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BACKGROUND: Increased exposure to ambient air pollution, especially fine particulate matter [less than or equal to]2.5 [micro]m ([PM.sub.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.sub.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.sub.2.5] and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio ([LC.sub.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.sub.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.sub.CNR] in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between [PM.sub.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.sub.2.5] and rostral-middle [LC.sub.CNR] (b = -0.16; p = 0.02), whereby higher exposure to [PM.sub.2.5] was associated with lower [LC.sub.CNR]. A co-twin control analysis found that, within monozygotic pairs, individuals with higher [PM.sub.2.5] exposure showed lower [LC.sub.CNR] (b = - 0.11; p = 0.02), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between [PM.sub.2.5] and caudal [LC.sub.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, Introduction Neuropathological studies indicate that abnormal tau may first appear in the locus coeruleus (LC) starting early in life, (1,2) with substantial accumulation occurring during the course of Alzheimer's disease [...]

ObjectiveTo determine associations of alcohol use with cognitive aging among middle-aged men.Method1,608 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.ResultsPerformance 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.ConclusionsAlcohol 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.

ObjectiveAlzheimer'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..MethodWe 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

BackgroundClarifying 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.MethodsThe 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)].ResultsTotal 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).ConclusionsA 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.

ObjectiveTo investigate the genetic architecture of internalizing symptoms in childhood and adolescence.MethodIn 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.ResultsThe meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.ConclusionGenetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

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.

Background and aimsSmoking 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.DesignProspective 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.SettingPopulation-based United States sample.Participants/casesParticipants 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.MeasurementsSelf-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).FindingsIn 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.ConclusionsHeavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men.

ObjectivesDispersion 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.MethodTo promote transparency and reliability, we applied preregistration and conceptual replication via coordinated analysis. Drawing data from seven longitudinal studies of aging (Ntotal = 33,581; Mage 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.ResultsSynthesized 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.ConclusionHigher 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).

BackgroundBlood-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.MethodsIn 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.ResultsPlasma 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 (h2=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).ConclusionsAdjusting 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.

BackgroundEpidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available.ObjectiveWe apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the twin design of the sample to validate the results.MethodsUsing 10 twin studies, we implement a latent variable approach that aligns different tests available in each study to assess cognitive, memory, and functional ability. The model separates general cognitive ability from components indicative of dementia. We examine the validity of this continuous latent dementia index (LDI). We then identify cut-off points along the LDI distributions in each study and align them across studies to distinguish individuals with and without probable dementia. Finally, we validate the LDI by determining its heritability and estimating genetic and environmental correlations between the LDI and clinically diagnosed dementia where available.ResultsResults indicate that coordinated estimation of LDI across 10 studies has validity against clinically diagnosed dementia. The LDI can be fit to heterogeneous sets of memory, other cognitive, and functional ability variables to extract a score reflective of likelihood of dementia that can be interpreted similarly across studies despite diverse study designs and sampling characteristics. Finally, the same genetic sources of variance strongly contribute to both the LDI and clinical diagnosis.ConclusionThis latent dementia indicator approach may serve as a model for other research consortia confronted with similar data integration challenges.

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.

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.

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.

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer's disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer's disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246-367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51-60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer's disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61-71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer's disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.

IntroductionThe locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.MethodsParticipants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.ResultsHeritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.DiscussionReduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

This study examined the temporal relationship between attitude toward mathematics and mathematics achievement among first-year secondary (i.e. middle) school students (grade 7, about 14-15 years) with a focus on sex differences in Central Uganda. Random-intercept cross-lagged panel models, based on structural equation modeling, were used to analyze data which were collected through students' questionnaires and mathematics tests at three measurement points. The proportion of variance at the class and school level was larger for the achievement measures than for the attitude measures. At these two levels, also the correlation coefficients between the two constructs were higher for boys than for girls. The study found evidence in support of the reciprocal-effects model as the best-fitting structural model within and across both sexes. Between the first and second measurement points, there was evidence for the self-enhancement model (attitude influencing achievement), while between the second and third points, the skill-development model (achievement influencing attitude) was supported.

Despite the relevance of semantic fluency measures to risk for dementia and psychiatric disorders, little is known about their genetic and environmental architecture in mid-to-late life. Participants represent 21,684 middle-aged and older adult twins (M = 60.84 years, SD = 11.21; Range 40-89) from six studies from three countries participating in the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium. All completed the same measure of semantic fluency (naming animals in 60 seconds). Results revealed small-to-moderate phenotypic associations with age and education, with education more strongly and positively associated with fluency performance in females than males. Heritability and environmental influences did not vary by age. Environmental variance was smaller with higher levels of education, but this effect was observed only in males. This is the largest study to examine the genetic and environmental architecture of semantic fluency, and the first to demonstrate that environmental influences vary based on levels of education.

BackgroundAlthough not strongly correlated with current objective cognitive ability, subjective cognitive decline (SCD) is a risk factor for Alzheimer's disease. Most studies focus on SCD in relation to future decline rather than objective prior decline that it purportedly measures.ObjectiveWe evaluated whether self-report of cognitive decline-as a continuous measure-corresponds to objectively-assessed episodic memory and executive function decline across the same period.Methods1,170 men completed the Everyday Cognition Questionnaire (ECog) at mean age 68 assessing subjective changes in cognitive ability relative to 10 years prior. A subset had mild cognitive impairment (MCI), but MCI was diagnosed without regard to subjective decline. Participants completed up to 3 objective assessments of memory and executive function (M = 56, 62, and 68 years). Informant-reported ECogs were completed for 1,045 individuals. Analyses controlled for depression and anxiety symptoms assessed at mean age 68.ResultsParticipant-reported ECog scores were modestly associated with objective decline for memory (β= -0.23, 95%CI [-0.37, -0.10]) and executive function (β= -0.19, 95%CI [-0.33, -0.05]) over the same time period. However, these associations were nonsignificant after excluding MCI cases. Results were similar for informant ratings. Participant-rated ECog scores were more strongly associated with concurrent depression and anxiety symptoms, (β= 0.44, 95%CI [0.36, 0.53]).ConclusionContinuous SCD scores are correlated with prior objective cognitive changes in non-demented individuals, though this association appears driven by individuals with current MCI. However, participants' current depression and anxiety ratings tend to be strongly associated with their SCD ratings. Thus, what primarily drives SCD ratings remains unclear.

Individual differences in music traits are heritable and correlated with the development of cognitive and communication skills, but little is known about whether diverse modes of music engagement (e.g., playing instruments vs. singing) reflect similar underlying genetic/environmental influences. Moreover, the biological etiology underlying the relationship between musicality and childhood language development is poorly understood. Here we explored genetic and environmental associations between music engagement and verbal ability in the Colorado Adoption/Twin Study of Lifespan behavioral development & cognitive aging (CATSLife). Adolescents (N = 1,684) completed measures of music engagement and intelligence at approximately age 12 and/or multiple tests of verbal ability at age 16. Structural equation models revealed that instrument engagement was highly heritable (a[superscript 2] = 0.78), with moderate heritability of singing (a[superscript 2] = 0.43) and dance engagement (a[superscript 2] = 0.66). Adolescent self-reported instrument engagement (but not singing or dance engagement) was genetically correlated with age 12 verbal intelligence and still was associated with age 16 verbal ability, even when controlling for age 12 full-scale intelligence, providing evidence for a longitudinal relationship between music engagement and language beyond shared general cognitive processes. Together, these novel findings suggest that shared genetic influences in part accounts for phenotypic associations between music engagement and language, but there may also be some (weak) direct benefits of music engagement on later language abilities.

ObjectiveTo test the hypothesis that individual differences in episodic memory and verbal fluency in cognitively normal middle-aged adults will predict progression to amnestic mild cognitive impairment (MCI) after 6 years.MethodThe cohort analyzed included 842 male twins who were cognitively normal at baseline (mean 56 years) and completed measures of episodic memory and verbal fluency at baseline and again 6 years later (mean 62 years).ResultsPoor episodic memory predicted progression to both amnestic MCI (odds ratio [OR], 4.42; 95% confidence interval [CI], 2.44-10.60) and nonamnestic MCI (OR, 1.92; 95% CI, 1.32-3.44). Poor semantic verbal fluency also independently predicted progression to amnestic MCI (OR, 1.86; 95% CI, 1.12-3.52). In the full sample, a semantic-specific fluency latent variable at wave 1 (which controls for letter fluency) predicted change in episodic memory at wave 2 (β = 0.13), but not vice versa (β = 0.04). Associations between episodic memory and verbal fluency factors were primarily explained by genetic, rather than environmental, correlations.ConclusionsAmong individuals who were cognitively normal at wave 1, episodic memory moderately to strongly predicted progression to MCI at average age 62, emphasizing the fact that there is still meaningful variability even among cognitively normal individuals. Episodic memory, which is typically a primary focus for Alzheimer disease (AD) risk, declined earlier and more quickly than fluency. However, semantic fluency at average age 56 predicted 6-year change in memory as well as progression to amnestic MCI even after accounting for baseline memory performance. These findings emphasize the utility of memory and fluency measures in early identification of AD risk.

Trauma-exposed adults with high levels of posttraumatic stress symptoms (PTSS) report poorer health-related quality of life (HRQOL), but less is known about the persistence of this relationship over time. Participants from the Vietnam Era Twin Study of Aging reported on PTSS, health, and sociodemographic characteristics at average age 38; 775 participants reported having been exposed to trauma. Later, at average ages 56 and 62, mental and physical HRQOL were assessed with the Short-Form 36. Premorbid risk for anxiety/neuroticism was evaluated with a polygenic risk score derived from a large genome-wide association study meta-analysis. In multivariate mixed models, having higher levels of PTSS, poorer self-rated health, lower income, and less education at age 38 were associated with worse physical and mental HRQOL two decades later. Chronic health problems at age 38 predicted midlife physical but not mental HRQOL. Although genetic risk for neuroticism was correlated with HRQOL and PTSS, it was no longer significant in multivariate models. Health-related quality of life (HRQOL) predicts morbidity and mortality independently of objective health measures; early interventions may help to mitigate the ongoing impact of trauma on quality of life.

This study assessed change in self-reported Big Five personality traits. We conducted a coordinated integrative data analysis using data from 16 longitudinal samples, comprising a total sample of over 60 000 participants. We coordinated models across multiple datasets and fit identical multi-level growth models to assess and compare the extent of trait change over time. Quadratic change was assessed in a subset of samples with four or more measurement occasions. Across studies, the linear trajectory models revealed declines in conscientiousness, extraversion, and openness. Non-linear models suggested late-life increases in neuroticism. Meta-analytic summaries indicated that the fixed effects of personality change are somewhat heterogeneous and that the variability in trait change is partially explained by sample age, country of origin, and personality measurement method. We also found mixed evidence for predictors of change, specifically for sex and baseline age. This study demonstrates the importance of coordinated conceptual replications for accelerating the accumulation of robust and reliable findings in the lifespan developmental psychological sciences.

IntroductionPredicting risk for Alzheimer's disease when most people are likely still biomarker negative would aid earlier identification. We hypothesized that combining multiple memory tests and scores in middle-aged adults would provide useful, and non-invasive, prediction of 6-year progression to MCI.MethodsWe examined 849 men who were cognitively normal at baseline (mean age ± SD = 55.69 ± 2.45).ResultsCalifornia Verbal Learning Test learning trials was the best individual predictor of amnestic MCI (OR = 4.75). A latent factor incorporating seven measures across three memory tests provided much stronger prediction (OR = 9.88). This compared favorably with biomarker-based prediction in a study of much older adults.DiscussionNeuropsychological tests are sensitive and early indicators of MCI risk at an age when few individuals are likely to have yet become biomarker positive. The single best measures may appear time- and cost-effective, but 30 additional minutes of testing and use of multiple scores within tests provide substantially improved prediction.

Objectives: First, we test for differences in various cognitive abilities across trajectories of body mass index (BMI) over the later life course. Second, we examine whether genetic risk factors for unhealthy BMIs-assessed via polygenic risk scores (PRS)-predict cognitive abilities in late-life. Methods: The study used a longitudinal sample of Vietnam veteran males to explore the associations between BMI trajectories, measured across four time points, and later cognitive abilities. The sample of 977 individuals was drawn from the Vietnam Era Twin Study of Aging. Cognitive abilities evaluated included executive function, abstract reasoning, episodic memory, processing speed, verbal fluency, and visual spatial ability. Multilevel linear regression models were used to estimate the associations between BMI trajectories and cognitive abilities. Then, BMI PRS was added to the models to evaluate polygenic associations with cognitive abilities. Results: There were no significant differences in cognitive ability between any of the BMI trajectory groups. There was a significant inverse relationship between BMI-PRS and several cognitive ability measures. Discussion: While no associations emerged for BMI trajectories and cognitive abilities at the phenotypic levels, BMI PRS measures did correlate with key cognitive domains. Our results suggest possible polygenic linkages cutting across key components of the central and peripheral nervous system.

The ε4 allele of APOE is a well-established genetic risk factor for cognitive aging and dementia, but its influence on early life cognition is unknown. Consequently, we assessed associations of APOE genotypes with cognitive performance during 7, 12, and 16 year-assessments in our ongoing Colorado Adoption/Twin Study of Lifespan behavioral development (CATSLife). In general, APOE ε4 was associated with lower Verbal, Performance, and Full Scale IQ scores during childhood and adolescence (e.g., Full Scale IQ was lower by 1.91 points per ε4 allele, d = -0.13), with larger effects in females (e.g., average Full Scale IQ scores were 3.41 points lower in females per each ε4 allele vs. 0.33 points lower in males). Thus, these results suggest that deleterious effects of the APOE ε4 allele are manifested before adulthood, especially in females, and support both early origin theories and differential life-course vulnerabilities for later cognitive impairment.

Understanding genetic influences on Alzheimer's disease (AD) may improve early identification. AD polygenic risk scores (AD-PRSs) are associated with increased odds of AD and mild cognitive impairment (MCI). Additional sources of genetic risk may also contribute to disease outcomes. Coronary artery disease (CAD) is a risk factor for AD, interacts with AD pathology, and is also heritable. We showed that incidence-based and prevalence-based CAD-PRSs moderate the association between the AD-PRS and MCI, but in opposing directions. Higher incidence-based CAD-PRSs interacted with the AD-PRS to further increase MCI risk. Conversely, the AD-PRS was predictive of MCI when prevalence-based CAD-PRSs were low. The latter finding is likely due to prevalent CAD cases being biased toward longer postevent survival times, perhaps selecting for protective loci that offset AD risk. These results demonstrate (1) the importance of examining multiple PRSs and their interactions; (2) how genetic risk for one disease can modify the impact of genetic risk for another; and (3) the importance of considering ascertainment procedures of GWAS used for genetic risk prediction.

Locus coeruleus (LC) tau accumulation begins early. Targeting LC (dys)function might improve early identification for Alzheimer's disease (AD) risk. Pupillary responses during cognitive tasks are driven by the LC and index cognitive effort. Despite equivalent task performance, adults with mild cognitive impairment have greater pupil dilation/effort during digit span than cognitively normal (CN) individuals. We hypothesized that AD polygenic risk scores (AD-PRSs) would be associated with pupillary responses in middle-aged CN adults. Pupillary responses during digit span tasks were heritable (h2 = 0.30-0.36) in 1119 men aged 56-66 years. In a CN subset-all with comparable span capacities (n = 539)-higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit) cognitive load condition (Cohen's d = 0.36 for upper vs. lower quartile of AD-PRS distribution). Results held up after controlling for APOE genotype. Results support pupillary response-and by inference, LC dysfunction-as a genetically mediated biomarker of early mild cognitive impairment/AD risk. In combination with other biomarkers, task-evoked pupillary responses may provide additional information for early screening of genetically at-risk individuals even before cognitive declines.

ObjectiveProcessing Speed (PS) is an important domain in cognitive aging that is characterized by multiple related but nonidentical abilities. Few studies have directly investigated the relationships among PS measures, and none have used genetically informed methods. In this study, we examined the relationship between measures of PS at up to two time points during middle age.MethodWe examined data from 1,262 middle-aged men when the sample was at a mean age of 56 and a mean age 62 years. Participants completed 6 measures of PS from three different cognitive tests. We used a genetically informative, confirmatory factor analytic approach to evaluate the phenotypic and genetic relationships cross-sectionally at both single time points and across time.ResultsA higher-order common PS factor accounted for the covariance among three test-specific factors, and each test-specific factor accounted for the covariance between two observed measures. The general PS factor was explained primarily by genetic influences at both time points (a²age56 = .75, a²age62 = .64), and all test-specific factors were heritable (a² range: .45 to .65). Factor loadings from the test-specific factors to the general PS factor varied from λ = .46 to .82. The model was stable over time, although there were differing rates of phenotypic change among latent factors (.20 SD to .44 SD). Cross-time genetic correlations were near unity for all latent factors.ConclusionThese results suggest that PS is highly heritable when considered at a latent variable level, and that there are different rates of change in tests of PS within this sample. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Longitudinal measurement invariance is a major concern for developmental scholars who seek to evaluate the same underlying construct across time. Unfortunately, discontinuities in the expression of various psychological constructs, as well as essential changes in measurement that are necessitated by shifting developmental capacities and practice effects over time, make the task of establishing longitudinal invariance extremely difficult. Drawing on 5 waves of longitudinal data from 392 families (52% female; Mage_W1 = 12.89, SD = .48; Mage_W5 = 21.95, SD = .77; 199 European American and 193 Mexican American families), the current investigation sought to establish measurement invariance across developmentally appropriate changes in measures of depressive symptomatology from early adolescence through early adulthood. Using a combination of item parceling and the common and unique items from 2 assessment instruments for depressive symptoms, the data supported strong factorial invariance in youth's depressive symptoms across 5 waves of measurement. Findings suggest that traditional invariance approaches can be adapted to determine whether the same construct underlies different measurement instruments across time. This analytic strategy can allow researchers and clinicians to use more sophisticated techniques to understand changes in symptomatology regardless of changes in measurement or developmental capacity. Applying this approach to model patterns of depressive symptomatology from early adolescence to early adulthood has important clinical implications for elucidating periods when youth experience elevations in depressive symptoms and heightened needs for intervention services.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Early identification of younger, non-demented adults at elevated risk for Alzheimer's disease (AD) is crucial because the pathological process begins decades before dementia onset. Toward that end, we showed that an AD polygenic risk score (PRS) could identify mild cognitive impairment (MCI) in adults who were only in their 50s. Participants were 1176 white, non-Hispanic community-dwelling men of European ancestry in the Vietnam Era Twin Study of Aging (VETSA): 7% with amnestic MCI (aMCI); 4% with non-amnestic MCI (naMCI). Mean age was 56 years, with 89%

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56-66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for

Whether awaiting biopsy results, a grade on a midterm, or a decision from a journal editor, people feel distressed as they wait for uncertain news. In the present study, we investigated how people's perceptions of their romantic partner, specifically their partner's responsiveness to their support needs, corresponds with key aspects of the waiting experience. In a longitudinal study of 184 law students awaiting their result on the California bar exam, we examined changes in perceived responsiveness over time and associations between perceived responsiveness and expectation management strategies, health, and well-being. Results revealed temporal patterns in perceived responsiveness, with the greatest responsiveness perceived at the start and end of the wait. Perceived responsiveness was also intertwined with efforts to manage one's expectations while awaiting uncertain news and was associated with more positive emotions, better subjective coping, and greater self-reported sleep quality during the wait. (PsycINFO Database Record