Search

Objectives: Childhood disadvantage is associated with lower general cognitive ability (GCA) and brain structural differences in midlife and older adulthood. However, the neuroanatomical mechanisms underlying childhood disadvantage effects on later-life GCA remain poorly understood. Although total surface area (SA) has been linked to lifespan GCA differences, total SA does not capture the non-uniform nature of childhood disadvantage effects on neuroanatomy, which varies across unimodal and transmodal cortices. Here, we examined whether cortical SA profile-the extent to which the spatial patterning of SA deviates from the normative unimodal-transmodal cortical organization-is a mediator of childhood disadvantage effects on later-life GCA., Method: In 477 community-dwelling men aged 56-72 years old, childhood disadvantage index (CDI) was derived from four indicators of disadvantages and GCA was assessed using a standardized test. Cortical SA was obtained from structural magnetic resonance imaging. For cortical SA profile, we calculated the spatial similarity between maps of individual cortical SA and MRI-derived principal gradient (i.e., unimodal-transmodal organization). Mediation analyses were conducted to examine the indirect effects of CDI through cortical SA profile on GCA., Results: Around 1.31% of CDI effects on later-life GCA were mediated by cortical SA profile, whereas total SA did not. Higher CDI was associated with more deviation of the cortical SA spatial patterning from the principal gradient, which in turn related to lower later-life GCA., Discussion: Childhood disadvantage may contribute to later-life GCA differences partly by influencing the spatial patterning of cortical SA in a way that deviates from the normative cortical organizational principle., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: About 10%-30% of individuals with obesity are metabolically healthy, but the specific characteristics of the metabolically healthy obesity (MHO) phenotype remain unclear. We aimed to examine how physical activity, education, depressive symptoms and genetic predisposition to obesity differ between individuals with MHO and those with metabolically unhealthy obesity (MUO), and whether these factors predict stability in MHO or conversion to a metabolically unhealthy state., Materials and Methods: We retrieved data on 9809 individuals with obesity from the Health and Retirement Study collected between 2006 and 2016. We compared how physical activity, education, depressive symptoms and a polygenic score for higher body mass index (BMI) (PGS BMI ) differed cross-sectionally between MHO and MUO using logistic regression. We then examined if the same factors predict conversion to a metabolically unhealthy state over 4 years in individuals with MHO., Results: Individuals with MHO had higher physical activity (odds ratio [OR] = 0.81), higher education (OR = 0.83) and lower depressive symptoms (OR = 1.14) compared to those with MUO but did not differ in the PGS BMI . The associations were slightly attenuated in mutually adjusted models. None of the factors were associated with conversion from MHO to a metabolically unhealthy state. However, a higher PGS BMI indicated 24% lower risk of conversion to a metabolically unhealthy state (p = 0.07)., Conclusions: Physical activity, education and depressive symptoms differed between MHO and MUO, even when mutually adjusted for, but did not predict conversion from a metabolically healthy to unhealthy state. Although not statistically significant, the results indicated that those with genetically predicted high BMI are more likely to maintain MHO and not convert to a metabolically unhealthy state., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: DNA methylation-derived epigenetic clocks and frailty are well-established biological age measures capturing different aging processes. However, whether they are dynamically linked to each other across chronological age remains poorly understood., Methods: This analysis included 1 309 repeated measurements in 524 individuals aged 50-90 years from the Swedish Adoption/Twin Study of Aging. Frailty was measured using a validated 42-item frailty index (FI). Five epigenetic clocks were calculated, including 4 principal component (PC)-based clocks trained on chronological age (PCHorvathAge and PCHannumAge) and aging-related physiological conditions (PCPhenoAge and PCGrimAge), and a pace of aging clock (DunedinPACE). Using dual change score models, we examined the dynamic, bidirectional associations between each of the epigenetic clocks and the FI over age to test for potential causal associations., Results: The FI exhibited a nonlinear, accelerated increase across the older adulthood, whereas the epigenetic clocks mostly increased linearly with age. For PCHorvathAge, PCHannumAge, PCPhenoAge, and PCGrimAge, their associations with the FI were primarily due to correlated levels at age 50 but with no evidence of a dynamic longitudinal association. In contrast, we observed a unidirectional association between DunedinPACE and the FI, where a higher DunedinPACE predicted a subsequent increase in the FI, but not vice versa., Conclusions: Our results highlight a temporal order between epigenetic aging and frailty such that changes in DunedinPACE precede changes in the FI. This potentially suggests that the pace of aging clock can be used as an early marker of the overall physiological decline at system level., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bruellman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pubertal development has short- and long-term effects on psychological adjustment. Many studies of long-term effects rely on retrospective measurement of pubertal timing, but such measures often reflect different aspects of puberty than those assessed in adolescence, raising questions about the utility and interpretation of retrospective reports. The present study leveraged longitudinal data collected in adolescence and established adulthood to determine: (1) the correspondence between pubertal timing indexed from logistic growth curves of self-reported physical development assessed contemporaneously across adolescence and pubertal timing indexed relative to peers assessed retrospectively in adulthood; (2) the associations between the two pubertal timing measures and psychological adjustment; and (3) potential recall biases. Participants were 748 individuals (50.1% female; 91.6% White) from two longitudinal studies who reported on their pubertal development annually from Grades 3-9, psychological adjustment (age at sexual initiation, substance use, depression) in late adolescence, and retrospective pubertal timing in established adulthood ( M age = 32.76; SD = 4.43). Results indicate moderate-to-high convergence between retrospective and contemporaneous indices. Most participants, especially women, had the same pubertal timing classification (i.e., early, on time, or late), but early-maturing adolescents often recalled on-time development as adults. Retrospective and contemporaneous indices were associated with psychological adjustment in similar ways, with some attenuation in the retrospective measure, especially for men. There was little evidence of recall bias due to age at retrospective assessment or time since puberty. Findings generally support the use of retrospective pubertal timing measures, with the recognition that some relations with adjustment may be weakened. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

We examined how brain reserve in midlife, measured by brain-predicted age difference scores (Brain-PADs), predicted executive function concurrently and longitudinally into early old age, and whether these associations were moderated by young adult cognitive reserve or APOE genotype. 508 men in the Vietnam Era Twin Study of Aging (VETSA) completed neuroimaging assessments at mean age 56 and six executive function tasks at mean ages 56, 62, and 68 years. Results indicated that greater brain reserve at age 56 was associated with better concurrent executive function (r=.10, p=.040) and less decline in executive function over 12 years (r=.34, p=.001). These associations were not moderated by cognitive reserve or APOE genotype. Twin analysis suggested associations with executive function slopes were driven by genetic influences. Our findings suggest that greater brain reserve allowed for better cognitive maintenance from middle- to old age, driven by a genetic association. The results are consistent with differential preservation of executive function based on brain reserve that is independent of young adult cognitive reserve or APOE genotype., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers., Methods: Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau., Results: No clear evidence that Aβ40 or Aβ42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL., Discussion: Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau. In contrast, Aβ aggregation may causally impact NFL in cognitively unimpaired men in their late 60s., Competing Interests: Conflicts No authors reported a conflict of interest.

Introduction: This study investigates the relationship between cognitive functioning and 59 modifiable and intrinsic factors at the cusp of midlife., Methods: We analyzed data from 1221 participants in the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife; M age  = 33.20, %Female = 52.74). We assessed the impact of 59 factors on cognitive functioning using regularized regression and co-twin control models, controlling for earlier-life cognitive functioning and gray matter volume., Results: Eight robust factors were identified, including education attainment, cognitive complexity, purpose-in-life, and smoking status. Twins reporting higher levels of cognitive complexity and purpose-in-life showed better cognitive performance than their cotwin, while smoking was negatively associated. Using meta-analytically derived effect size threshold, we additionally identified that twins experiencing more financial difficulty tend to perform less well compared with their cotwin., Discussion: The findings highlight the early midlife link between cognitive functioning and lifestyle/psychological factors, beyond prior cognitive performance, brain status, genetic and familial confounders. Our results further highlight the potential of established adulthood as a crucial window for dementia prevention interventions targeting lifestyle and psychosocial factors., Highlights: Cog complexity(+), purpose-in-life(+) were associated with cognition in early midlife.Smoking(-) was also associated with cognition in early midlife.Results were consistent controlling for genetic and environmental confounds.Association between EA and cognition might be mostly genetic and familial confounded., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the Supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Increased exposure to ambient air pollution, especially fine particulate matter ≤ 2.5 μ m ( PM 2.5 ) is associated with poorer brain health and increased risk for Alzheimer's disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants., Objective: Our aim was to investigate if exposure to PM 2.5 was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia., Methods: We examined the relationship between PM 2.5 and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio ( LC CNR ) in 381 men [ mean age = 67.3 ; standard deviation ( SD ) = 2.6 ] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to PM 2.5 was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on LC CNR in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between PM 2.5 exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment., Results: Multiple linear regressions revealed a significant association between PM 2.5 and rostral-middle LC CNR ( β = - 0.16 ; p = 0.02 ), whereby higher exposure to PM 2.5 was associated with lower LC CNR . A co-twin control analysis found that, within monozygotic pairs, individuals with higher PM 2.5 exposure showed lower LC CNR ( β = - 0.11 ; p = 0.02 ), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between PM 2.5 and caudal LC CNR or hippocampal volume, suggesting a degree of specificity to the rostral-middle portion of the LC., Discussion: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. https://doi.org/10.1289/EHP14344.

The internalizing construct captures shared variance underlying risk for mood and anxiety disorders. Internalizing factors based on diagnoses (or symptoms) of major depressive disorder (MDD) and generalized anxiety disorder (GAD) are well established. Studies have also integrated self-reported measures of associated traits (e.g., questionnaires assessing neuroticism, worry, and rumination) onto these factors, despite having not tested the assumption that these measures truly capture the same sets of risk factors. This study examined the overlap among both sets of measures using converging approaches. First, using genomic structural equation modeling, we constructed internalizing factors based on genome-wide association studies (GWASs) of internalizing diagnoses (e.g., MDD) and traits associated with internalizing (neuroticism, loneliness, and reverse-scored subjective well-being). Results indicated the two factors were highly ( r g = .79) but not perfectly genetically correlated ( r < .001). Second, we constructed similar latent factors in a combined twin/adoption sample of adults from the Colorado Adoption/Twin Study of Lifespan Behavioral Development and Cognitive Aging. Again, both factors demonstrated strong overlap at the level of genetic ( g < 1.0, p < .001). Second, we constructed similar latent factors in a combined twin/adoption sample of adults from the Colorado Adoption/Twin Study of Lifespan Behavioral Development and Cognitive Aging. Again, both factors demonstrated strong overlap at the level of genetic ( r g = .76, 95% confidence interval [CI] [0.40, 0.97]) and nonshared environmental influences ( r e = .80, 95% CI [0.53, 1.0]). Shared environmental influences were estimated near zero for both factors. Our findings are consistent with current frameworks of psychopathology, though they suggest there are some unique genetic influences captured by internalizing diagnosis compared to trait measures, with potentially more nonadditive genetic influences on trait measures. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Traumatic brain injury (TBI) is associated with increased risk of dementia. However, whether TBI is associated with greater cognitive decline over time in specific cognitive domains among older adults is not well understood. This prospective cohort study used data from 1476 male Vietnam Era Twin Study of Aging participants (average age at study entry = 57.9 years, range = 51-71 years; 97.6% non-Hispanic; 92.5% White) collected from 2003 to 2019, who had complete information on prior TBI. Participants completed a comprehensive neuropsychological assessment at up to three visits over up to a 12-year follow-up period during which they also self-reported their history of TBI. Multivariable, linear mixed-effects models were used to assess associations between TBI and cognitive performance trajectories. Effect measure modification by apolipoprotein E ( APOE ) epsilon 4 ( ε4 ) genotype status was assessed in a subset of participants. Thirty-one percent of participants reported a history of TBI; 29.4% were APOE ε4 carrier status, TBI was associated with a larger magnitude of decline in executive function for APOE ε4 carrier status, TBI was associated with a larger magnitude of decline in executive function for APOE ε4 carriers and among those who reported TBI in early life. These findings support the importance of a life course perspective when considering factors that may influence cognitive health in aging.P Interaction = 0.03). In sensitivity analyses, TBI earlier in life (before military induction, average age = 20 years) was associated with faster declines in executive function compared to no TBI, irrespective of APOE ε4 status. In this sample of middle-to-older aged men, TBI was associated with faster declines in executive function among APOE ε4 carriers and among those who reported TBI in early life. These findings support the importance of a life course perspective when considering factors that may influence cognitive health in aging., (© Alexander Ivan B. Posis et al., 2024; Published by Mary Ann Liebert, Inc.)

Epigenetics plays an important role in the aging process, but it is unclear whether epigenetic factors also influence frailty, an age-related state of physiological decline. In this study, we performed a meta-analysis of epigenome-wide association studies in four samples drawn from the Swedish Adoption/Twin Study of Aging (SATSA) and the Longitudinal Study of Aging Danish Twins (LSADT) to explore the association between DNA methylation and frailty. Frailty was defined using the frailty index (FI), and DNA methylation levels were measured in whole blood using Illumina's Infinium HumanMethylation450K and MethylationEPIC arrays. In the meta-analysis consisting of a total of 829 participants, we identified 589 CpG sites that were statistically significantly associated with either the continuous or categorical FI (false discovery rate <0.05). Many of these CpGs have previously been associated with age and age-related diseases. The identified sites were also largely directionally consistent in a longitudinal analysis using mixed-effects models in SATSA, where the participants were followed up to a maximum of 20 years. Moreover, we identified three differentially methylated regions within the MGRN1, MIR596, and TAPBP genes that have been linked to neuronal aging, tumor growth, and immune functions. Furthermore, our meta-analysis results replicated 34 of the 77 previously reported frailty-associated CpGs at p < 0.05. In conclusion, our findings demonstrate robust associations between frailty and DNA methylation levels in 589 novel CpGs, previously unidentified for frailty, and strengthen the role of neuronal/brain pathways in frailty., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Antihypertensive, lipid-lowering, and blood glucose-lowering drugs have slowed down the aging process in animal models. In humans, studies are limited, have short follow-up times, and show mixed results. Therefore, this study aimed to estimate the effects of commonly used medications on functional aging, cognitive function, and frailty. We included information on individuals from three Swedish longitudinal population-based studies collected between 1986 and 2014. Our exposures were the 21 most used groups of medications among individuals aged 65 years and older in the Swedish population in 2022. Functional aging index (n = 1191), cognitive function (n = 1094), and frailty index (n = 1361) were the outcomes of interest. To estimate the medication effects, we used a self-controlled analysis, where each individual is his/her own control, thereby adjusting for all time-stable confounders. The analysis was additionally adjusted for time-varying confounders (chronological age, Charlson Comorbidity Index, smoking, body mass index, and the number of drugs). The participants were 65.5-82.8 years at the first in-person assessment. Adrenergics/inhalants (effect size = 0.089) and lipid-modifying agents/plain (effect size = 0.082) were associated with higher values of cognitive function (improvement), and selective calcium channel blockers with mainly vascular effects (effect size = -0.129) were associated with lower values of the functional aging index (improvement). No beneficial effects were found on the frailty index. Adrenergics/inhalants, lipid-modifying agents/plain, and selective calcium channel blockers with mainly vascular effects may benefit functional biomarkers of aging. More research is needed to investigate their clinical value in preventing adverse aging outcomes., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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., Competing Interests: The authors have declared that competing interests exist., (Copyright: © 2024 Gresko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations., Methods: We examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter., Results: After adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals., Conclusions: These results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature., (© 2024. The Author(s).)

Obesity and metabolic syndrome (MetS) share common pathophysiological characteristics with aging. To better understand their interplay, we examined how body mass index (BMI) and MetS jointly associate with physiological age, and if the associations changed from midlife to late-life. We used longitudinal data from 1,825 Swedish twins. Physiological age was measured as frailty index (FI) and functional aging index (FAI) and modeled independently in linear mixed-effects models adjusted for chronological age, sex, education, and smoking. We assessed curvilinear associations of BMI and chronological age with physiological age, and interactions between BMI, MetS, and chronological age. We found a significant three-way interaction between BMI, MetS, and chronological age on FI (p-interaction = 0·006), not FAI. Consequently, we stratified FI analyses by age: < 65, 65-85, and ≥ 85 years, and modeled FAI across ages. Except for FI at ages ≥ 85, BMI had U-shaped associations with FI and FAI, where BMI around 26-28 kg/m 2 was associated with the lowest physiological age. MetS was associated with higher FI and FAI, except for FI at ages < 65, and modified the BMI-FI association at ages 65-85 (p-interaction = 0·02), whereby the association between higher BMI levels and FI was stronger in individuals with MetS. Age modified the MetS-FI association in ages ≥ 85, such that it was stronger at higher ages (p-interaction = 0·01). Low BMI, high BMI, and metabolic syndrome were associated with higher physiological age, contributing to overall health status among older individuals and potentially accelerating aging., (© 2023. The Author(s).)

Background: The study explores whether frailty at midlife predicts mortality and levels of biomarkers associated with Alzheimer's disease and related dementias (ADRD) and neurodegeneration by early old age. We also examine the heritability of frailty across this age period., Methods: Participants were 1,286 community-dwelling men from the Vietnam Era Twin Study of Aging at average ages 56, 62 and 68, all without ADRD at baseline. The cumulative deficit frailty index (FI) comprised 37 items assessing multiple physiological systems. Plasma biomarkers at age 68 included beta-amyloid (Aβ40, Aβ42), total tau (t-tau) and neurofilament light chain (NfL)., Results: Being frail doubled the risk of all-cause mortality by age 68 (OR = 2.44). Age 56 FI significantly predicted age 68 NfL (P = 0.014), Aβ40 (P = 0.001) and Aβ42 (P = 0.023), but not t-tau. Age 62 FI predicted all biomarkers at age 68: NfL (P = 0.023), Aβ40 (P = 0.002), Aβ42 (P = 0.001) and t-tau (P = 0.001). Age 68 FI scores were associated with age 68 levels of NfL (P = 0.027), Aβ40 (P < 0.001), Aβ42 (P = 0.001) and t-tau (P = 0.003). Genetic influences accounted for 45-48% of the variance in frailty and significantly contributed to its stability across 11 years., Conclusions: Frailty during one's 50s doubled the risk of mortality by age 68. A mechanism linking frailty and ADRD may be through its associations with biomarkers related to neurodegeneration. Cumulative deficit frailty increases with age but remains moderately heritable across the age range studied. With environmental factors accounting for about half of its variance, early interventions aimed at reducing frailty may help to reduce risk for ADRD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Childhood disadvantage is a prominent risk factor for cognitive and brain aging. Childhood disadvantage is associated with poorer episodic memory in late midlife and functional and structural brain abnormalities in the default mode network (DMN). Although age-related changes in DMN are associated with episodic memory declines in older adults, it remains unclear if childhood disadvantage has an enduring impact on this later-life brain-cognition relationship earlier in the aging process. Here, within the DMN, we examined whether its cortical microstructural integrity-an early marker of structural vulnerability that increases the risk for future cognitive decline and neurodegeneration-is associated with episodic memory in adults at ages 56-66, and whether childhood disadvantage moderates this association., Methods: Cortical mean diffusivity (MD) obtained from diffusion magnetic resonance imaging was used to measure microstructural integrity in 350 community-dwelling men. We examined both visual and verbal episodic memory in relation to DMN MD and divided participants into disadvantaged and nondisadvantaged groups based on parental education and occupation., Results: Higher DMN MD was associated with poorer visual memory but not verbal memory (β = -0.11, p = .040 vs β = -0.04, p = .535). This association was moderated by childhood disadvantage and was significant only in the disadvantaged group (β = -0.26, p = .002 vs β = -0.00, p = .957)., Conclusions: Lower DMN cortical microstructural integrity may reflect visual memory vulnerability in cognitively normal adults earlier in the aging process. Individuals who experienced childhood disadvantage manifested greater vulnerability to cortical microstructure-related visual memory dysfunction than their nondisadvantaged counterparts who exhibited resilience in the face of low cortical microstructural integrity., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The educational gradient in late-life health is well established. Despite this, there are still ambiguities concerning the role of underlying confounding by genetic influences and gene-environment (GE) interplay. Here, we investigate the role of educational factors (attained and genetic propensities) on health and mortality in late life using genetic propensity for educational attainment (as measured by a genome-wide polygenic score, PGSEdu) and attained education., Methods: By utilizing genetically informative twin data from the Swedish Twin Registry (n = 14,570), we investigated influences of the educational measures, familial confounding as well as the possible presence of passive GE correlation on both objective and subjective indicators of late-life health, that is, the Frailty Index, Multimorbidity, Self-rated health, cardiovascular disease, and all-cause mortality., Results: Using between-within models to adjust for shared familial factors, we found that the relationship between educational level and health and mortality later in life persisted despite controlling for familial confounding. PGSEdu and attained education both uniquely predicted late-life health and mortality, even when mutually adjusted. Between-within models of PGSEdu on the health outcomes in dizygotic twins showed weak evidence for passive GE correlation (prGE) in the education-health relationship., Discussion: Both genetic propensity to education and attained education are (partly) independently associated with health in late life. These results lend further support for a causal education-health relationship but also raise the importance of genetic contributions and GE interplay., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Introduction: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored., Methods: Plasma amyloid beta 40 (Aβ40), Aβ42, the Aβ42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (μ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them., Results: Additive genetics explained 44% to 52% of Aβ42, Aβ40, t-tau, and NfL. The Aβ42/40 ratio was not heritable. Aβ40 and Aβ42 were genetically near identical (r g  = 0.94). Both Aβ40 and Aβ42 were genetically correlated with NfL (r g  = 0.35 to 0.38), but genetically unrelated to t-tau., Discussion: Except for Aβ42/40, plasma biomarkers are heritable. Aβ40 and Aβ42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aβs and t-tau is not consistent with the amyloid cascade hypothesis., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: Frailty is not an end state of aging, but rather represents physiological vulnerability across multiple systems that unfolds across adulthood. However, examinations of frailty at the midlife transition, and how frailty may impact other age-sensitive traits, such as processing speed (PS), remain scarce. Our research aims were to examine frailty and frailty-speed associations before midlife, a ripe developmental period for healthy aging interventions., Methods: Using data from the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (N = 1,215; Mage = 33.23 years; standard deviation = 4.98), we constructed 25-item (FI25) and 30-item (FI30) frailty indices. PS was measured using the Colorado Perceptual Speed task and WAIS-III Digit Symbol (DS) subtest. Multilevel models accounted for clustering among siblings and adjusted for sex, race, ethnicity, adoption status, educational attainment, and age., Results: Reliability of FI measures was apparent from strong intraclass correlations (ICCs) among identical twin siblings, although ICC patterns across all siblings suggested that FI variability may include nonadditive genetic contributions. Higher FI was associated with poorer PS performance but was significant for DS only (BFI25 = -1.17, p = .001, d = -0.12; BFI30 = -1.21, p = .001, d = -0.12). Furthermore, the negative frailty-DS association was moderated by age (BFI25×age = -0.14, p = .042; BFI30×age=-0.19, p = .008) where increasingly worse performance with higher frailty emerged at older ages., Discussion: Frailty is evident before midlife and associated with poorer PS, an association that magnifies with age. These findings help elucidate the interrelationship between indicators of frailty and cognitive performance for adults approaching midlife, an understudied period within life-span development., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Composite scores of magnetic resonance imaging-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed AD signatures, have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared with thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities and whether diffusion- and thickness/volume-based signatures each capture unique AD-related phenotypic or genetic information remains unknown., Methods: Our validated thickness/volume signature, our novel mean diffusivity (MD) signature, and a magnetic resonance imaging-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) (baseline/wave 1: mean age [years] = 56.1, SD = 2.6, range = 51.1-60.2). Subsequent waves occurred at approximately 5.7-year intervals., Results: MD and thickness/volume signatures were highly heritable (56%-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance., Conclusions: Cortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall ( N = 35,204 individuals; 21,792 twin pairs) and prose recall ( N = 3,805 individuals; 2,028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning., Competing Interests: Declaration of Competing Interests: None

Importance: Subjective memory concern has long been considered a state-related indicator of impending cognitive decline or dementia. The possibility that subjective memory concern may itself be a heritable trait is largely ignored, yet such an association would substantially confound its use in clinical or research settings., Objective: To assess the heritability and traitlike dimensions of subjective memory concern and its clinical correlates., Design, Setting, and Participants: This longitudinal twin cohort study was conducted from 1967 to 2019 among male adults with a mean (SD) age of 37.75 (2.52) years to follow-up at mean ages of 56.15 (2.72), 61.50 (2.43), and 67.35 (2.57) years (hereafter, 38, 56, 62, and 67 years, respectively) in the Vietnam Era Twin Study of Aging. The study included a national community-dwelling sample with health, education, and lifestyle characteristics comparable to a general sample of US men in this age cohort. Participants were monozygotic and dizygotic twins randomly recruited from the Vietnam Era Twin Registry. Data were analyzed from May 2021 to December 2022., Main Outcomes and Measures: Measures included subjective memory concern at 4 time points; objective memory, depressive symptoms, and anxiety at the last 3 time points; negative emotionality (trait neuroticism) at age 56 years; polygenic risk scores (PRSs) for neuroticism, depression, and Alzheimer disease; APOE genotype; and parental history of dementia. Primary outcomes were heritability and correlations between subjective memory concern and other measures., Results: The sample included 1555 male adults examined at age 38 years, 520 at age 56 years (due to late introduction of subjective memory concern questions), 1199 at age 62 years, and 1192 at age 67 years. Phenotypically, subjective memory concerns were relatively stable over time. At age 56 years, subjective memory concern had larger correlations with depressive symptoms (r, 0.32; 95% CI, 0.21 to 0.42), anxiety (r, 0.36; 95% CI, 0.18 to 0.51), and neuroticism (r, 0.34; 95% CI, 0.26 to 0.41) than with objective memory (r, -0.24; 95% CI, -0.33 to -0.13). Phenotypic results were similar at ages 62 and 67 years. A best-fitting autoregressive twin model indicated that genetic influences on subjective memory concern accumulated and persisted over time (h2 = 0.26-0.34 from age 38-67 years). At age 56 years, genetic influences for subjective memory concern were moderately correlated with genetic influences for anxiety (r, 0.36; 95% CI, 0.18 to 0.51), negative emotionality (r, 0.51; 95% CI, 0.44-0.57), and depressive symptoms (r, 0.20; 95% CI, 0.10 to 0.29) as well as objective memory (r, -0.22; 95% CI, -0.30 to -0.14). Similar genetic correlations were seen at ages 62 and 67 years. The neuroticism PRS was associated with subjective memory concern at age 38 years (r, 0.10; 95% CI, 0.03. to 0.18) and age 67 years (r, 0.09; 95% CI, 0.01 to 0.16). Subjective memory concern was not associated with any Alzheimer disease risk measures., Conclusions and Relevance: This cohort study found stable genetic influences underlying subjective memory concern dating back to age 38 years. Subjective memory concern had larger correlations with affect-related measures than with memory-related measures. Improving the utility of subjective memory concern as an indicator of impending cognitive decline and dementia may depend on isolating its statelike component from its traitlike component.

Objectives: To evaluate temporal dynamics between loneliness and both objective and subjective health (i.e. functional impairment and self-rated health) in mid- to late-adulthood., Method: We applied bivariate dual-change-score models to longitudinal data from 3 Swedish twin studies ( N  = 1,939) to explore dynamic associations between loneliness and health across 3 age ranges (50-69, 70-81, and 82+ years) to investigate whether associations between loneliness and health change with age due to increasing incidence of chronic health conditions and bereavement., Results: Results showed bidirectional associations between loneliness and both objective and subjective health, with adverse impacts of loneliness observed on subsequent subjective and objective health beginning at age 70. Associations between health and subsequent loneliness were observed after age 82 and varied for subjective and objective health, with subjective health associated with less loneliness and objective health associated with greater loneliness., Conclusions: Our results indicate dynamic associations between loneliness and health with age in mid- to late-adulthood, with earlier impacts of loneliness on health and later impacts of health on loneliness that vary for objective and subjective measures of health. These findings suggest impacts of health on loneliness may arise later in life when worsening health or mobility interfere with social interaction.

Aging is a major risk factor for many chronic diseases. This study aimed to examine the effects of antihypertensive, lipid-lowering, and antidiabetic drugs on biological aging. We included 672 participants and 2746 repeated measurements from the Swedish Adoption/Twin Study of Aging. Self-reported medicine uses were categorized into antidiabetic, antihypertensive, and lipid-lowering drugs. A total of 12 biomarkers for biological aging (BA biomarkers) were included as outcomes. Conditional generalized estimating equations were applied conditioning on individuals to estimate the drug effect on BA biomarker level within the same person when using or not using the drug. Chronological age, body mass index, smoking status, number of multiple medication uses, blood pressure, blood glucose level, and apoB/apoA ratio were adjusted for as covariates in the model. Overall, using antihypertensive drugs was associated with a decrease in one DNA-methylation age (PCGrimAge: beta = - 0.39, 95%CI = - 0.67 to - 0.12). When looking into drug subcategories, calcium channel blockers (CCBs) were associated with a decrease in several DNA-methylation ages (PCHorvathAge beta = - 1.28, 95%CI = - 2.34 to - 0.21; PCSkin&bloodAge beta = - 1.34, 95%CI = - 2.61 to - 0.07; PCPhenoAge beta = - 1.74, 95%CI = - 2.58 to - 0.89; PCGrimAge beta = - 0.57, 95%CI = - 0.96 to - 0.17) and in functional biological ages (functional age index beta = - 2.18, 95%CI = - 3.65 to - 0.71; frailty index beta = - 1.31, 95%CI = - 2.43 to - 0.18). However, the results within other drug subcategories were inconsistent. Calcium channel blockers may decrease biological aging captured by the BA biomarkers measured at epigenetic and functional level. Future studies are warranted to confirm these effects and understand the underlying biological mechanisms., (© 2023. The Author(s).)

Background: Evidence indicates that the adverse health effects of obesity differ between genetically and environmentally influenced obesity. We examined differences in the association between obesity and cardiovascular disease (CVD) between individuals with a genetically predicted low, medium, or high body mass index (BMI)., Methods: We used cohort data from Swedish twins born before 1959 who had BMI measured between the ages of 40-64 years (midlife) or at the age of 65 years or later (late-life), or both, and prospective CVD information from nationwide register linkage through 2016. A polygenic score for BMI (PGS BMI ) was used to define genetically predicted BMI. Individuals missing BMI or covariate data, or diagnosed with CVD at first BMI measure, were excluded, leaving an analysis sample of 17,988 individuals. We applied Cox proportional hazard models to examine the association between BMI category and incident CVD, stratified by the PGS BMI . Co-twin control models were applied to adjust for genetic influences not captured by the PGS BMI ., Findings: Between 1984 and 2010, the 17,988 participants were enrolled in sub-studies of the Swedish Twin Registry. Midlife obesity was associated with a higher risk of CVD across all PGS BMI categories, but the association was stronger with genetically predicted lower BMI (hazard ratio from 1.55 to 2.08 for those with high and low PGS BMI , respectively). Within monozygotic twin pairs, the association did not differ by genetically predicted BMI, indicating genetic confounding not captured by the PGS BMI . Results were similar when obesity was measured in late-life, but suffered from low power., Interpretation: Obesity was associated with CVD regardless of PGS BMI category, but obesity influenced by genetic predisposition (genetically predicted high BMI) was less harmful than obesity influenced by environmental factors (obesity despite genetically predicted low BMI). However, additional genetic factors, not captured by the PGS BMI , still influence the associations., Funding: The Strategic Research Program in Epidemiology at Karolinska Institutet; Loo and Hans Osterman's Foundation; Foundation for Geriatric Diseases at Karolinska Institutet; the Swedish Research Council for Health, Working Life and Welfare; the Swedish Research Council; and the National Institutes of Health., Competing Interests: JJ reports grant funding paid to their institution from the 10.13039/501100004359Swedish Research Council (grant 2018-02077), 10.13039/501100002341Academy of Finland (grant 349335), 10.13039/501100006306Sigrid Jusélius Foundation, 10.13039/100010114Yrjö Jahnsson Foundation, and 10.13039/501100008413Instrumentarium Science Foundation. CAR reports honorarium from the National Institute on Aging and grant funding from the 10.13039/100000002National Institutes of Health (grants NIH 1R01 DA054087, NIH 2R01 AG046938, NIH 2R01 AG050595, NIH 1R01 AG059329, NIH 1RF1 AG058068, NIH 1R01 AG077742, and NIH 1R01 AG053217). IKK reports payments to their institution from the Karolinska Institutet Research Foundation (grant 2022-01718) and Eurolife (mobility grant). IKK also reports payment via a Promising Researcher Award from The Nordic Gerontological Federation. All other authors declare no competing interests., (© 2023 The Author(s).)

Objective: To determine associations of alcohol use with cognitive aging among middle-aged men., Method: 1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003-2007 to 2016-2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1-4 drinks in past 14 days), light (5-14 drinks), moderate (15-28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors., Results: Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by -0.21 SD (95% CI -0.35, -0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, -0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD ; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association., Conclusions: Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

Background: Frailty is a complex, dynamic geriatric condition, but limited evidence has shown how genes and environment may contribute to its longitudinal changes. We sought to investigate sources of individual differences in the longitudinal trajectories of frailty, considering potential selection bias when including a sample of oldest-old twins., Methods: Data were from 2 Swedish twin cohort studies: a younger cohort comprising 1 842 adults aged 29-96 years followed up to 15 waves, and an older cohort comprising 654 adults aged ≥79 years followed up to 5 waves. Frailty was measured using the frailty index (FI). Age-based latent growth curve models were used to examine longitudinal trajectories, and extended to a biometric analysis to decompose variability into genetic and environmental etiologies., Results: A bilinear model with an inflection point at age 75 best described the data, indicating a fourfold to fivefold faster FI increase after 75 years. Twins from the older cohort had significantly higher mean FI at baseline but slower rate of increase afterward. FI level at age 75 was moderately heritable in both men (42%) and women (55%). Genetic influences were relatively stable across age for men and increasing for women, although the most salient amplification in FI variability after age 75 was due to individual-specific environmental influences for both men and women; conclusions were largely consistent when excluding the older cohort., Conclusion: Increased heterogeneity of frailty in late life is mainly attributable to environmental influences, highlighting the importance of targeting environmental risk factors to mitigate frailty in older adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Objective: Alzheimer's disease (AD) is highly heritable, and AD polygenic risk scores (AD-PRSs) have been derived from genome-wide association studies. However, the nature of genetic influences very early in the disease process is still not well known. Here we tested the hypothesis that an AD-PRSs would be associated with changes in episodic memory and executive function across late midlife in men who were cognitively unimpaired at their baseline midlife assessment.., Method: We examined 1168 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively normal (CN) at their first of up to three assessments across 12 years (mean ages 56, 62, and 68). Latent growth models of episodic memory and executive function were based on 6-7 tests/subtests. AD-PRSs were based on Kunkle et al. (Nature Genetics, 51, 414-430, 2019), p  < 5×10 -8 threshold., Results: AD-PRSs were correlated with linear slopes of change for both cognitive abilities. Men with higher AD-PRSs had steeper declines in both memory ( r  = -.19, 95% CI [-.35, -.03]) and executive functioning ( r  = -.27, 95% CI [-.49, -.05]). Associations appeared driven by a combination of APOE and non- APOE genetic influences., Conclusions: Memory is most characteristically impaired in AD, but executive functions are one of the first cognitive abilities to decline in midlife in normal aging. This study is among the first to demonstrate that this early decline also relates to AD genetic influences, even in men CN at baseline.

Background: Blood-based neurofilament light chain (NfL) is a promising biomarker of neurodegeneration across multiple neurodegenerative diseases. However, blood-based NfL is highly associated with renal function in older adults, which leads to the concern that blood-based NfL levels may be influenced by renal function, rather than neurodegeneration alone. Despite growing interest in using blood-based NfL as a biomarker of neurodegeneration in research and clinical practices, whether renal function should always be accounted for in these settings remains unclear. Moreover, the mechanisms underlying this association between blood-based measures of NfL and renal function remain elusive. In this study, we first evaluated the effect of renal function on the associations of plasma NfL with other measures of neurodegeneration. We then examined the extent of genetic and environmental contributions to the association between plasma NfL and renal function., Methods: In a sample of 393 adults (mean age=75.22 years, range=54-90), we examined the associations of plasma NfL with cerebrospinal fluid (CSF) NfL and brain volumetric measures before and after adjusting for levels of serum creatinine (an index of renal function). In an independent sample of 969 men (mean age=67.57 years, range=61-73) that include monozygotic and dizygotic twin pairs, we replicated the same analyses and leveraged biometrical twin modeling to examine the genetic and environmental influences on the plasma NfL and creatinine association., Results: Plasma NfL's associations with cerebrospinal fluid NfL and brain volumetric measures did not meaningfully change after adjusting for creatinine levels. Both plasma NfL and creatinine were significantly heritable (h 2 =0.54 and 0.60, respectively). Their phenotypic correlation (r=0.38) was moderately explained by shared genetic influences (genetic correlation=0.46) and unique environmental influences (unique environmental correlation=0.27)., Conclusions: Adjusting for renal function is unnecessary when assessing associations between plasma NfL and other measures of neurodegeneration but is necessary if plasma NfL is compared to a cutoff for classifying neurodegeneration-positive versus neurodegeneration-negative individuals. Blood-based measures of NfL and renal function are heritable and share common genetic influences., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

While prior research has demonstrated a relationship between sleep and cognitive performance, how sleep relates to underlying genetic and environmental etiologies contributing to cognitive functioning, regardless of the level of cognitive function, is unclear. The present study assessed whether the importance of genetic and environmental contributions to cognition vary depending on an individual's aging-related sleep characteristics. The large sample consisted of twins from six studies within the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium spanning mid- to late-life (Average age [Mage] = 57.6, range = 27-91 years, N = 7052, Female = 43.70%, 1525 complete monozygotic [MZ] pairs, 2001 complete dizygotic [DZ] pairs). Quantitative genetic twin models considered sleep duration as a primary moderator of genetic and environmental contributions to cognitive performance in four cognitive abilities (Semantic Fluency, Spatial-Visual Reasoning, Processing Speed, and Episodic Memory), while accounting for age moderation. Results suggested genetic and both shared and nonshared environmental contributions for Semantic Fluency and genetic and shared environmental contributions for Episodic Memory vary by sleep duration, while no significant moderation was observed for Spatial-Visual Reasoning or Processing Speed. Results for Semantic Fluency and Episodic Memory illustrated patterns of higher genetic influences on cognitive function at shorter sleep durations (i.e. 4 hours) and higher shared environmental contributions to cognitive function at longer sleep durations (i.e. 10 hours). Overall, these findings may align with associations of upregulation of neuroinflammatory processes and ineffective beta-amyloid clearance in short sleep contexts and common reporting of mental fatigue in long sleep contexts, both associated with poorer cognitive functioning., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems., Methods: The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)]., Results: Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60)., Conclusions: A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

The present study examined putative environmental predictors of adolescent substance use, using a prospective adoption design to distinguish between environmental mediation (i.e., parenting influencing adolescent substance use), passive gene-environment correlation (i.e., parental genetic predisposition influencing the association between parenting characteristics and adolescent substance use), and evocative gene-environment correlation (i.e., children's genetic predisposition influencing parenting). Longitudinal data from the Colorado Adoption Project (395 adoptees, 491 nonadoptees, 485 adoptive parents, and 490 biological parents) were examined. Children (48% girls) were assessed at ages 1 to 17 years. Over 90% of the sample were non-Hispanic White. Associations between parenting and adolescent substance use were compared between adoptive and nonadoptive families. Positive, negative, and inconsistent parenting measures in early childhood through adolescence were not consistently associated with adolescent substance use, with only 6% of correlations being statistically significant ( r = -0.152 to .207). However, parent-child relationship quality assessed from childhood to adolescence and orientation to parents assessed during adolescence were significantly, negatively associated with adolescent substance use, with 71% of correlations being statistically significant ( r = -0.88 to -0.11). There was little evidence of sex differences in the associations. Environmental mediation, rather than passive or evocative gene-environment correlation, explained most associations.

Genome-wide association studies (GWAS) have successfully identified common variants associated with BMI. However, the stability of aggregate genetic variation influencing BMI from midlife and beyond is unknown. By analysing 165,717 men and 193,073 women from the UKBiobank, we performed BMI GWAS on six independent five-year age intervals between 40 and 72 years. We then applied genomic structural equation modeling to test competing hypotheses regarding the stability of genetic effects for BMI. LDSR genetic correlations between BMI assessed between ages 40 to 73 were all very high and ranged 0.89 to 1.00. Genomic structural equation modeling revealed that molecular genetic variance in BMI at each age interval could not be explained by the accumulation of any age-specific genetic influences or autoregressive processes. Instead, a common set of stable genetic influences appears to underpin genome-wide variation in BMI from middle to early old age in men and women alike., Competing Interests: The authors have declared that no competing interests exist.

Much debate has concerned the separability of executive function abilities and intelligence, with some evidence that the 2 constructs are genetically indistinguishable in children and adolescents but phenotypically and genetically distinct in older adolescents and adults. The current study leveraged data from twin and adoption studies to examine executive function's genetic structure in adulthood ( M = 33.15 years, SD = 4.96) and its overlap with intelligence. 1,238 individuals (170 MZ twin pairs, 154 DZ twin pairs, 95 biological sibling pairs, 80 adoptive sibling pairs, and 240 unpaired individuals) completed 6 executive function tasks as well as the Weschler Adult Intelligence Scale-III as part of the Colorado Adoption/Twin study of Life span behavioral development and cognitive aging (CATSLife). Results replicated the unity/diversity model of executive function that distinguishes general executive function abilities (Common EF) from abilities specific to working memory updating (Updating-specific) and mental set shifting (Shifting-specific). In the final model, broad-sense heritability was high for Common EF (h² = .72), Updating-specific (h² = 1.0), and Shifting-specific (h² = .60) factors, as well as for full-scale intelligence (h² = .74). Intelligence was phenotypically and genetically correlated with Common EF ( r = .49, broad-sense r g = .44) and Updating-specific ( r = .60, r g = .69) abilities. This study represents the first executive function study to apply the adoption design. Leveraging the combined twin and adoptive design allowed us to estimate both additive and nonadditive genetic effects underlying these associations. These findings highlight the commonality and separability of executive function and intelligence. Common EF abilities are distinct from intelligence in adulthood, with intelligence also strongly associated with Updating-specific abilities. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

We examined whether the often-reported protective association of alcohol with cardiovascular disease (CVD) risk could arise from confounding. Our sample comprised 908 men (56−67 years), free of prevalent CVD. Participants were categorized into 6 groups: never drinkers, former drinkers, and very light (1−4 drinks in past 14 days), light (5−14 drinks), moderate (15−28 drinks), and at-risk (>28 drinks) drinkers. Generalized linear mixed effect models examined the associations of alcohol use with three established CVD risk scores: The Framingham Risk Score (FRS); the atherosclerotic CVD (ASCVD) risk score; and the Metabolic Syndrome (MetS) Severity score, adjusting for group differences in demographics, body size, and health-related behaviors. In separate models we additionally adjusted for several groups of potentially explanatory factors including socioeconomic status, social support, physical and mental health status, childhood factors, and prior history of alcohol misuse. Results showed lower CVD risk among light and moderate alcohol drinkers, relative to very light drinkers, for all CVD risk scores, independent of demographics, body size, and health-related behaviors. Alcohol-CVD risk associations were robust to further adjustment for several groups of potential explanatory factors. Study limitations include the all-male sample with limited racial and ethnic diversity, and the inability to adjust for sugar consumption and for patterns of alcohol consumption. Although this observational study does not address causation, results show that middle-aged men who consume alcohol in moderation have lower CVD risk and better cardiometabolic health than men who consume little or no alcohol, independent of a variety of health, behavioral, psychosocial, and earlier life factors.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects., (© 2022. The Author(s).)

Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimer's Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 51-72 years. Biometrical genetic analyses "twin models" revealed significant and highly correlated estimates of additive genetic heritability ranging from 59 to 75%. Multivariate longitudinal modeling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences., Competing Interests: NAG hold equity in Cassava Sciences, Inc. LKM holds equity in CorTechs Labs, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gillespie, Hatton, Hagler, Dale, Elman, McEvoy, Eyler, Fennema-Notestine, Logue, McKenzie, Puckett, Tu, Whitsel, Xian, Reynolds, Panizzon, Lyons, Neale, Kremen and Franz.)

Background: There is robust evidence that in midlife, higher body mass index (BMI) and metabolic syndrome (MetS), which often co-exist, are associated with increased mortality risk. However, late-life findings are inconclusive, and few studies have examined how metabolic health status (MHS) affects the BMI-mortality association in different age categories. We, therefore, aimed to investigate how mid- and late-life BMI and MHS interact to affect the risk of mortality., Methods: This cohort study included 12,467 participants from the Swedish Twin Registry, with height, weight, and MHS measures from 1958-2008 and mortality data linked through 2020. We applied Cox proportional hazard regression with age as a timescale to examine how BMI categories (normal weight, overweight, obesity) and MHS (identification of MetS determined by presence/absence of hypertension, hyperglycemia, low HDL, hypertriglyceridemia), independently and in interaction, are associated with the risk of all-cause mortality. Models were adjusted for sex, education, smoking, and cardiovascular disease., Results: The midlife group included 6,252 participants with a mean age of 59.6 years (range = 44.9-65.0) and 44.1% women. The late-life group included 6,215 participants with mean age 73.1 years (65.1-95.3) and 46.6% women. In independent effect models, metabolically unhealthy status in midlife increased mortality risks by 31% [hazard ratio 1.31; 95% confidence interval 1.12-1.53] and in late-life, by 18% (1.18;1.10-1.26) relative to metabolically healthy individuals. Midlife obesity increased the mortality risks by 30% (1.30;1.06-1.60) and late-life obesity by 15% (1.15; 1.04-1.27) relative to normal weight. In joint models, the BMI estimates were attenuated while those of MHS were less affected. Models including BMI-MHS categories revealed that, compared to metabolically healthy normal weight, the metabolically unhealthy obesity group had increased mortality risks by 53% (1.53;1.19-1.96) in midlife, and across all BMI categories in late-life (normal weight 1.12; 1.01-1.25, overweight 1.10;1.01-1.21, obesity 1.31;1.15-1.49). Mortality risk was decreased by 9% (0.91; 0.83-0.99) among those with metabolically healthy overweight in late-life., Conclusions: MHS strongly influenced the BMI-mortality association, such that individuals who were metabolically healthy with overweight or obesity in mid- or late-life did not carry excess risks of mortality. Being metabolically unhealthy had a higher risk of mortality independent of their BMI., (© 2022. The Author(s).)

Background and Aims: Smoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early mid-life would have older than predicted brain age 16-28 years later., Design: Prospective cohort observational study, utilizing smoking pack years data from average age 40 (early mid-life) predicting predicted brain age difference scores (PBAD) at average ages 56, 62 (later mid-life) and 68 years (early old age). Early mid-life alcohol use was also evaluated., Setting: Population-based United States sample., Participants/cases: Participants were male twins of predominantly European ancestry who served in the United States military between 1965 and 1975. Structural magnetic resonance imaging (MRI) began at average age 56. Subsequent study waves included most baseline participants; attrition replacement subjects were added at later waves., Measurements: Self-reported smoking information was used to calculate pack years smoked at ages 40, 56, 62, and 68. MRIs were processed with the Brain-Age Regression Analysis and Computation Utility software (BARACUS) program to create PBAD scores (chronological age-predicted brain age) acquired at average ages 56 (n = 493; 2002-08), 62 (n = 408; 2009-14) and 68 (n = 499; 2016-19)., Findings: In structural equation modeling, age 40 pack years predicted more advanced age 56 PBAD [β = -0.144, P = 0.012, 95% confidence interval (CI) = -0.257, -0.032]. Age 40 pack years did not additionally predict PBAD at later ages. Age 40 alcohol consumption, but not a smoking × alcohol interaction, predicted more advanced PBAD at age 56 (β = -0.166, P = 0.001, 95% CI = -0.261, -0.070) with additional influences at age 62 (β = -0.115, P = 0.005, 95% CI = -0.195, -0.036). Age 40 alcohol did not predict age 68 PBAD. Within-twin-pair analyses suggested some genetic mechanism partially underlying effects of alcohol, but not smoking, on PBAD., Conclusions: Heavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men., (© 2021 Society for the Study of Addiction.)

Objectives: Dispersion in cognitive test performance within a single testing session is proposed as an early marker of poor brain health. Existing research, however, has not investigated factors that may explain individual differences in cognitive dispersion. We investigate the extent to which the Big Five personality traits are associated with cognitive dispersion in older adulthood., Method: To promote transparency and reliability, we applied preregistration and conceptual replication via coordinated analysis. Drawing data from seven longitudinal studies of aging ( N total = 33,581; M age range = 56.4-71.2), cognitive dispersion scores were derived from cognitive test results. Independent linear regression models were fit in each study to examine personality traits as predictors of dispersion scores, adjusting for mean cognitive performance and sociodemographics (age, sex, education). Results from individual studies were synthesized using random effects meta-analyses., Results: Synthesized results revealed that openness was positively associated with cognitive dispersion, 0.028, 95% CI [0.003, 0.054]. There was minimal evidence for associations between cognitive dispersion and the other personality traits in independent analyses or meta-analyses. Mean cognitive scores were negatively associated with cognitive dispersion across the majority of studies, while sociodemographic variables were not consistently associated with cognitive dispersion., Conclusion: Higher levels of openness were associated with greater cognitive dispersion across seven independent samples, indicating that individuals higher in openness had more dispersion across cognitive tests. Further research is needed to investigate mechanisms that may help to explain the link between openness and cognitive dispersion, as well as to identify additional individual factors, beyond personality traits, that may be associated with cognitive dispersion. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The heritability of Alzheimer's disease estimated from twin studies is greater than the heritability derived from genome-based studies, for reasons that remain unclear. We apply both approaches to the same twin sample, considering both Alzheimer's disease polygenic risk scores and heritability from twin models, to provide insight into the role of measured genetic variants and to quantify uncaptured genetic risk. A population-based heritability and polygenic association study of Alzheimer's disease was conducted between 1986 and 2016 and is the first study to incorporate polygenic risk scores into biometrical twin models of Alzheimer's disease. The sample included 1586 twins drawn from the Swedish Twin Registry which were nested within 1137 twin pairs (449 complete pairs and 688 incomplete pairs) with clinically based diagnoses and registry follow-up ( M age  = 85.28, SD   = 7.02; 44% male; 431 cases and 1155 controls). We report contributions of polygenic risk scores at P  , considering a full polygenic risk score (PRS), PRS without the -5 , considering a full polygenic risk score (PRS), PRS without the APOE region (PRS.no.APOE) and PRS.no.APOE plus directly measured APOE alleles. Biometric twin models estimated the contribution of environmental influences and measured (PRS) and unmeasured genes to Alzheimer's disease risk. The full PRS and PRS.no.APOE contributed 10.1 and 2.4% to Alzheimer's disease risk, respectively. When APOE ɛ4 alleles were added to the model with the PRS.no.APOE, the total contribution was 11.4% to Alzheimer's disease risk, where APOE region accounts for much of the measurable genetic contribution to Alzheimer's disease, with a smaller contribution from other measured polygenic influences. Importantly, substantial background genetic influences remain to be understood.APOE region accounts for much of the measurable genetic contribution to Alzheimer's disease, with a smaller contribution from other measured polygenic influences. Importantly, substantial background genetic influences remain to be understood., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

An interaction between socioeconomic status (SES) and the heritability of IQ, such that the heritability of IQ increases with higher SES, has been reported in some US twin studies, although not in others, and has generally been absent in studies outside the US (England, Europe, Australia). Is such an interaction present in US adoption studies? Data from two such studies, the Texas and the Colorado Adoption Projects, were examined, involving 238-469 adopted children given IQ tests at various ages. A mini multi-level analysis was made of the prediction of the IQs by the SES of the rearing home (a composite of parental education and occupation), by the birth mother's intelligence, and by the interaction of the two. Neither study showed any substantial heritability × SES interaction: the effect size estimates in units comparable to twin moderation models were negative (- 0.042 and - 0.004), and the meta-analytic estimate for the combined analysis was - 0.27 (SE = 0.042) with a 95% confidence interval of - 0.109 to 0.054. Thus, while we cannot rule out positive moderation based on our two studies, the joint agreement across these studies, and with the non-US twin studies, warrants attention in further research. SES may not fully capture proximal familial-environmental aspects that moderate child IQ., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging., Competing Interests: Disclosure statement L.K. McEvoy has stock options in CorTechs Laboratories, Inc. A.M. Dale is a founder of and holds equity in CorTechs Laboratories, Inc and serves on its Scientific Advisory Board. He is a member of the Scientific Advisory Board of Human Longevity, Inc and receives funding through research agreements with General Electric Healthcare and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by University of California, San Diego in accordance with conflict of interest policies. The remaining authors disclose no conflicts., (Published by Elsevier Inc.)