Predicting incident dementia 3-8 years after brief cognitive tests in the UK Biobank prospective study of 500,000 people.

INTRODUCTION: Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. METHODS: We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three- to eight-year follow-up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. RESULTS: We found associations of cognitive task performance with all-cause and cause-specific dementia (P <  .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. DISCUSSION: This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.

Childhood IQ and survival to 79: Follow-up of 94% of the Scottish Mental Survey 1947.

OBJECTIVE: To extend previous literature that suggests higher IQ in youth is associated with living longer. Previous studies have been unable to assess reliably whether the effect differs across sexes and ages of death, and whether the effect is graded across different levels of IQ. METHODS: We test IQ-survival associations in 94% of the near-entire population born in Scotland in 1936 who took an IQ test at age 11 (n = 70,805) and were traced in a 68-year follow-up. RESULTS: Higher IQ at age 11 years was associated with a lower risk of death (HR = 0.80, 95% CI = 0.79, 0.81). The decline in risk across categories of IQ scores was graded across the full range with the effect slightly stronger in women (HR = 0.79, 95% CI = 0.77, 0.80) than in men (HR = 0.82, 95% CI = 0.81, 0.84). Higher IQ had a significantly stronger association with death before and including age 65 (HR = 0.76, 95% CI = 0.74, 0.77) than in those participants who died at an older age (HR = 0.79, 95% CI = 0.78, 0.80). CONCLUSIONS: Higher childhood IQ is associated with lower risk of all-cause mortality in both men and women. This is the only near-entire population study to date that examines the association between childhood IQ and mortality across most of the human life course.

Childhood body weight in relation to morbidity from cardiovascular disease and cancer in older adulthood: 67-year follow-up of participants in the 1947 Scottish Mental Survey.

Although it has been well documented that elevated body weight in middle- and older-aged populations is associated with multiple morbidities, the influence of childhood body weight on health endpoints other than coronary heart disease is not well understood. Accordingly, using a subsample of 4,620 participants (2,288 women) from the Scottish Mental Survey of 1947, we examined the association between body mass index measured at 11 years of age and future risk of 9 independent health endpoints as ascertained from national hospital admissions and cancer registers until 2014 (up to age 77 years). Although there was some evidence of a relationship between elevated childhood body mass index and higher rates of peripheral vascular disease (per each 1-standard deviation increase in body mass index, hazard ratio = 1.21, 95% confidence interval: 1.07, 1.37) and smoking-related cancers (per each 1-standard deviation increase in body mass index, hazard ratio = 1.09, 95% confidence interval: 1.01, 1.17), there was no apparent association with coronary heart disease, stroke (including ischemic stroke), heart failure, or carcinomas of the colorectum, stomach, lung, prostate, or breast. In conclusion, a relationship between childhood body weight and later morbidity was largely lacking in the present study.

Childhood Club Participation and All-Cause Mortality in Adulthood: A 65-Year Follow-Up Study of a Population-Representative Sample in Scotland.

OBJECTIVES: Social participation in middle and older age is associated with lower mortality risk across many prospective cohort studies. However, there is a paucity of evidence on social participation in youth in relation to mortality, which could help inform an understanding of the origin of the association and give credence to causality. The present study investigates the relation of early-life club membership-a proxy measure of social participation-with mortality risk in older age in a nationally representative sample. METHODS: We linked historical data collected on the 6-Day Sample of the Scottish Mental Survey 1947 during the period 1947 to 1963 with vital status records up to April 2014. Analyses were based on 1059 traced participants (446 deceased). RESULTS: Club membership at age 18 years was associated with lower mortality risk by age 78 years (hazard ratio = 0.54, 95% confidence interval = 0.44-0.68, p < .001). Club membership remained a significant predictor in models that included early-life health, socioeconomic status, measured intelligence, and teachers' ratings of dependability in personality. CONCLUSIONS: In a study that circumvented the problem of reverse causality, a proxy indicator of social participation in youth was related to lower mortality risk. The association may be mediated by several behavioral and neurobiological factors, which prospective aging cohort studies could address.

Multivariate genetic analyses of cognition and academic achievement from two population samples of 174,000 and 166,000 school children.

The genetic influence on the association between contemporaneously measured intelligence and academic achievement in childhood was examined in nationally representative cohorts from England and The Netherlands using a whole population indirect twin design, including singleton data. We identified 1,056 same-sex (SS) and 495 opposite-sex (OS) twin pairs among 174,098 British 11 year-olds with test scores from 2004, and, 785 SS and 327 OS twin pairs among 120,995 Dutch schoolchildren, aged 8, 10 or 12 years, with assessments from 1994 to 2002. The estimate of intelligence heritability was large in both cohorts, consistent with previous studies (h (2) = 0.70 ± 0.14, England; h (2) = 0.43 ± 0.28-0.67 ± 0.31, The Netherlands), as was the heritability of academic achievement variables (h (2) = 0.51 ± 0.16-0.81 ± 0.16, England; h (2) = 0.36 ± 0.27-0.74 ± 0.27, The Netherlands). Additive genetic covariance explained the large majority of the phenotypic correlations between intelligence and academic achievement scores in England, when standardised to a bivariate heritability (Biv h (2) = 0.76 ± 0.15-0.88 ± 0.16), and less consistent but often large proportions of the phenotypic correlations in The Netherlands (Biv h (2) = 0.33 ± 0.52-1.00 ± 0.43). In the British cohort both nonverbal and verbal reasoning showed very high additive genetic covariance with achievement scores (Biv h (2) = 0.94-0.98; Biv h (2) = 0.77-1.00 respectively). In The Netherlands, covariance estimates were consistent across age groups. The heritability of intelligence-academic achievement associations in two population cohorts of elementary schoolchildren, using a twin pair extraction method, is at the high end of estimates reported by studies of largely preselected twin samples.

Association of Multimorbidity, Disease Clusters, and Modification by Genetic Factors With Risk of Dementia.

Importance: Individual conditions have been identified as risk factors for dementia; however, it is important to consider the role of multimorbidity, as conditions often co-occur. Objective: To investigate whether multimorbidity is associated with incident dementia and whether associations vary by different clusters of disease and genetic risk for dementia. Design, Setting, and Participants: This population-based prospective cohort study used data from the UK Biobank cohort, with baseline data collected between 2006 and 2010 and with up to 15 years of follow-up. Participants included women and men without dementia and aged at least 60 years at baseline. Medical conditions were captured as part of nurse-led verbal interviews conducted at baseline assessment centers. Data were analyzed from October 2020 to July 2022. Exposures: The presence of at least 2 long-term conditions from a preselected list of 42 conditions was used to define multimorbidity. High genetic risk for dementia was based on presence of 1 or 2 apolipoprotein (APOE) ε4 alleles. Main Outcomes and Measures: The main outcome, incident dementia, was derived from hospital inpatient and death registry records. Associations of multimorbidity with dementia were assessed with Cox proportional hazards models. Results: A total of 206 960 participants (mean [SD] age, 64.1 [2.9] years, 108 982 [52.7%] women) were included in the final sample, of whom 89 201 participants (43.1%) had multimorbidity. Over a mean (SD) of 11.8 (2.2) years of follow-up, 6182 participants (3.0%) developed dementia. The incidence rate was 1.87 (95% CI, 1.80-1.94) per 1000 person-years for those without multimorbidity and 3.41 (95% CI, 3.30-3.53) per 1000 person-years for those with multimorbidity. In Cox proportional hazards models adjusted for age, sex, ethnicity, education, socioeconomic status, and APOE-ε4 carrier status, multimorbidity was associated with an increased risk of incident dementia (hazard ratio [HR], 1.63 [95% CI, 1.55-1.71]). The highest dementia risk was observed for the hypertension, diabetes, and coronary heart disease cluster (HR, 2.20 [95% CI, 1.98-2.46]) and pain, osteoporosis, and dyspepsia cluster (HR, 2.00 [95% CI, 1.68-2.37]) in women and in the diabetes and hypertension cluster (HR, 2.24 [95% CI, 1.97-2.55]) and coronary heart disease, hypertension, and stroke cluster (HR, 1.94 [95% CI, 1.71-2.20]) in men, compared with no multimorbidity. The associations between multimorbidity and dementia were greater in those with a lower genetic risk of dementia (HR, 1.96 [95% CI, 1.81-2.11]) than in those with a higher genetic risk of dementia (HR, 1.39 [95% CI, 1.30-1.49]). Similar findings were observed when stratifying diseases clusters by genetic risk for dementia. Conclusions and Relevance: These findings suggest that multimorbidity was associated with an increased risk of dementia. The associations varied by clusters of disease and genetic risk for dementia. These findings could help with the identification of individuals at high risk of dementia as well as the development of targeted interventions to reduce or delay dementia incidence.

Cognitive ability in early adulthood is associated with systemic inflammation in middle age: the Vietnam experience study.

We examined the prospective association between cognitive ability in early adulthood and erythrocyte sedimentation rate, a marker of inflammation, in middle age. Participants were 4256 male Vietnam era US veterans. Data on cognitive ability, assessed by the Army General Technical Test, ethnicity, and place of service were extracted from enlistment files. Smoking behaviour, alcohol consumption, basic socio-demographics, and whether participants suffered from a physician diagnosed chronic disease were determined by telephone interview in middle-age in 1985. Erythrocyte sedimentation rate, cholesterol, blood pressure, height, and weight were measured at a 3-day medical examination in 1986. In linear regression models that adjusted for age and then additionally for circumstantial, socio-demographic, lifestyle, and health factors, poor cognitive ability in early adulthood was associated with greater erythrocyte sedimentation rate in middle age, ß=-.09. Thus, it would appear that not only does systemic inflammation influence cognition, but also that poor cognitive ability earlier in life is associated with inflammation in middle-age.

Prediction of Alzheimer's disease biomarker status defined by the 'ATN framework' among cognitively healthy individuals: results from the EPAD longitudinal cohort study.

BACKGROUND: The Amyloid/Tau/Neurodegeneration (ATN) framework has been proposed as a means of evidencing the biological state of Alzheimer's disease (AD). Predicting ATN status in pre-dementia individuals therefore provides an important opportunity for targeted recruitment into AD interventional studies. We investigated the extent to which ATN-defined biomarker status can be predicted by known AD risk factors as well as vascular-related composite risk scores. METHODS: One thousand ten cognitively healthy older adults were allocated to one of five ATN-defined biomarker categories. Multinomial logistic regression tested risk factors including age, sex, education, APOE4, family history of dementia, cognitive function, vascular risk indices (high systolic blood pressure, body mass index (BMI), high cholesterol, physical inactivity, ever smoked, blood pressure medication, diabetes, prior cardiovascular disease, atrial fibrillation and white matter lesion (WML) volume), and three vascular-related composite scores, to predict five ATN subgroups; ROC curve models estimated their added value in predicting pathology. RESULTS: Age, APOE4, family history, BMI, MMSE and white matter lesions (WML) volume differed between ATN biomarker groups. Prediction of Alzheimer's disease pathology (versus normal AD biomarkers) improved by 7% after adding family history, BMI, MMSE and WML to a ROC curve that included age, sex and APOE4. Risk composite scores did not add value. CONCLUSIONS: ATN-defined Alzheimer's disease biomarker status prediction among cognitively healthy individuals is possible through a combination of constitutional and cardiovascular risk factors but established dementia composite risk scores do not appear to add value in this context.

Sex-specific moderation by lifestyle and psychosocial factors on the genetic contributions to adiposity in 112,151 individuals from UK Biobank.

Evidence suggests that lifestyle factors, e.g. physical activity, moderate the manifestation of genetic susceptibility to obesity. The present study uses UK Biobank data to investigate interaction between polygenic scores (PGS) for two obesity indicators, and lifestyle and psychosocial factors in the prediction of the two indicators, with attention to sex-specific effects. Analyses were of 112 151 participants (58 914 females; 40 to 73 years) whose genetic data passed quality control. Moderation effects were analysed in linear regression models predicting body mass index (BMI) and waist-to-hip ratio (WHR), including interaction terms for PGS and each exposure. Greater physical activity, more education, higher income, moderate vs low alcohol consumption, and low material deprivation were each associated with a relatively lower risk for manifestation of genetic susceptibility to obesity (p < 0.001); the moderating effects of physical activity and alcohol consumption were greater in women than men (three-way interaction: p = 0.009 and p = 0.008, respectively). More income and less neuroticism were related to reduced manifestation of genetic susceptibility to high WHR (p = 0.007; p = 0.003); the effect of income was greater in women (three-way interaction: p = 0.001). Lifestyle and psychosocial factors appear to offset genetic risk for adiposity in mid to late adulthood, with some sex-specific associations.

Childhood intelligence in relation to major causes of death in 68 year follow-up: prospective population study.

Objectives To examine the association between intelligence measured in childhood and leading causes of death in men and women over the life course.Design Prospective cohort study based on a whole population of participants born in Scotland in 1936 and linked to mortality data across 68 years of follow-up.Setting Scotland.Participants 33 536 men and 32 229 women who were participants in the Scottish Mental Survey of 1947 (SMS1947) and who could be linked to cause of death data up to December 2015.Main outcome measures Cause specific mortality, including from coronary heart disease, stroke, specific cancer types, respiratory disease, digestive disease, external causes, and dementia.Results Childhood intelligence was inversely associated with all major causes of death. The age and sex adjusted hazard ratios (and 95% confidence intervals) per 1 SD (about 15 points) advantage in intelligence test score were strongest for respiratory disease (0.72, 0.70 to 0.74), coronary heart disease (0.75, 0.73 to 0.77), and stroke (0.76, 0.73 to 0.79). Other notable associations (all P<0.001) were observed for deaths from injury (0.81, 0.75 to 0.86), smoking related cancers (0.82, 0.80 to 0.84), digestive disease (0.82, 0.79 to 0.86), and dementia (0.84, 0.78 to 0.90). Weak associations were apparent for suicide (0.87, 0.74 to 1.02) and deaths from cancer not related to smoking (0.96, 0.93 to 1.00), and their confidence intervals included unity. There was a suggestion that childhood intelligence was somewhat more strongly related to coronary heart disease, smoking related cancers, respiratory disease, and dementia in women than men (P value for interactions <0.001, 0.02, <0.001, and 0.02, respectively).Childhood intelligence was related to selected cancer presentations, including lung (0.75, 0.72 to 0.77), stomach (0.77, 0.69 to 0.85), bladder (0.81, 0.71 to 0.91), oesophageal (0.85, 0.78 to 0.94), liver (0.85, 0.74 to 0.97), colorectal (0.89, 0.83 to 0.95), and haematopoietic (0.91, 0.83 to 0.98). Sensitivity analyses on a representative subsample of the cohort observed only small attenuation of the estimated effect of intelligence (by 10-26%) after adjustment for potential confounders, including three indicators of childhood socioeconomic status. In a replication sample from Scotland, in a similar birth year cohort and follow-up period, smoking and adult socioeconomic status partially attenuated (by 16-58%) the association of intelligence with outcome rates.Conclusions In a whole national population year of birth cohort followed over the life course from age 11 to age 79, higher scores on a well validated childhood intelligence test were associated with lower risk of mortality ascribed to coronary heart disease and stroke, cancers related to smoking (particularly lung and stomach), respiratory diseases, digestive diseases, injury, and dementia.

Childhood Body Weight in Relation to Cause-Specific Mortality: 67 Year Follow-up of Participants in the 1947 Scottish Mental Survey.

The association between childhood body weight and adult health has been little-examined, and findings are inconsistent.In a representative sample of the Scottish nation (the Scottish Mental Survey of 1947), we examined the association between body mass index measured at 11 years of age and future cause-specific mortality by age 77 years. In this cohort study, a maximum of 67 years of follow-up of 3839 study members gave rise to 1568 deaths (758 from cardiovascular disease, 610 from any malignancy). After adjustment for covariates, there was some evidence of a relation between elevated childhood body mass index and rates of mortality ascribed to all-causes (hazard ratio per 1 SD increase in body mass index; 95% confidence interval: 1.09; 1.03, 1.14), cardiovascular disease (1.09; 1.01, 1.17), all cancers combined (1.12; 1.03, 1.21), smoking-related cancers (1.13; 1.03, 1.25), and breast cancer in women (1.27; 1.04, 1.56).In conclusion, we provide further observational evidence for the need for weight control measures in youth.

Childhood intelligence and midlife inflammatory and hemostatic biomarkers: the National Child Development Study (1958) cohort.

OBJECTIVE: In a prospective cohort study the authors examined associations between childhood intelligence at age 11 and inflammatory and hemostatic biomarkers in middle age. METHOD: Participants were 9,377 men and women born in the United Kingdom in March 1958, and whose blood plasma samples at age 45 years were analyzed for levels of C-reactive protein (CRP), D-dimer, fibrinogen, tissue plasminogen activator (t-PA) antigen, and von Willebrand factor (VWF). Sex-adjusted linear regression models tested cognition-blood biomarker associations, with and without adjustment for potential confounding by parental socioeconomic status and potential mediation by cardiovascular disease (CVD) risk factors at midlife. Cognitive tests taken at age 50 enabled the inflammation-cognition association to be tested for reverse causation, by adjusting for age 11 intelligence. RESULTS: Higher childhood intelligence test scores were significantly associated (p < .001) with lower adult levels of CRP (beta coefficient = -0.068), t-PA antigen (ß = -0.014), D-dimer (ß = -0.011), fibrinogen (ß = -0.011), and VWF antigen (ß = -0.008). Early life factors including parental socioeconomic status accounted for 24%-44% of these associations, whereas further adjustment for adult CVD risk factors largely attenuated the effects (82%-100%). The significant inverse associations between age 45 biomarker levels and age 50 cognition could be accounted for to a substantial degree by childhood intelligence (50%-100% attenuation). CONCLUSIONS: Childhood intelligence is predictive of inflammatory and hemostatic biomarker status at middle age, which may be largely explained by health behaviors. This highlights the need to consider possible bidirectional associations between cognition and inflammation (and hemostasis) in lifecourse models of CVD-related health.

Intelligence in youth and all-cause-mortality: systematic review with meta-analysis.

BACKGROUND: A number of prospective cohort studies have examined the association between intelligence in childhood or youth and life expectancy in adulthood; however, the effect size of this association is yet to be quantified and previous reviews require updating. METHODS: The systematic review included an electronic search of EMBASE, MEDLINE and PSYCHINFO databases. This yielded 16 unrelated studies that met inclusion criteria, comprising 22,453 deaths among 1,107,022 participants. Heterogeneity was assessed, and fixed effects models were applied to the aggregate data. Publication bias was evaluated, and sensitivity analyses were conducted. RESULTS: A 1-standard deviation (SD) advantage in cognitive test scores was associated with a 24% (95% confidence interval 23-25) lower risk of death, during a 17- to 69-year follow-up. There was little evidence of publication bias (Egger's intercept = 0.10, P = 0.81), and the intelligence-mortality association was similar for men and women. Adjustment for childhood socio-economic status (SES) in the nine studies containing these data had almost no impact on this relationship, suggesting that this is not a confounder of the intelligence-mortality association. Controlling for adult SES in five studies and for education in six studies attenuated the intelligence-mortality hazard ratios by 34 and 54%, respectively. CONCLUSIONS: Future investigations should address the extent to which attenuation of the intelligence-mortality link by adult SES indicators is due to mediation, over-adjustment and/or confounding. The explanation(s) for association between higher early-life intelligence and lower risk of adult mortality require further elucidation.