Genetic contributions to stability and change in intelligence from childhood to old age.

Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change.

Increased diastolic blood pressure is associated with MRI biomarkers of dementia-related brain pathology in normative ageing.

Background: hypertension is a risk for brain ageing, but the mechanisms underlying this effect remain unclear. Magnetic resonance imaging (MRI) detected biomarkers of brain ageing include white matter hyperintensities (WMHs), a marker of cerebrovascular disease, and hippocampal volume, a marker of Alzheimer's disease pathology. Objective: to examine relationships between blood pressure (BP) components and brain pathology in older adults. Subjects: two hundred and twenty-seven members of the Aberdeen 1936 Birth Cohort between ages 64 and 68 years. Methods: BP was assessed biennially between 64 and 68 years and brain MRI performed at 68 years. The risk factors of interest were diastolic and systolic BP and their visit-to-visit variability. Outcomes were WMH abundance and hippocampal volume. Regression models, controlling for confounding factors, examined their relationships. Results: higher diastolic BP predicted increased WMH (ß = 0.13, P = 0.044) and smaller hippocampi (ß = -0.25, P = 0.006). In contrast, increased systolic BP predicted larger hippocampi (ß = 0.22, P = 0.013). Variability of diastolic BP predicted lower hippocampal volume (ß = -0.15, P = 0.033). These relationships were independent of confounding life-course risk factors. Anti-hypertensive medication did not modify these relationships, but was independently associated with increased WMH (ß = 0.17, P = 0.011). Conclusion: increased diastolic BP is associated with biomarkers of both cerebrovascular and Alzheimer's diseases, whereas the role of systolic BP is less clear, with evidence for a protective effect on hippocampal volume. These differing relationships emphasise the importance of considering individual BP components with regard to brain ageing and pathology. Interventions targeting diastolic hypertension and its chronic variability may provide new strategies able to slow the accumulation of these harmful pathologies.

Late-life deficits in cognitive, physical and emotional functions, childhood intelligence and occupational profile: a life-course examination of the Aberdeen 1936 Birth Cohort (ABC1936).

OBJECTIVES: the 'triad of impairment' phenomenon describes the co-occurrence of age-related cognitive, emotional and physical functioning deficits. We investigated how occupational profile and childhood intelligence contribute to the triad of impairment in late life. METHODS: we analysed data of a subsample of the Aberdeen Birth Cohort of 1936 (n = 346). Data were collected on participants' childhood intelligence, late-life cognitive ability, physical functioning, depressive symptoms and main lifetime occupation. We summarised the various occupational and impairment measures into two latent variables, 'occupational profile' and the 'triad of impairment'. We used a series of data reduction approaches and structural equation models (SEMs) of increasing complexity to test both the validity of the models and to understand causal relationships between the life-course risks for the triad of impairment. RESULTS: occupational profile had a significant effect on the triad of impairment independent of childhood intelligence. Childhood intelligence was the predominant influence on the triad of impairment and exerted its effect directly and indirectly via its influence on occupation. The direct effect of childhood intelligence exceeded the independent influence of the occupational profile on impairment by a factor of 1.7-1.8 and was greater by a factor of ∼4 from the indirect pathway (via occupation). CONCLUSIONS: childhood intelligence was the predominant influence on the triad of impairment in late life, independently of the occupational profile. Efforts to reduce impairment in older adults should be informed by a life-course approach with special attention to the early-life environment.

Structural brain complexity and cognitive decline in late life--a longitudinal study in the Aberdeen 1936 Birth Cohort.

Brain morphology and cognitive ability change with age. Gray and white matter volumes decrease markedly by the 7th decade of life when cognitive decreases first become readily detectable. As a consequence, the shape complexity of the cortical mantle may also change. The purposes of this study are to examine changes over a five year period in brain structural complexity in late life, and to investigate cognitive correlates of any changes. Brain magnetic resonance images at 1.5 Tesla were acquired from the Aberdeen 1936 Birth Cohort at about ages 68 years (243 participants) and 73 years (148 participants returned). Measures of brain complexity were extracted using Fractal Dimension (FD) and calculated using the box-counting method. White matter complexity, brain volumes and cognitive performance were measured at both 68 and 73 years. Childhood ability was measured at age 11 using the Moray House Test. FD and brain volume decrease significantly from age 68 to 73 years. Using a multilevel linear modeling approach, we conclude that individual decreases in late life white matter complexity are not associated with differences in executive function but are linked to information processing speed, auditory-verbal learning, and reasoning in specific models-with adjustment for childhood mental ability. A significant association was found after adjustment for age, brain volume and childhood mental ability. Complexity of white matter is associated with higher fluid cognitive ability and, in a longitudinal study, predicts retention of cognitive ability within late life.

Homocysteine, antioxidant micronutrients and late onset dementia.

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.

Childhood socioeconomic status and adult brain size: childhood socioeconomic status influences adult hippocampal size.

OBJECTIVE: To investigate in older adults without dementia the relationships between socioeconomic status (SES) in childhood and magnetic resonance imaging (MRI)-derived brain volume measures typical of brain aging and Alzheimer's disease (AD). METHODS: Using a cross-sectional and longitudinal observation approach, we invited volunteers without dementia, all born in 1936, and who were participants in the 1947 Scottish Mental Survey, for MR brain imaging; 249 of 320 (77%) agreed. We measured whole brain and hippocampal volumes and recorded childhood SES history, the number of years of education undertaken, and adult SES history. Mental ability at age 11 years was recorded in 1947 and was also available. RESULTS: Analysis shows a significant association between childhood SES and hippocampal volume after adjusting for mental ability at age 11 years, adult SES, gender, and education. INTERPRETATION: A significant association between childhood SES and hippocampal volumes in late life is consistent with the established neurodevelopmental findings that early life conditions have an effect on structural brain development. This remains detectable more than 50 years later.

Depressive symptoms in late life and cerebrovascular disease: the importance of intelligence and lesion location.

BACKGROUND: The influence of white matter lesions on depressive symptoms in healthy ageing populations remains unclear. In this study, we examined the relationship between depressive symptoms and magnetic resonance imaging (MRI) detected cerebrovascular disease in a normal population living independently in the community, and measured the influence of location of brain abnormalities, fluid intelligence, living alone, and sex. METHODS: Prospective cohort: 497 community dwelling individuals all born in 1936, who took part in the Scottish Mental Survey of 1947, were followed up in 2000 and at biannual intervals in a longitudinal study of health and cognitive aging. Two hundred forty-four volunteered for brain MRI in 2004-2006. Suitable data were available in 219/244, of whom 115 were men. Brain hyperintensities in lobar white matter, basal ganglia , periventricular, and infratentorial regions were measured using Scheltens' scale. Depressed mood was assessed using the Hospital Anxiety and Depression Scale (HADS) on three biannual intervals. Relationships between Scheltens' scores, HADS-D scores, fluid intelligence, living alone, and sex were assessed using general linear modeling. RESULTS: The main predictor of depressive symptom scores was poorer fluid intelligence (partial η(2) =0.023-0.028, P < .05). Ischemic change in the brainstem (partial η(2) = 0.026, P ≤.05) and basal ganglia (partial η(2) =0.018, P ≤ .05) also predicted HADS-D scores. There was no relationship with sex or living alone. CONCLUSIONS: Hyperintensities in the brainstem and basal ganglia are associated with depressive symptoms. Higher fluid intelligence is associated with lower depressive symptoms in this normal, ageing population.

Genetic and environmental factors in late onset dementia: possible role for early parental death.

OBJECTIVE: We aimed to investigate three reports of a possible role of early parental death in late onset dementia. We tested a multivariate model of risk factors for late onset dementia that included established (female sex, a family history of dementia, APOE ε4) and putative influences (vascular risk factors, years of full-time education, parental ages at death, and childhood IQ) on dementia risk. METHODS: We examined contributions of early life and late life risk factors for dementia by using childhood social and family data and blood samples obtained at interview at age about 78 years. In 1997-1999, we recruited 281 subjects without dementia from a 1932 Scottish IQ survey of children born in 1921 and followed them up to 2010 (at age 88). Binary logistic regression and Bayesian structural equation modelling were used to model dementia risk. RESULTS: Risk of dementia was associated with increasing age from 77 to 88 years, female sex, death of either parent before age 11 and APOE ε4 genotype. Family history of dementia, childhood IQ, years of education and vascular risk factors did not contribute to the model. CONCLUSIONS: Our multivariate models of the possible causes of late onset dementia confirm previous associations of dementia with female sex and APOE ε4 genotype and supports earlier reports of a role for early parental death.

Brain structural complexity and life course cognitive change.

Fractal measures such as fractal dimension (FD) can quantify the structural complexity of the brain. These have been used in clinical neuroscience to investigate brain development, ageing and in studies of psychiatric and neurological disorders. Here, we examined associations between the FD of white matter and cognitive changes across the life course in the absence of detectable brain disease. The FD was calculated from segmented cerebral white matter MR images in 217 subjects aged about 68years, in whom archived intelligence scores from age 11years were available. Cognitive test scores of fluid and crystallised intelligence were obtained at the time of MR imaging. Significant differences were found (intracranial volume, brain volume, white matter volume and Raven's Progressive Matrices score) between men and women at age 68years and novel associations were found between FD and measures of cognitive change over the life course from age 11 to 68years. Those with greater FD were found to have greater than expected fluid abilities at age 68years than predicted by their childhood intelligence and less cognitive decline from age 11 to 68years. These results are consistent with other reports that FD measures of cortical structural complexity increase across the early life course during maturation of the cerebral cortex and add new data to support an association between FD and cognitive ageing.

The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer's diseases.

The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the deleterious effects of cerebrovascular disease and Alzheimer's disease and highlights the importance of quantifying cognitive reserve in dementia research.

Cognitive Test Scores and Progressive Cognitive Decline in the Aberdeen 1921 and 1936 Birth Cohorts.

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.

How useful are the SF-36 sub-scales in older people? Mokken scaling of data from the HALCyon programme.

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.

Solvent exposure and cognitive ability at age 67: a follow-up study of the 1947 Scottish Mental Survey.

OBJECTIVES: Organic solvent exposure may be associated with cognitive impairment in later life although the evidence for this association is inconsistent. This study sought to examine the association between organic solvent exposure and cognitive function in later life. METHODS: A prospective longitudinal study set in Aberdeen, Scotland examined 336 men and women born in 1936 who participated in the 1947 Scottish Mental Survey. Cognitive function at age 67 years was measured using the Trail Making Test B (TMT B), the Digit Symbol (DS) test, and the Auditory Verbal Learning Test (AVLT). Occupational hygienists reviewed occupational histories, blind to cognitive function, and estimated lifetime solvent exposures. Multiple regression analyses were employed to explore the association between solvent exposure and cognitive performance after adjustment for confounders. RESULTS: After adjusting for childhood IQ, smoking, alcohol and sex, the solvent exposed group took on average almost 10 s longer than the unexposed group to complete the TMT B, a highly significant difference. For the DS test, after adjusting for childhood IQ, smoking and gender, the exposed group scored on average two points lower than the unexposed group, which was again highly significant. There was no evidence of an effect for cumulative solvent exposure on the TMT B or DS test. For the AVLT there were no significant differences associated with exposure. CONCLUSIONS: This study of subjects with generally low exposures, found no clear evidence of an association between solvent exposure and cognitive function.

Pollution, Particles, and Dementia: A Hypothetical Causative Pathway.

Epidemiological studies of air pollution have shown associations between exposure to particles and dementia. The mechanism of this is unclear. As these seem unlikely in terms of the very small dose likely to reach the brain in usual Western urban circumstances, we extend our 1995 hypothetical explanation of the association of air pollution with cardiac deaths as a plausible alternative explanation of its associations with dementia. Since our original proposal, it has become apparent that inflammation may be carried by blood from organ to organ by biologic microparticles derived from cell membranes. These transmit inflammatory messages to endothelial cells throughout the body as part of a general defensive response to assumed bacterial infection; particulate air pollution has recently been shown to be associated with their release into the blood. We propose that episodic release of biologic microparticles from pollution-induced lung inflammation causes secondary inflammation in the blood-brain barrier and cerebral microbleeds, culminating over time in cognitive impairment. Ultimately, by incomplete repair and accumulation of amyloid, this increases the risk of Alzheimer's disease. Importantly, this mechanism may also explain the relationships of other inflammatory conditions and environmental factors with cognitive decline, and point to new opportunities to understand and prevent dementia.

Aspirin moderates the association between cardiovascular risk, brain white matter hyperintensity total lesion volume and processing speed in normal ageing.

OBJECTIVES: Cardiovascular risk is associated with cognitive decline and this effect is attributed to brain pathology, including white matter hyperintensity (WMH) burden. Low-dose aspirin is frequently recommended for reducing vascular events. We investigated the effect of taking aspirin on the association between cardiovascular risk, WMH burden and cognitive function. STUDY DESIGN: The study sample was drawn from 318 dementia-free adults aged 67-71 years. Brain magnetic resonance imaging (MRI) scans were acquired from 239 participants. MAIN OUTCOME MEASURES: WMH total lesion volumes (TLV) were extracted using the automated lesion segmentation algorithm. We measured cardiovascular risk by calculating ASSIGN score. Cognitive ability was measured using a test of processing speed. We developed structural equation models to test our hypothesis. RESULTS: Sixty-eight participants (47.1 % male, mean age = 68.8 years) reported that they took aspirin. The demographic measures did not differ significantly by aspirin use. Among aspirin users, there was a strong negative association between WMH TLV and cognition (ß = -0.43, p-value < 0.001), while in non-users of aspirin the only significant predictor of poorer cognition was cardiovascular risk (ß = -0.17, p-value = 0.001). CONCLUSIONS: Aspirin use moderates the negative effect of WMH burden on cognition. Considering WMH burden in addition to cardiovascular risk could improve the prediction of cognitive decline in older adults with aspirin use.

Testing replication of a 5-SNP set for general cognitive ability in six population samples.

A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population samples of varying size and age from Australia, the UK (Scotland and England) and the Netherlands. Results from the largest sample (N=1310) approached significance (P=0.06) in the direction of the original finding, but results from the other samples (N=205-758) were mixed. A meta-analysis of the results--allowing for effect size heterogeneity between samples--yielded a non-significant correlation (r=-0.01, P=0.57), indicating that this SNP set was not associated with general cognitive ability in the populations studied.

n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood.

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.

PPARG Pro12Ala genotype and risk of cognitive decline in elders? Maybe with diabetes.

The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPARG; NCBI dbSNP rs1801282) has been associated with preservation of cognitive function, decreased risk of diabetes, and increased risk of obesity. We attempted to replicate these associations, testing cognitive function and lifetime cognitive change in 519 participants who took the same cognitive test at ages 11 and 79 years. Scores were also available for other cognitive tests at age 79 years, along with history of diabetes, current Body Mass Index (BMI), and other disease and demographic variables. Pro12Ala carrier status was not directly associated with diabetes history or BMI. In carriers who contracted diabetes despite carrying the protective allele, cognitive decline as measured by one test was significantly greater than in other groups. Only six individuals fell into this group; the other cognitive tests did not show this effect. This sample did not replicate the direct association of the PPARG Pro12Ala allele with diabetes status or preserved cognitive function. The data did suggest that risk of cognitive decline is greater when Pro12Ala carriers contract diabetes.

Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation.

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.

All-cause mortality in the Aberdeen 1921 birth cohort: effects of socio-demographic, physical and cognitive factors.

BACKGROUND: Childhood intelligence predicts mortality throughout most of the life span. However, it is unknown whether its effect persists into advanced old age. METHODS: The Aberdeen Birth Cohort born in 1921 (n = 354) and that had an IQ test as part of the national Scottish Mental Survey of 1932 were seen in 1997 at age 76 years when childhood and adult socio-environmental, medical and cognitive data were collected. Participants were followed until May 2007 and vital status determined from the General Register for Scotland records. Univariate associations between baseline variables and mortality were determined and multivariable survival analysis performed with Cox's proportional hazards modelling. RESULTS: One hundred and fifty-eight (44.6%) of the 354 cohort members had died by the census date. Significantly more men (n = 102) died during follow-up than women (n = 56, chi2 = 5.27, p = .022). Lower scores on four of the six cognitive tests at age 76 years were associated with increased mortality, but not IQ age 11. Survival was associated with gender (H.R. 0.32, 95% C.I. 0.11-0.89 for women versus men), peak expiratory flow rate (H.R. 0.997, 95% C.I. 0.992-1.001 per l/min) and the Uses of Common Objects test (H.R. 0.91, 95% C.I. 0.82-1.01) CONCLUSION: Both physical and psychological variables independently predicted survival in old age: respiratory function and executive function in particular. Male gender conferred increased risk of mortality and this was not explained by the broad range of socio-environmental, mental ability and health status variables examined in the study.