examined. Subjects were nondemented and living independently. They were all born in 1936, had been participants in the same Scottish national IQ survey in 1947, and were reexamined at age about 64 years in 2000-2002. Current smokers and nonsmokers had significantly different mental test scores at age 64. This difference remained after adjustment for childhood IQ. Multiple linear regression identified childhood IQ, level of education, occupational code, lung function, and smoking history as significant independent predictors of mental function at age 64. In this sample, smoking makes a small (<1% variance) independent negative contribution to cognitive aging.

Background: Food supplement use is widely promoted, but little is known about the cognitive effects of food supplements., Objective: We examined the effects of food supplement use on cognitive aging., Design: This was an observational study of subjects born in 1936 whose mental ability was tested in 1947 and who were followed up in 2000-2001, at which time cognition, diet, food supplement use, and risk factors for vascular disease were assessed. In a nested case-control study, fish-oil users were matched with nonusers, and cognitive function was related to erythrocyte n-3 fatty acid composition., Results: Childhood intelligence quotient (IQ) did not differ significantly by category of food supplement use (ie, none, fish oil, vitamins, and other). At the age of 64 y, cognitive function was higher in food supplement users than in nonusers before adjustment for childhood IQ. After adjustment for childhood IQ, digit symbol (mental speed) test scores were higher in food supplement users. Fish-oil supplement users consumed more vitamin C and vegetable and cereal fiber than did non-supplement-users. In a nested case-control study, erythrocyte membrane n-3 content was higher in fish-oil supplement users than in nonusers, but cognitive function did not differ significantly between groups. Total erythrocyte n-3 fatty acids and the ratio of docosahexaenoic acid to arachidonic acid was associated with better cognitive function in late life before and after adjustment for childhood IQ., Conclusions: Food supplement use and erythrocyte n-3 content are associated with better cognitive aging. If associations with n-3 content are causal, optimization of n-3 and n-6 fatty acid intakes could improve retention of cognitive function in old age.

Objectives: To examine associations between age at natural menopause, childhood IQ and cognition at age 65 years. To determine if lower age at menopause partly mediates the effect of childhood IQ on cognition at age 65 years., Methods: Data were provided by a sub-cohort of women participating in a longitudinal study of brain ageing and health. Main variables were childhood IQ from a 1947 national survey of children born in 1936, age at natural menopause and five cognitive tests measured in 2000-2001., Results: Age at menopause was associated with childhood IQ (r = 0.221, P = 0.008) and with general cognitive function age 65 years (r = 0.246, P = 0.004). Multiple regression showed 44.4% of the reliable variance in cognitive ability age 65 years is contributed by IQ at an age of 11 years to which, years of education contributed an additional 3.9%. Structural equation modelling suggested that childhood IQ differences contribute 4.8% of the variance to age at natural menopause and that the relation between age at menopause and cognition at age 65 years was accounted for by childhood IQ., Conclusion: Childhood IQ and age at menopause each have significant relations with general cognitive function age 65 years but the link between cognition age 65 years and age at menopause might be wholly explained by childhood IQ. The association between childhood IQ and age at menopause may be attributed to central neural mechanisms or, as argued here, to the effects of childhood IQ on adult general health.

The ageing brain adapts to the accumulation of damage caused by oxidative stress and inflammation. Adaptive processes include neuroprotective and neurorestorative mechanisms. Individual differences in susceptibility to dementia arise when these mechanisms are impaired or are overwhelmed by the molecular pathology of Alzheimer's disease. Neuroprotection relies upon extrinsic and intrinsic defences. An adequate intake of antioxidant micronutrients (eg, vitamin C and vitamin E) and anti-inflammatory macronutrients (eg, omega-3 polyunsaturated fatty acids) forms an essential component of extrinsic defences against brain ageing. There are many epidemiological data to support an association between an inadequate intake of antioxidants and/or fish oils (an important source of omega-3 polyunsaturated fatty acids) and a greater than expected incidence of late onset dementia. These associations are confounded by established links between poverty, poor diet and failing health, especially in old age. Such links may be sufficient to explain some of the effects of an inadequate diet on the retention of cognitive function and increased risk of dementia in old age. More compelling is the association between increased plasma homocysteine concentration and later increased risk of dementia. This association is possibly caused by an inadequate intake of vitamin B(12)/folate.

The cerebral reserve hypothesis is a heuristic concept used to explain apparent protection from the onset of cerebral disease and/or cognitive decline in old age. A significant obstacle when investigating the reserve hypothesis is the absence of baseline data with which to compare current cognitive status. We tested the influence of three hypothesized proxies of reserve (education, head size and occupational attainment [OCC]) in 92 volunteers born in 1921, whose cognitive function was measured at age 11 and 79 years, and who underwent brain MRI. The association between each proxy and old age cognitive function was tested, adjusting for variance contributed by childhood mental ability and detrimental age-related pathological changes measured using MRI. The results showed that education and OCC, but not total intracranial volume (TICV), contribute to cerebral reserve and help retain cognitive function in old age. Education was found to contribute between 5 and 6% of the variance found in old age memory function but was found to have no significant association with reasoning abilities. OCC was found to contribute around 5% of the variance found in old age memory function and between 6 and 8% of the variance found in old age reasoning abilities. We conclude that the intellectual challenges experienced during life, such as education and occupation, accumulate reserve and allow cognitive function to be maintained in old age.

There is a marked variation in whether people retain sufficient cognitive function to maintain their quality of life and independence in old age, even among those without dementia, so it would be valuable to identify the determinants of normal age-related cognitive change. We have retested non-demented 80-year-olds who were participants in the Scottish Mental Survey of 1932, and find that the variation in their non-pathological cognitive change from age 11 to 80 is related to their apolipoprotein E (APOE) genotype. This effect of the APOE epsilon 4 allele on normal cognitive ageing may be mediated by a mechanism that is at least partly independent of its predisposing effect towards Alzheimer's disease.

Background: Old age is associated with reduced cognitive performance. Nutritional factors may contribute to this association., Objective: We tested associations between cognitive performance and plasma vitamin B-12, folate, and homocysteine concentrations in the elderly., Design: We studied survivors of the Scottish Mental Surveys of 1932 (Aberdeen 1921 Birth Cohort, or ABC21) and 1947 (Aberdeen 1936 Birth Cohort, or ABC36), which surveyed childhood intelligence quotient. We measured folate, vitamin B-12, and homocysteine concentrations in fasting blood samples and cognitive performance by the Mini Mental State Examination (MMSE), National Adult Reading Test (NART), Raven's Progressive Matrices (RPM), Auditory Verbal Learning Test (AVLT), digit symbol (DS) subtest, and block design (BD) subtest., Results: Homocysteine was higher in the ABC21 than in the ABC36 (P < 0.0001). There were positive correlations between folate and vitamin B-12 and negative correlations between homocysteine and both folate and vitamin B-12. MMSE, RPM, AVLT, DS, and BD scores were higher in the ABC36. In the ABC21, folate, vitamin B-12, and MMSE score were positively correlated and homocysteine was negatively correlated with RPM, DS, and BD scores. Folic acid was positively correlated with AVLT and DS scores. In the ABC36, folate was positively correlated with BD score. After adjustment for childhood intelligence quotient, partial correlations were strengthened between vitamin B-12 and NART score and between homocysteine and RPM score but weakened between red blood cell folate and DS score., Conclusions: B vitamins and homocysteine are associated with cognitive variation in old age. In the ABC21 but not the ABC36, homocysteine accounted for approximately 7-8% of the variance in cognitive performance. This may prove relevant to the design of neuroprotective studies in late life.