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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.

There is evidence for long-lasting effects of birth characteristics on cognitive ability in childhood and adulthood. Further, low cognitive ability throughout the lifetime has been linked to age-related cognitive decline and dementia risk. However, little is known about the effects of birth characteristics on cognitive dysfunction late in life. Here we explore potential associations between birth characteristics (weight, head circumference, length, and gestational age), adjusted and not adjusted for gestational age, and cognitive impairment and dementia late in life. Data from twins in the Swedish Twin Registry born 1926-1960 were merged with information from the Swedish birth, patient, and cause of death registries, resulting in a sample of 35,191 individuals. A subsample of 4,000 twins aged 65 years and older also participated in a telephone cognitive screening in 1998-2002. Associations of birth characteristics with registry-based dementia diagnoses and on telephone-assessed cognitive impairment were investigated in the full sample and subsample, respectively. The full sample contained 907 (2.6%) individuals with a dementia diagnosis (an incidence rate of 5.9% per 100,000 person-years), 803 (2.4%) individuals born small for gestational age, and 929 (2.8%) individuals born with a small head for gestational age. The subsample contained 569 (14.2%) individuals with cognitive impairment. Low birth weight for gestational age and being born with a small head for gestational age were significant risk factors for cognitive dysfunction late in life, with an up to 2-fold risk increase (p < 0.001) compared to infants with normal growth and head size, even after controlling for familial factors, childhood socioeconomic status, and education in adulthood. In line with this, each additional 100 g birth weight and each additional millimeter head circumference significantly reduced the risk for dementia (hazard ratio 0.98, 95% confidence interval 0.97 to 0.99, p = 0.004) and cognitive impairment (odds ratio 0.99, 95% confidence interval 0.99 to 1.00, p = 0.004), respectively. Within-pair analyses of identical twins, though hampered by small sample size, suggested that the observed associations between birth characteristics and dementia are likely not due to underlying shared genetic or environmental etiology. A limitation of the present study is that registry-based dementia diagnoses likely miss some of the true dementia cases in the population. Further, a more precise measure of cognitive reserve early in life as well as a date of onset for the cognitive impairment measure in the subsample would have been favorable. In this study, we found that infants of smaller birth size (i.e., low birth weight or small head circumference adjusted and unadjusted for gestational age) have a significantly higher risk of age-related cognitive dysfunction compared to those with normal growth, highlighting the importance of closely monitoring the cognitive development of such infants and evaluating the potential of early life interventions targeted at enhancing cognitive reserve.

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.

Cognitive testing in large population surveys is frequently used to describe cognitive aging and determine the incidence rates, risk factors, and long-term trajectories of the development of cognitive impairment. As these surveys are increasingly administered on internet-based platforms, web-based and self-administered cognitive testing calls for close investigation. Web-based, self-administered versions of 2 age-sensitive cognitive tests, the Stop and Go Switching Task for executive functioning and the Figure Identification test for perceptual speed, were developed and administered to adult participants in the Understanding America Study. We examined differences in cognitive test scores across internet device types and the extent to which the scores were associated with self-reported distractions in everyday environments in which the participants took the tests. In addition, national norms were provided for the US population. Data were collected from a probability-based internet panel representative of the US adult population-the Understanding America Study. Participants with access to both a keyboard- and mouse-based device and a touch screen-based device were asked to complete the cognitive tests twice in a randomized order across device types, whereas participants with access to only 1 type of device were asked to complete the tests twice on the same device. At the end of each test, the participants answered questions about interruptions and potential distractions that occurred during the test. Of the 7410 (Stop and Go) and 7216 (Figure Identification) participants who completed the device ownership survey, 6129 (82.71% for Stop and Go) and 6717 (93.08% for Figure Identification) participants completed the first session and correctly responded to at least 70% of the trials. On average, the standardized differences across device types were small, with the absolute value of Cohen d ranging from 0.05 (for the switch score in Stop and Go and the Figure Identification score) to 0.13 (for the nonswitch score in Stop and Go). Poorer cognitive performance was moderately associated with older age (the absolute value of r ranged from 0.32 to 0.61), and this relationship was comparable across device types (the absolute value of Cohen q ranged from 0.01 to 0.17). Approximately 12.72% (779/6123 for Stop and Go) and 12.32% (828/6721 for Figure Identification) of participants were interrupted during the test. Interruptions predicted poorer cognitive performance (P<.01 for all scores). Specific distractions (eg, watching television and listening to music) were inconsistently related to cognitive performance. National norms, calculated as weighted average scores using sampling weights, suggested poorer cognitive performance as age increased. Cognitive scores assessed by self-administered web-based tests were sensitive to age differences in cognitive performance and were comparable across the keyboard- and touch screen-based internet devices. Distraction in everyday environments, especially when interrupted during the test, may result in a nontrivial bias in cognitive testing.

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural–geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a 2  = 0.43; 0.41–0.44), but also environmental variation shared by co-twins was substantial (c 2  = 0.31; 0.30–0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900–1949 (a 2  = 0.44; 0.41–0.46) than in the later cohorts born in 1950–1989 (a 2  = 0.38; 0.36–0.40), with a corresponding lower influence of common environmental factors (c 2  = 0.31; 0.29–0.33 and c 2  = 0.34; 0.32–0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.

Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1–19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments.

Late-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years. We studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (β = -0.42/year, 95% CI: -0.44, -0.40) and episodic memory (β = -0.59/year, 95% CI: -0.64, -0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (βPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.001, 0.05; βNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (βPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.02, 0.12; βNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability. In this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging.

Background: High midlife body mass index (BMI) has been linked to a greater risk of dementia in late life, but few have studied the effect of BMI across midlife on cognitive abilities and cognitive change in a dementia-free sample. Methods: We investigated the association between BMI, measured twice across midlife (mean age 40 and 61 years, respectively), and cognitive change in four domains across two decades in the Swedish Adoption/Twin Study of Aging. Results: Latent growth curve models fitted to data from 657 non-demented participants showed that persons who were overweight/obese in early midlife had significantly lower cognitive performance across domains in late life and significantly steeper decline in perceptual speed, adjusting for cardio-metabolic factors. Both underweight and overweight/obesity in late midlife were associated with lower cognitive abilities in late life. However, the association between underweight and low cognitive abilities did not remain significant when weight decline between early and late midlife was controlled for. Conclusion: There is a negative effect on cognitive abilities later in life related to being overweight/obese across midlife. Moreover, weight decline across midlife rather than low weight in late midlife per se was associated with low cognitive abilities. Weight patterns across midlife may be prodromal markers of late life cognitive health.

In post-industrial settings, apolipoprotein E4 ( APOE4 ) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia ( N = 1266, 50% female), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low body mass indices (BMIs). These results suggest that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population. Genes contain the instructions needed for a cell to make molecules called proteins, which perform various roles in the body. Different variants of a gene can affect how the protein works, and in some cases, can increase a person’s risk to develop certain diseases. For example, people who carry a version of the apolipoprotein E gene called APOE4 have a greater risk of developing Alzheimer’s disease or heart disease. Individuals with two copies of this genetic variant have a 45% higher risk of heart disease and 12 times higher risk of Alzheimer’s disease. Studies in industrialized countries suggest this increased risk may be the result of higher cholesterol and inflammation in people with APOE4. But if APOE4 is harmful, why does it continue to be so common worldwide? One potential explanation is that APOE4, which has been around since before modern humans, may be beneficial in some contexts. Cholesterol is essential for many vital tasks in the body. In physically demanding environments where parasitic infections are common – conditions similar to those experienced by early humans – APOE4 might be beneficial. Under those circumstances, having more cholesterol might help fuel metabolic activities, fight infections, or reduce inflammation caused by infections. Garcia et al. investigated the link between the APOE4 genetic variant, cholesterol and inflammation in 1,266 Indigenous Tsimane people from 80 villages in Bolivia. Tsimane people live an active lifestyle foraging and farming for food. Parasite infections are a common problem in their communities, but obesity rates are very low. Garcia et al. found that Tsimane people with at least one copy of the APOE4 have lower levels of inflammation and higher levels of cholesterol than those who have two copies of the APOE3 version of the gene. Very lean people with APOE4 had especially high levels of the so called “bad” low density lipoprotein (LDL) cholesterol compared to people with APOE3 only. However, in this situation, storing a little extra cholesterol may not be so bad. The findings contradict other studies that have linked obesity to higher LDL levels and APOE4 to higher levels of inflammation. For the majority of human history, humans lived in more physically strenuous and calorically restrictive environments, with less access to clean water. Garcia et al. suggest that the harmful effects of APOE4 seen in studies in more industrialized societies – where people tend to be more sedentary and have less exposure to pathogens – may reflect a mismatch between a person’s environment and their genes. More studies that capture the diversity of environmental conditions under which people live will help clarify the role of APOE4 health and disease.

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.