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Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies. Family-based study designs have been applied to resolve confounding by population stratification, dynastic effects and assortative mating in genetic association analyses. Here, Brumpton et al. describe theory and simulations for overcoming such biases in Mendelian randomization through within-family studies.

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56–66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for <1% of the variance in cognitive outcomes. The impact of these other factors likely reflects reverse causation—namely, downstream effects of early adult GCA. Supporting that idea, age 20 GCA, but not education, was associated with late midlife cortical surface area (n = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.

Leisure activity associations with cognition may operate differently depending on an individual’s context. We evaluated whether activity-cognition associations were influenced by community and geographic features in CATSLife ( M age = 33.17 years, N = 1201). Measures included cognition indexed by IQ and activity engagement indexed by time, cognitive demand, and frequency. County-level Index of Relative Rurality (IRR) and Social Capital Index (SCI), i.e., the availability of social networks and resources, captured environmental features. In multilevel models, activity engagement was more strongly associated with IQ than SCI and rurality. We found evidence that activity-IQ associations were magnified in urban environments when SCI was high, but associations were reduced when SCI was low. However, adolescent IQ diminished associations, revealing selection effects. Our findings highlight interrelated individual, community, and geographic factors influencing cognitive functioning, but also the saliency of earlier life cognition to attained contexts, that together may contribute to cognitive maintenance at midlife and beyond.

Body mass index (BMI) is associated with cognitive abilities, but the nature of the relationship remains largely unexplored. We aimed to investigate the bidirectional relationship from midlife through late-life, while considering sex differences and genetic predisposition to higher BMI. We used data from 23,892 individuals of European ancestry from the Health and Retirement Study, with longitudinal data on BMI and three established cognitive indices: mental status, episodic memory, and their sum, called total cognition. To investigate the dynamic relationship between BMI and cognitive abilities, we applied dual change score models of change from age 50 through 89, with a breakpoint at age 65 or 70. Models were further stratified by sex and genetic predisposition to higher BMI using tertiles of a polygenic score for BMI (PGS BMI ). We demonstrated bidirectional effects between BMI and all three cognitive indices, with higher BMI contributing to steeper decline in cognitive abilities in both midlife and late-life, and higher cognitive abilities contributing to less decline in BMI in late-life. The effects of BMI on change in cognitive abilities were more evident in men compared to women, and among those in the lowest tertile of the PGS BMI compared to those in the highest tertile, while the effects of cognition on BMI were similar across groups. In conclusion, these findings highlight a reciprocal relationship between BMI and cognitive abilities, indicating that the negative effects of a higher BMI persist from midlife through late-life, and that weight-loss in late-life may be driven by cognitive decline.

Current physical activity guidelines may be insufficient to address health consequences in a world increasing in sedentary behavior. Physical activity is a key lifestyle factor to promote healthy aging, but few studies examine activity in conjunction with sitting. We examine how activity intensity and sitting behavior influence health and the extent to which physical activity might counter sitting. We analyzed data from the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife) in adults aged 28-49 years (M = 33.16, SD = 4.93). We fit a linear mixed-effect model for body mass index (BMI) and total cholesterol/high-density lipoprotein ratio (TC/HDL). Leveraging the co-twin control approach, we explore the trade-off between sitting and physical activity. Across established adulthood, TC/HDL and BMI demonstrated increasing age trends with prolonged sitting and vigorous activity inversely associated. Moreover, after considering sitting time, we found an age-equivalent benefit of vigorous exercise where those performing 30 minutes daily had expected TC/HDL and BMI estimates that mirrored sedentary individuals 5 and 10 years younger, respectively. Co-twin control analysis suggests partial exposure effects for TC/HDL, indicating greater vigorous activity may counter sitting-health effects but with diminishing returns. Our findings support the counteracting influence of prolonged sitting and physical activity on indicators of cardiovascular and metabolic health. A compensating role of vigorous activity on sitting health links is indicated while reducing sitting time appears paramount. Public health initiatives should consider sitting and vigorous activity in tandem in guidelines to promote health maintenance and combat accelerated aging.

Background Obesity and aging share biological processes, but their relationship remains unclear, especially in late life. Understanding how body mass index (BMI) and biological aging influence each other can guide strategies to reduce age‐ and obesity‐related health risks. We examined the bidirectional, longitudinal association between changes in BMI and biological aging, measured by frailty index (FI) and functional aging index (FAI), across late life. Methods This longitudinal cohort study used data from the Swedish Twin Registry substudies, GENDER, OCTO‐Twin and SATSA, collected via in‐person assessments from 1986 to 2014 at 2‐ to 4‐year intervals. We analysed 6216–6512 evaluations from 1902 to 1976 Swedish twins. Dual change score models were applied to assess the bidirectional, longitudinal association between BMI and FI or FAI from ages 60.0–91.9. FI measured physiological aging, while FAI assessed functional aging through a composite score of functional abilities. Results At first measurement, mean age was 74 ± 8, and 41% were males. BMI–FI relationship was bidirectional (p value ≤ 0.001): Higher BMI predicted a greater increase in FI over time (coupling effect [γ] = 0.86, 95% confidence interval [CI] = 0.65–1.06, p value ≤ 0.001), and higher FI predicted steeper decline in BMI (γ = −0.04, 95% CI = −0.05 to −0.03, p value ≤ 0.001). When including coupling from FI, BMI showed a nonlinear trajectory with a mean intercept of 26.32 kg/m2 (95% CI = 25.76–26.88), declining more rapidly after age 75. When including BMI coupling, FI increased from a mean intercept of 7.91% (95% CI = 6.41–9.42), with steeper growth from ages 60–75. BMI–FAI relationship was unidirectional (p value ≤ 0.001): Higher FAI predicted a steeper BMI decline (γ = −0.02, 95% CI = −0.02 to −0.01, p value ≤ 0.001). By including FAI coupling, BMI had a mean intercept of 26.10 kg/m2 (95% CI = 25.47–26.74), declining rapidly after age 75. FAI increased exponentially from a mean intercept of 36.49 (95% CI = 34.54–38.43). Conclusions Higher BMI predicted a steeper increase in FI, substantiating the hypothesis that obesity accelerates biological aging. Higher biological aging, measured as FI and FAI, drove a steeper BMI decline in late life, signalling that late‐life weight loss may result from accelerated aging. Higher BMI may accelerate aspects of the aging process, and the aging process, in turn, accelerates late‐life BMI decline, necessitating an integrated approach to manage both obesity and unintentional weight loss among older adults.

Background While a high body mass index (BMI) in midlife is associated with higher risk of dementia, high BMI in late-life may be associated with lower risk. This study combined genetic designs with longitudinal data to achieve a better understanding of this paradox. Methods We used longitudinal data from 22,156 individuals in the Swedish Twin Registry (STR) and 25,698 from the Health and Retirement Study (HRS). The STR sample had information about BMI from early adulthood through late-life, and the HRS sample from age 50 through late-life. Survival analysis was applied to investigate age-specific associations between BMI and dementia risk. To examine if the associations are influenced by genetic susceptibility to higher BMI, an interaction between BMI and a polygenic score for BMI (PGS BMI ) was included in the models and results stratified into those with genetic predisposition to low, medium, and higher BMI. In the STR, co-twin control models were applied to adjust for familial factors beyond those captured by the PGS BMI . Results At age 35–49, 5 units higher BMI was associated with 15% (95% CI 7–24%) higher risk of dementia in the STR. There was a significant interaction ( p  = 0.04) between BMI and the PGS BMI , and the association present only among those with genetic predisposition to low BMI (HR 1.38, 95% CI 1.08–1.78). Co-twin control analyses indicated genetic influences. After age 80, 5 units higher BMI was associated with 10–11% lower risk of dementia in both samples. There was a significant interaction between late-life BMI and the PGS BMI in the STR ( p  = 0.01), but not the HRS, with the inverse association present only among those with a high PGS BMI (HR 0.70, 95% CI 0.52–0.94) . No genetic influences were evident from co-twin control models of late-life BMI. Conclusions Not only does the association between BMI and dementia differ depending on age at BMI measurement, but also the effect of genetic influences. In STR, the associations were only present among those with a BMI in opposite direction of their genetic predisposition, indicating that the association between BMI and dementia across the life course might be driven by environmental factors and hence likely modifiable.

The present study examined early socioeconomic status (SES) and neighborhood disadvantage (ND) as independent predictors of antisocial behavior (ASB) and addressed the etiology of the associations (i.e., genes versus the environment) using a longitudinal adoption design. Prospective data from the Colorado Adoption Project (435 adoptees, 598 nonadopted children, 526 biological grandparents of adoptees, 481 adoptive parents, and 617 nonadoptive parents including biological parents of unrelated siblings of adoptees) were examined. SES and ND were assessed during infancy and ASB was evaluated from ages four through 16 using parent and teacher report. Associations between predictors and ASB were compared across adoptive and nonadoptive families and sex. Early SES was a nominally significant, independent predictor of antisocial ASB, such that lower SES predicted higher levels of ASB in nonadoptive families only. ND was not associated with ASB. Associations were consistent across aggression and delinquency, and neither SES nor ND was associated with change in ASB over time. Nominally significant associations did not remain significant after controlling for multiple testing. As such, despite nonsignificant differences in associations across sex or adoptive status, we were unable to make definitive conclusions regarding the genetic versus environmental etiology of or sex differences in the influence of SES and ND on ASB. Despite inconclusive findings, in nonadoptees, results were consistent—in effect size and direction—with previous studies in the literature indicating that lower SES is associated with increased risk for ASB.

While midlife adiposity is a risk factor for dementia, adiposity in late-life appears to be associated with lower risk. What drives the associations is poorly understood, especially the inverse association in late-life. Using results from genome-wide association studies, we identified inflammation and lipid metabolism as biological pathways involved in both adiposity and dementia. To test if these factors mediate the effect of midlife and/or late-life adiposity on dementia, we then used cohort data from the Swedish Twin Registry, with measures of adiposity and potential mediators taken in midlife (age 40–64, n = 5999) or late-life (age 65–90, n = 7257). Associations between body-mass index (BMI), waist-hip ratio (WHR), C-reactive protein (CRP), lipid levels, and dementia were tested in survival and mediation analyses. Age was used as the underlying time scale, and sex and education included as covariates in all models. Fasting status was included as a covariate in models of lipids. One standard deviation (SD) higher WHR in midlife was associated with 25% (95% CI 2–52%) higher dementia risk, with slight attenuation when adjusting for BMI. No evidence of mediation through CRP or lipid levels was present. After age 65, one SD higher BMI, but not WHR, was associated with 8% (95% CI 1–14%) lower dementia risk. The association was partly mediated by higher CRP, and suppressed when high-density lipoprotein levels were low. In conclusion, the negative effects of midlife adiposity on dementia risk were driven directly by factors associated with body fat distribution, with no evidence of mediation through inflammation or lipid levels. There was an inverse association between late-life adiposity and dementia risk, especially where the body’s inflammatory response and lipid homeostasis is intact.

In this report we analyzed genetically informative data to investigate within-person change and between-person differences in late-life cognitive abilities as a function of childhood social class. We used data from nine testing occasions spanning 28 y in the Swedish Adoption/Twin Study of Aging and parental social class based on the Swedish socioeconomic index. Cognitive ability included a general factor and the four domains of verbal, fluid, memory, and perceptual speed. Latent growth curve models of the longitudinal data tested whether level and change in cognitive performance differed as a function of childhood social class. Between–within twin-pair analyses were performed on twins reared apart to assess familial confounding. Childhood social class was significantly associated with mean-level cognitive performance at age 65 y, but not with rate of cognitive change. The association decreased in magnitude but remained significant after adjustments for level of education and the degree to which the rearing family was supportive toward education. A between-pair effect of childhood social class was significant in all cognitive domains, whereas within-pair estimates were attenuated, indicating genetic confounding. Thus, childhood social class is important for cognitive performance in adulthood on a population level, but the association is largely attributable to genetic influences.