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Background: Internalizing and externalizing psychopathology factors explain much of the covariance among psychiatric conditions, especially at the level of genetic risk. However, few studies have examined internalizing and externalizing factors in middle-aged samples, especially their ability to predict later symptoms across midlife. The goals of the current study were (i) to quantify the genetic and environmental influences on internalizing and externalizing psychopathology in individuals in their early 40s, and (ii) examine the extent to which these genetic and environmental influences predict self-reported measures of internalizing and externalizing symptoms 15-20 years later., Method: 1484 male twins completed diagnostic interviews of psychopathology at mean age 41 and self-reported measures of anxiety, depression, substance use, and related variables at up to two time-points in late middle age (mean ages 56 and 62)., Results: Structural equation modeling of the diagnostic interviews confirmed that internalizing and externalizing factors accounted for most of the genetic variance in individual disorders, with substantial genetic (ra = 0.70) and environmental (re = 0.77) correlations between the factors. Internalizing psychopathology at age 41 was correlated with latent factors capturing anxiety, depression, and/or post-traumatic stress symptoms at ages 56 (r = 0.51) and 62 (r = 0.43). Externalizing psychopathology at age 41 was correlated r = 0.67 with a latent factor capturing aggression, tobacco use, and alcohol use at age 56. Stability of both factors was driven by genetic influences., Conclusions: These findings demonstrate the considerable stability of internalizing and externalizing psychopathology symptoms across middle age, especially their genetic influences. Diagnostic interviews effectively predict self-reported symptoms and behaviors 15-20 years later.

The Vietnam Era Twin Study of Aging (VETSA) is a longitudinal behavioral genetic study with a primary focus on cognitive and brain aging in men, particularly early identification of risk for mild cognitive impairment (MCI) and Alzheimer's disease (AD). It comprises a subset of over 1600 twins from the Vietnam Era Twin Registry. Twins live all over the USA. Assessments began when participants were in their 50s. Follow-ups were conducted every 5-6 years, and wave 3 has been completed as of this writing. The age range of participants is narrow (about 10 years). An extensive neurocognitive test battery has added precision in assessing differences in middle-aged adults, and predicting progression to MCI. Young adult cognitive test data (at an average age of 20 years) provide a means of disentangling aging effects from longstanding differences. Genome wide genotyping and plasma assays of AD biomarkers from waves 1 and 3 were conducted in wave 3. These features make the VETSA ideal for studying the heterogeneity of within-individual trajectories from midlife to old age, and for early detection of risk factors for cognitive decline.

Research on executive functions (EFs) has revealed that individual differences in general EF abilities are highly correlated across the first few decades of life, especially at the level of genetic influences. Our work has also provided evidence for substantial heritability of this Common EF factor in midlife, but it remains unclear whether individual differences in Common EFs continue to show strong stability in middle age. We examined data from 1,464 middle-aged twins from the Vietnam Era Twin Study of Aging, most of whom completed 7 neuropsychological measures of EFs at 2 points in middle age (M ages = 56 and 62). Confirmatory factor analysis indicated that individual differences in Common EF, a latent factor explaining variation in seven neuropsychological EF tasks, were highly correlated across this 6-year period (r = .97), and that the same genetic and environmental influences were operating across this interval (genetic and shared environmental correlations = 1.0, nonshared environment correlation = .95). Similar phenotypic and genetic stability was observed for a Working Memory (WM)-Specific latent factor, which explained additional variance in working memory span tasks not captured by Common EF (r = .98, genetic correlation = 1.0, nonshared environmental correlation = .88). There was a large mean-level performance decline in Common EF (d = -.60) but not WM-Specific (d = -.03). These results suggest that there is substantial decline in Common EF abilities across middle age but that individual differences are almost perfectly stable. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.

Circadian rhythms are associated with the preference for sleep-wake timing, also known as morningness-eveningness (ME). Both circadian rhythms and ME are influenced by genetic factors. Studies show an association between eveningness and depression. This study investigates the heritability of ME and whether ME and depression share common genetic influences. Study participants (n = 1237) were from the Vietnam Era Twin Study of Aging, a longitudinal study of aging with a baseline in midlife. Participants received the Morningness-Eveningness Questionnaire (MEQ) and the Center for Epidemiologic Studies Depression (CES-D) Scale as part of an extensive neurocognitive and psychosocial assessment. MEQ correlations between members of twin pairs were 0.41 (95% CI 0.31-0.49) for monozygotic (MZ) twins and 0.28 for dizygotic (DZ) twins (95% CI 0.19-0.41). CES-D correlations were 0.38 (95% CI 0.28-0.46) for MZ twins and 0.24 (95% CI 0.14-0.36) for DZ twins. Greater eveningness (i.e. lower MEQ scores) was significantly related to more depression symptoms (phenotypic correlation = -0.15 (95% CI -0.21 to -0.09). In the best fitting model, the heritability estimates are 0.42 for the MEQ and 0.37 for the CES-D. A significant genetic correlation of -0.21 indicated that ME and depression share a significant amount of their underlying genetic variance. The genetic covariance between ME and depression accounted for 59.1% of the phenotypic correlation. Of the CES-D sub-scales, Depressed Mood and Interpersonal Difficulties were significantly heritable, while only Well-Being had a significant genetic correlation with ME. ME and depression are both heritable (ME 0.42, depression 0.37) and share common genetic factors, suggesting an overlap in etiology and the relevance of circadian rhythms to depression. Further study of this relationship may help elucidate etiological factors in depression and targets for treatment.

The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Right-left regional cerebral differences are a feature of the human brain linked to functional abilities, aging, and neurodevelopmental and mental disorders. The role of genetic factors in structural asymmetry has been incompletely studied. We analyzed data from 515 individuals (130 monozygotic twin pairs, 97 dizygotic pairs, and 61 unpaired twins) from the Vietnam Era Twin Study of Aging to answer three questions about genetic determinants of brain structural asymmetry: First, does the magnitude of heritability differ for homologous regions in each hemisphere? Despite adequate power to detect regional differences, heritability estimates were not significantly larger in one hemisphere versus the other, except left > right inferior lateral ventricle heritability. Second, do different genetic factors influence left and right hemisphere size in homologous regions? Interhemispheric genetic correlations were high and significant; in only two subcortical regions (pallidum and accumbens) did the estimate statistically differ from 1.0. Thus, there was little evidence for different genetic influences on left and right hemisphere regions. Third, to what extent do genetic factors influence variability in left-right size differences? There was no evidence that variation in asymmetry (i.e., the size difference) of left and right homologous regions was genetically determined, except in pallidum and accumbens. Our findings suggest that genetic factors do not play a significant role in determining individual variation in the degree of regional cortical size asymmetries measured with MRI, although they may do so for volume of some subcortical structures. Despite varying interpretations of existing data, we view the present results as consistent with previous findings.

Understanding the genetics of neuropsychiatric disorders requires an understanding of the genetics of brain structure and function. The Vietnam Era Twin Study of Aging (VETSA) is a longitudinal behavioral genetic study focused on cognitive and brain aging. Here, we describe basic science work carried out within the VETSA MRI study that provides meaningful contributions toward the study of neuropsychiatric disorders. VETSA produced the first comprehensive assessment of the heritability of cortical and subcortical brain structure sizes, all within the same individuals. We showed that neocortical thickness and surface area are largely genetically distinct. With continuous neocortical thickness maps, we demonstrated regional specificity of genetic influences, and that genetic factors did not conform to traditional regions of interest (ROIs). However, there was some evidence for different genetic factors accounting for different types of cortex, and for genetic relationships across cortical regions corresponding to anatomical and functional connectivity and brain maturation patterns. With continuous neocortical surface area maps, we confirmed the anterior-posterior gradient of genetic influences on cortical area patterning demonstrated in animal models. Finally, we used twin methods to create the first map of cortical ROIs based entirely on genetically informative data. We conclude that these genetically based cortical phenotypes may be more appropriate for genetic studies than traditional ROIs based on structure or function. Our results also suggest that cortical volume-the product of thickness and surface area-is a problematic phenotype for genetic studies because two independent sets of genes may be obscured. Examples supporting the validity of these conclusions are provided., (© 2013 Wiley Periodicals, Inc.)

Understanding the genetic and environmental contributions to measures of brain structure such as surface area and cortical thickness is important for a better understanding of the nature of brain-behavior relationships and changes due to development or disease. Continuous spatial maps of genetic influences on these structural features can contribute to our understanding of regional patterns of heritability, since it remains to be seen whether genetic contributions to brain structure respect the boundaries of any traditional parcellation approaches. Using data from magnetic resonance imaging scans collected on a large sample of monozygotic and dizygotic twins in the Vietnam Era Twin Study of Aging, we created maps of the heritability of areal expansion (a vertex-based area measure) and cortical thickness and examined the degree to which these maps were affected by adjustment for total surface area and mean cortical thickness. We also compared the approach of estimating regional heritability based on the average heritability of vertices within the region to the more traditional region-of-interest (ROI)-based approach. The results suggested high heritability across the cortex for areal expansion and, to a slightly lesser degree, for cortical thickness. There was a great deal of genetic overlap between global and regional measures for surface area, so maps of region-specific genetic influences on surface area revealed more modest heritabilities. There was greater inter-regional variability in heritabilities when calculated using the traditional ROI-based approach compared to summarizing vertex-by-vertex heritabilities within regions. Discrepancies between the approaches were greatest in small regions and tended to be larger for surface area than for cortical thickness measures. Implications regarding brain phenotypes for future genetic association studies are discussed.

The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal (WM/GM contrast) has been found to vary as a function of age and Alzheimer's disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environment determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59 years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using FreeSurfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (.50), and lowest in the cingulate cortex (.24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from ?.11 to ?.54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from ?.16 to ?.34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55.8 years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. However, a significant moderating effect of testosterone on the genetic and environmental determinants of hippocampal volume was observed. Genetic influences on hippocampal volume increased substantially as a function of increasing testosterone level, while environmental influences either decreased or remained stable. These findings provide evidence for an apparent gene-by-hormone interaction on hippocampal volume. To the best of our knowledge, this is the first study to demonstrate that the heritability of a brain structure in adults may be modified by an endogenous biological factor., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Animal data demonstrate that the development of distinct cortical areas is influenced by genes that exhibit highly regionalized expression patterns. In this paper, we show genetic patterning of cortical surface area derived from MRI data from 406 adult human twins. We mapped genetic correlations of areal expansion between selected seed regions and all other cortical locations, with the selection of seed points based on results from animal studies. "Marching seeds" and a data-driven, hypothesis-free, fuzzy-clustering approach provided convergent validation. The results reveal strong anterior-to-posterior graded, bilaterally symmetric patterns of regionalization, largely consistent with patterns previously reported in nonhuman mammalian models. Broad similarities in genetic patterning between rodents and humans might suggest a conservation of cortical patterning mechanisms, whereas dissimilarities might reflect the functionalities most essential to each species., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Although episodic memory is often conceptualized as consisting of multiple component processes, there is a lack of understanding as to whether these processes are influenced by the same or different genetic determinants. The aim of the present study was to utilize multivariate twin analyses to elucidate the degree to which learning and delayed recall, two critical measures of episodic memory performance, have common or different genetic and environmental influences., Method: Participants from the Vietnam Era Twin Study of Aging (314 monozygotic twin pairs, 259 dizygotic twin pairs, and 47 unpaired twins) were assessed using the second edition of the California Verbal Learning Test. Mean age at the time of the evaluation was 55.4 years (SD = 2.5)., Results: Model fitting revealed the presence of a higher-order latent factor influencing learning, short- and long-delay free recall, with a heritability of .36. The best-fitting model also indicated specific genetic influences on learning, which accounted for 10% of the overall variance. Given that learning involves the acquisition and retrieval of information, whereas delayed recall involves only retrieval, we conclude that these specific effects are likely to reflect genes that are specific to acquisition processes., Conclusion: These results demonstrate that even in nonclinical populations, it is possible to differentiate component processes in episodic memory. These different genetic influences may have implications for gene association studies, as well as other genetic studies of cognitive aging and disorders of episodic memory such as Alzheimer's disease or mild cognitive impairment., (PsycINFO Database Record (c) 2011 APA, all rights reserved.)

Delayed alternation and object alternation are classic spatial and non-spatial delayed response tasks. We tested 632 middle-aged male veteran twins on variants of these tasks in order to compare test difficulty, measure their inter-correlation, test order effects, and estimate heritabilities (proportion of observed variance due to genetic influences). Non-spatial alternation (NSA), which may involve greater reliance on processing of subgoals, was significantly more difficult than spatial alternation (SA). Despite their similarities, NSA and SA scores were uncorrelated. NSA performance was worse when administered second; there was no SA order effect. NSA scores were modestly heritable (h(2)=.25; 26); SA was not. There was shared genetic variance between NSA scores and general intellectual ability (r(g)=.55; .67), but this also suggests genetic influences specific to NSA. Compared with findings from small, selected control samples, high "failure" rates in this community-based sample raise concerns about interpretation of brain dysfunction in elderly or patient samples., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Little is known about genetic influences on the volume of subcortical brain structures in adult humans, particularly whether there is regional specificity of genetic effects. Understanding patterns of genetic covariation among volumes of subcortical structures may provide insight into the development of individual differences that have consequences for cognitive and emotional behavior and neuropsychiatric disease liability. We measured the volume of 19 subcortical structures (including brain and ventricular regions) in 404 twins (110 monozygotic and 92 dizygotic pairs) from the Vietnam Era Twin Study of Aging and calculated the degree of genetic correlation among these volumes. We then examined the patterns of genetic correlation through hierarchical cluster analysis and by principal components analysis. We found that a model with four genetic factors best fit the data: a Basal Ganglia/Thalamus factor; a Ventricular factor; a Limbic factor; and a Nucleus Accumbens factor. Homologous regions from each hemisphere loaded on the same factors. The observed patterns of genetic correlation suggest the influence of multiple genetic influences. There is a genetic organization among structures which distinguishes between brain and cerebrospinal fluid spaces and between different subcortical regions. Further study is needed to understand this genetic patterning and whether it reflects influences on early development, functionally dependent patterns of growth or pruning, or regionally specific losses due to genes involved in aging, stress response, or disease., (Copyright © 2010 Wiley-Liss, Inc.)

Psychopathic personality is characterized by interpersonal dominance, impulsivity, sensation seeking, poor planning, and aggressiveness. Studies have shown that the Multidimensional Personality Questionnaire (MPQ) can be used to estimate scores on the fearless-dominant (FD) and the impulsive-antisocial (IA) dimensions of the Psychopathic Personality Inventory (PPI), the best validated self-report measure of psychopathic personality traits. Prior behavior genetic studies reported roughly equal genetic and nonshared environmental influences for both FD and IA, which remained stable from adolescence to young adulthood. However, no prior studies address genetic and environmental influences on these dimensions beyond early adulthood. We utilized the classic twin method to examine genetic and environmental influences on variance in FD and IA in a sample of middle-aged male twins. Biometric modeling indicated that the variance in both factors is best explained by additive genetic and nonshared environmental influences. FD showed roughly equal contributions from genetic and environmental factors, whereas IA showed greater contributions from environmental than genetic factors. Additionally, the small phenotypic correlation between FD and IA was explained entirely by nonshared environmental factors.

Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51-59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.

Previous research has demonstrated stability of cognitive ability and marked heritability during adulthood, but questions remain about the extent to which genetic factors account for this stability. We conducted a 35-year longitudinal assessment of general cognitive ability using the Armed Forces Qualification Test administered to 7,232 male twins in early adulthood and readministered to a subset of 1,237 twins during late middle age. The proportion of variance in cognitive functioning explained by genetic factors was .49 in young adulthood and .57 in late middle age. The correlation between the two administrations was .74 with a genetic correlation of 1.0, indicating that the same genetic influences operated at both times. Genetic factors were primarily responsible for stability, and nonshared environmental factors were primarily responsible for change. The genetic factors influencing cognition may change across other eras, but the same genetic influences are operating from early adulthood to late middle age.

Genetic and environmental influences on cognitive components of reading span in 345 middle-aged male twin pairs were examined. Shared variance among word recognition (reading only), digits forward (short-term memory only), and reading span (concurrent reading plus memory) was almost entirely mediated by common genetic influences. Overall heritability was .52 for word recognition, .27 for digits forward, and .51 for reading span. All of the genetic influences on word recognition and digits forward, but only about one-half of the genetic influences on reading span, came from a common latent phenotype. The genetic influences that were specific to reading span were concluded to most likely reflect an executive function component. Implications for genetic studies of aging and prefrontal brain function are discussed., ((PsycINFO Database Record (c) 2007 APA, all rights reserved).)

Attention-deficit hyperactivity disorder (ADHD) is currently recognized as a neurobiological, genetically based disorder in both children and adults. In this article we examine whether, by using a sample of middle-aged male twin veterans, the phenotypic characterization, prevalence, heritability and the longitudinal course of the illness is comparable to results observed in samples of children and adolescents. We evaluated the utility of adult reports of lifetime ADHD symptoms by examining the heritability of retrospectively reported childhood symptoms, using both symptom-based and discrete classification-based approaches, as well as examining the persistence of ADHD symptoms into adulthood for that subsample of individuals who were judged to possibly have ADHD as children. Our results showed prevalence rates that were approximately similar to those observed in other studies, demonstrable familiality, similar item endorsement patterns, a strong genetic association between hyperactive and inattentive subtypes, and a longitudinal decline in symptom severity. We concluded that while assessing ADHD in adult probands may be less accurate than with children or adolescents, since it demonstrates several characteristics in common with other assessment techniques it remains a viable diagnostic and research strategy, even with population samples.

Background: Early alcohol use is associated with abuse and dependence of licit and illicit substances later in life. The role of genetic and environmental factors in this association is not conclusive., Method: In 1992, data on substance use, abuse/dependence and psychiatric disorders were collected from 8169 male twin members of the Vietnam Era Twin Registry. The interview obtained age of onset of regular drinking (one drink/month for 6 or more months). Regression analyses of twin pairs discordant for early alcohol use tested whether the association between early drinking (before age 17) and adult substance use and abuse/dependence remained after controlling for genetic factors, family environment and covariates. Twin models tested for common genetic and/or environmental influences on early drinking and adult alcohol dependence and ever use and abuse/dependence on marijuana and other drugs., Results: Co-twin analyses suggested the association between early regular alcohol use and adult alcohol dependence, marijuana and other drug use, and marijuana and other drug abuse/dependence could not be entirely explained by common genetic and shared family environmental factors. Genetic contributions to early regular drinking were significantly correlated with those on use of marijuana (rA=0.59), use of other drugs (rA=0.64), alcohol dependence (rA=0.54) and abuse/dependence of marijuana and other drugs (rA=0.63 and 0.66). Small but significant unique environmental correlations (rE range 0.11-0.22) indicated that familial factors could not entirely explain the association between early alcohol use and later substance use, abuse and dependence., Conclusions: Early regular drinking is associated with later alcohol dependence and use, abuse/dependence on drugs. The association is not entirely explained by genetic or shared family environmental factors. This suggests unique environmental factors contribute to transitions from early regular alcohol drinking to use, abuse and dependence on alcohol and other substances.

The role of genetic and environmental influences on age of initiation of first sexual relations and engaging in sexual activity with multiple partners (10 or more partners in 1 year) was investigated in male twins (N = 6,744) from the Vietnam Era Twin Registry. Individual differences in both types of sexual behaviors were heritable, but only age of onset of sexual relations was significantly influenced by the environment shared by the twins. There was a moderate negative correlation between age of initiation of sexual relations and the multiple partners variable; initiating sexual relations earlier was associated with a higher probability of having multiple partners. The additive genetic influence on age of initiation also influenced the multiple partners variable. The substantial unique environmental influences on each variable were uncorrelated with each other. The data suggest that the observed association between age of initiation of sexual relations and having multiple partners is due to genetic influences common to both behaviors.

The magnitude of the association between nicotine withdrawal and failed smoking cessation remains uncertain, and the potential genetic contribution to that relationship is unknown. We used a twin design study to test if genetic and environmental risk factors contribute to nicotine withdrawal and failed cessation. We then estimated the magnitude of genetic and environmental risk factors and the associated correlations. Cigarette consumption data were obtained in 1992 from 4,112 (1,806 pairs, 496 singletons) male twin pairs from the Vietnam Era Twin Registry. Participants responded to a telephone administration of the Diagnostic Interview Schedule. Odds ratios were computed for failed smoking cessation as a function of 12 individual nicotine withdrawal symptoms. Genetic model fitting was performed on a sample of 1818 twin pairs, all of whom were lifetime smokers; both twins of the pairs had made at least one quit attempt. After adjustment for cigarette consumption, odds of failed smoking cessation ranged from.87 (95% CI.76-.99) for "increased appetite/weight gain" to 1.85 (95% CI 1.55-2.22) for "depressed." Genetic influences accounted for 54% and 29.7% of the variance in risk for failed smoking cessation and nicotine withdrawal, respectively. The correlation between genetic influences was significant (r=.31, 95% CI.17-.45). The magnitude of the association between failed cessation and nicotine withdrawal varied by symptom. The risk of experiencing nicotine withdrawal after a quit attempt was related partly to genetic vulnerability; lifetime risk for both failed cessation and nicotine withdrawal was related partly to genetic factors that were correlated.

In this longitudinal study we examined the stability of general cognitive ability (GCA), as well as heterogeneity and genetic and environmental influences underlying individual differences in change. We investigated GCA from young adulthood through late midlife in 1,288 Vietnam Era Twin Study of Aging participants at ages ~20, ~56, and ~62 years. The correlations among the 3 occasions ranged from 0.73 to 0.85, reflecting substantial stability. The heritability was significant on each of the 3 occasions and ranged from 0.59 to 0.66. The influence of the shared environment was not significant at any of the ages. The genetic correlations across the 3 occasions ranged from 0.95 to 0.99 and did not differ significantly from 1.0. The nonshared environmental correlations ranged from 0.21 to 0.47. Latent growth curve analysis was applied to characterize trajectories over the 42-year period. Slope was significantly different from 0 and indicated that there was modest change over time. There was a significant genetic influence on initial level of GCA (h[superscript 2] = 0.67), but not change (h[superscript 2] = 0.23). Genetic factors primarily contribute to stability, while change reflects the influence of nonshared environmental influences. There was a significant negative correlation between initial level of GCA and change (r = -0.31). Latent class growth analysis identified 4 trajectories. In general, the 4 groups followed parallel trajectories and were differentiated mainly by differences in AFQT performance level at the time of military induction.

Epidemiological and clinical studies have consistently reported associations between smoking and posttraumatic stress disorder (PTSD). This study analyzed diagnostic interview data on 6,744 members of the Vietnam Era Twin Registry to clarify the PTSD-smoking relation and to examine whether genetic liability for smoking moderated this relation. Preexisting active (unremitted) PTSD increased risk of late-onset daily smoking. Remitted PTSD decreased risk. Active PTSD increased risk of smoking at all levels of genetic liability; the effect was strongest for those with least genetic liability. This suggests PTSD represents a nongenetic pathway to late-onset smoking among individuals who were nonsmokers prior to developing PTSD. If replicated, these results identify PTSD as a risk factor for smoking that should lead to early tobacco control treatment in this population.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

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.

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).

The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T1 -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T1 -weighted images.

Height and general cognitive ability are positively associated, but the underlying mechanisms of this relationship are not well understood. Both height and general cognitive ability are positively associated with brain size. Still, the neural substrate of the height-cognitive ability association is unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to investigate whether the association between height and cognitive ability is mediated by cortical size. In addition to cortical volume, we used genetically, ontogenetically and phylogenetically distinct cortical metrics of total cortical surface area and mean cortical thickness. Height was positively associated with general cognitive ability and total cortical volume and cortical surface area, but not with mean cortical thickness. Mediation models indicated that the well-replicated height-general cognitive ability association is accounted for by individual differences in total cortical volume and cortical surface area (highly heritable metrics related to global brain size), and that the genetic association between cortical surface area and general cognitive ability underlies the phenotypic height-general cognitive ability relationship.

Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD.

Increased mean diffusivity (MD) is hypothesized to reflect tissue degeneration and may provide subtle indicators of neuropathology as well as age-related brain changes in the absence of volumetric differences. Our aim was to determine the degree to which genetic and environmental variation in subcortical MD is distinct from variation in subcortical volume. Data were derived from a sample of 387 male twins (83 MZ twin pairs, 55 DZ twin pairs, and 111 incomplete twin pairs) who were MRI scanned as part of the Vietnam Era Twin Study of Aging. Quantitative estimates of MD and volume for 7 subcortical regions were obtained: thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens. After adjusting for covariates, bivariate twin models were fitted to estimate the size and significance of phenotypic, genotypic, and environmental correlations between MD and volume at each subcortical region. With the exception of the amygdala, familial aggregation in MD was entirely explained by additive genetic factors across all subcortical regions with estimates ranging from 46 to 84%. Based on bivariate twin modeling, variation in subcortical MD appears to be both genetically and environmentally unrelated to individual differences in subcortical volume. Therefore, subcortical MD may be an alternative biomarker of brain morphology for complex traits worthy of future investigation. Hum Brain Mapp 38:2589-2598, 2017. © 2017 Wiley Periodicals, Inc.

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle-aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56-66 years old. Using an atlas-based registration approach to delineate individual white matter tracts, we investigated mean DTI-based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%-80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community-based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026-2036, 2017. © 2017 Wiley Periodicals, Inc.

Magnetic resonance imaging (MRI) has become an important tool in the early detection of age-related and neuropathological brain changes. Recent studies suggest that changes in mean diffusivity (MD) of cortical gray matter derived from diffusion MRI scans may be useful in detecting early effects of Alzheimer's disease (AD), and that these changes may be detected earlier than alterations associated with standard structural MRI measures such as cortical thickness. Thus, due to its potential clinical relevance, we examined the genetic and environmental influences on cortical MD in middle-aged men to provide support for the biological relevance of this measure and to guide future gene association studies. It is not clear whether individual differences in cortical MD reflect neuroanatomical variability similarly detected by other MRI measures, or whether unique features are captured. For instance, variability in cortical MD may reflect morphological variability more commonly measured by cortical thickness. Differences among individuals in cortical MD may also arise from breakdowns in myelinated fibers running through the cortical mantle. Thus, we investigated whether genetic influences on variation in cortical MD are the same or different from those influencing cortical thickness and MD of white matter (WM) subjacent to the cortical ribbon. Univariate twin analyses indicated that cortical MD is heritable in the majority of brain regions; the average of regional heritability estimates ranged from 0.38 in the cingulate cortex to 0.66 in the occipital cortex, consistent with the heritability of other MRI measures of the brain. Trivariate analyses found that, while there was some shared genetic variance between cortical MD and each of the other two measures, this overlap was not complete (i.e., the correlation was statistically different from 1). A significant amount of distinct genetic variance influences inter-individual variability in cortical MD; therefore, this measure could be useful for further investigation in studies of neurodegenerative diseases and gene association studies.

General cognitive ability (GCA) has substantial explanatory power for behavioral and health outcomes, but its cortical substrate is still not fully established. GCA is highly polygenic and research to date strongly suggests that its cortical substrate is highly polyregional. We show in map-based and region-of-interest-based analyses of adult twins that a complex cortical configuration underlies GCA. Having relatively greater surface area in evolutionary and developmentally high-expanded prefrontal, lateral temporal, and inferior parietal regions is positively correlated with GCA, whereas relatively greater surface area in low-expanded occipital, medial temporal, and motor cortices is negatively correlated with GCA. Essentially the opposite pattern holds for relative cortical thickness. The phenotypic positive-to-negative gradients in our cortical-GCA association maps were largely driven by a similar pattern of genetic associations. The patterns are consistent with regional cortical stretching whereby relatively greater surface area is related to relatively thinner cortex in high-expanded regions. Thus, the typical "bigger is better" view does not adequately capture cortical-GCA associations. Rather, cognitive ability is influenced by complex configurations of cortical development patterns that are strongly influenced by genetic factors. Optimal cognitive ability appears to be driven both by the absolute size and the polyregional configuration of the entire cortex rather than by small, circumscribed regions.

Total gray matter volume is associated with general cognitive ability (GCA), an association mediated by genetic factors. It is expectable that total neocortical volume should be similarly associated with GCA. Neocortical volume is the product of thickness and surface area, but global thickness and surface area are unrelated phenotypically and genetically in humans. The nature of the genetic association between GCA and either of these 2 cortical dimensions has not been examined. Humans possess greater cognitive capacity than other species, and surface area increases appear to be the primary driver of the increased size of the human cortex. Thus, we expected neocortical surface area to be more strongly associated with cognition than thickness. Using multivariate genetic analysis in 515 middle-aged twins, we demonstrated that both the phenotypic and genetic associations between neocortical volume and GCA are driven primarily by surface area rather than thickness. Results were generally similar for each of 4 specific cognitive abilities that comprised the GCA measure. Our results suggest that emphasis on neocortical surface area, rather than thickness, could be more fruitful for elucidating neocortical-GCA associations and identifying specific genes underlying those associations.

Chronic cigarette use has been consistently associated with differences in the neuroanatomy of smokers relative to nonsmokers in case-control studies. However, the etiology underlying the relationships between brain structure and cigarette use is unclear. A community-based sample of male twin pairs ages 51-59 (110 monozygotic pairs, 92 dizygotic pairs) was used to determine the extent to which there are common genetic and environmental influences between brain structure and average lifetime cigarette use. Brain structure was measured by high-resolution structural magnetic resonance imaging, from which subcortical volume and cortical volume, thickness and surface area were derived. Bivariate genetic models were fitted between these measures and average lifetime cigarette use measured as cigarette pack-years. Widespread, negative phenotypic correlations were detected between cigarette pack-years and several cortical as well as subcortical structures. Shared genetic and unique environmental factors contributed to the phenotypic correlations shared between cigarette pack-years and subcortical volume as well as cortical volume and surface area. Brain structures involved in many of the correlations were previously reported to play a role in specific aspects of networks of smoking-related behaviors. These results provide evidence for conducting future research on the etiology of smoking-related behaviors using measures of brain morphology.

The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA.

BackgroundIdentifying mild cognitive impairment (MCI) in midlife could improve early identification of Alzheimer's disease (AD). Also, AD is highly heritable, but the heritability of MCI has not been established. We estimated prevalence rates, association with premorbid general cognitive ability (GCA) and heritability for different definitions of neuropsychologically defined MCI in adults in their 50s.MethodWe examined 1126 twins aged 51-59 years when recruited into the Vietnam Era Twin Study of Aging (VETSA). Six neurocognitive domains were assessed using tests designed to avoid ceiling effects. To differentiate MCI from low overall ability, criteria included adjustment for GCA measured at approximately age 20 years.ResultsAs in older adults, prevalence rates varied widely. Among the lower prevalence rates were some definitions of multiple-domain MCI and single-domain amnestic MCI, which may be less likely than other MCI categories to revert to normal on follow-up. Low prevalence rates in middle-aged adults are also more likely to be valid. MCI was also associated with lower premorbid GCA. Heritability estimates for any MCI and amnestic MCI averaged .40-.48.ConclusionsBy testing multiple cognitive domains and avoiding ceiling effects, MCI can be identified before age 60 years. Premorbid GCA is a risk/protective factor, but deficits after adjusting for early adult GCA suggest additional processes leading to declining trajectories. Heritabilities were comparable to AD, suggesting MCI as an appropriate phenotype for genetic association studies. Full validation will require follow-up assessments (currently under way). Community-based studies are important for this early identification because adults of this age are unlikely to present in clinics.

Animal data show that cortical development is initially patterned by genetic gradients largely along three orthogonal axes. We previously reported differences in genetic influences on cortical surface area along an anterior-posterior axis using neuroimaging data of adult human twins. Here, we demonstrate differences in genetic influences on cortical thickness along a dorsal-ventral axis in the same cohort. The phenomenon of orthogonal gradations in cortical organization evident in different structural and functional properties may originate from genetic gradients. Another emerging theme of cortical patterning is that patterns of genetic influences recapitulate the spatial topography of the cortex within hemispheres. The genetic patterning of both cortical thickness and surface area corresponds to cortical functional specializations. Intriguingly, in contrast to broad similarities in genetic patterning, two sets of analyses distinguish cortical thickness and surface area genetically. First, genetic contributions to cortical thickness and surface area are largely distinct; there is very little genetic correlation (i.e., shared genetic influences) between them. Second, organizing principles among genetically defined regions differ between thickness and surface area. Examining the structure of the genetic similarity matrix among clusters revealed that, whereas surface area clusters showed great genetic proximity with clusters from the same lobe, thickness clusters appear to have close genetic relatedness with clusters that have similar maturational timing. The discrepancies are in line with evidence that the two traits follow different mechanisms in neurodevelopment. Our findings highlight the complexity of genetic influences on cortical morphology and provide a glimpse into emerging principles of genetic organization of the cortex.

Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non-genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.

Twin studies generally show great consistency for the heritability of brain structures. Ironically, the lateral ventricles--perhaps the most reliably measured brain regions of interest--are the most inconsistent when it comes to estimating genetic influences on their volume. Heritability estimates in twin studies have ranged from zero to almost 0.80. Here we aggregate heritability estimates from extant twin studies, and we review and reinterpret some of the findings. Based on our revised estimates, we conclude that lateral ventricular volume is indeed heritable. The weighted average heritability of the revised estimates was 0.54. Although accumulated environmental insults might seem most logical as the predominant cause of age-related ventricular expansion, the data strongly suggest that genetic influences on lateral ventricular volume are increasing with age. Genetic influences accounted for 32-35% of the variance in lateral ventricular volume in childhood, but about 75% of the variance in late middle and older age. These conclusions have implications for the basic understanding of the genetic and environmental underpinnings of normative and pathological brain aging.

Although glucocorticoid receptors are highly expressed in the prefrontal cortex, the hippocampus remains the predominant focus in the literature examining relationships between cortisol and brain. We examined phenotypic and genetic associations of cortisol levels with the thickness of prefrontal and anterior cingulate cortex regions, and with hippocampal volume in a sample of 388 middle-aged male twins who were 51-59 years old. Small but significant negative phenotypic associations were found between cortisol levels and the thickness of left dorsolateral (superior frontal gyrus, left rostral middle frontal gyrus) and ventrolateral (pars opercularis, pars triangularis, pars orbitalis) prefrontal regions, and right dorsolateral (superior frontal gyrus) and medial orbital frontal cortex. Most of the associations remained significant after adjusting for general cognitive ability, cardiovascular risk factors, and depression. Bivariate genetic analyses suggested that some of the associations were primarily accounted for by shared genetic influences; that is, some of the genes that tend to result in increased cortisol levels also tend to result in reduced prefrontal cortical thickness. Aging has been associated with reduced efficiency of hypothalamic-pituitary-adrenal function, frontal lobe shrinkage, and increases in health problems, but our present data do not allow us to determine the direction of effects. Moreover, the degree or the direction of the observed associations and the extent of their shared genetic underpinnings may well change as these individuals age. Longitudinal assessments are underway to elucidate the direction of the associations and the genetic underpinnings of longitudinal phenotypes for changes in cortisol and brain morphology.

Cortisol is an indicator of hypothalamic–pituitary–adrenal axis responsivity to stress, but few twin studies have examined the heritability of cortisol concentrations in adults across the diurnal cycle and in different contexts. Saliva samples were provided by 783 middle-aged male twins on one laboratory and two home days as part of the Vietnam Era Twin Study of Aging. Significant cortisol heritability estimates were found for laboratory measures only: awakening (.56); 30 min after awakening (.48); 1000 h (.42); mean output across the day (.43); and mean cortisol awakening response (.64). Twin correlations at home were low. In the laboratory, they were unchanged for fraternal twins, but increased for identical twins. Greater measurement error at home did not appear to account for home-laboratory differences. The results suggest that genetic factors influence cortisol responses to specific environmental stressors. Thus, cortisol levels are correlated in identical twins only when they undergo similar experiences.

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. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is there a heritable, traitlike component of subjective memory concern that would confound its use as a state-related indicator of dementia risk? Findings: This cohort study of 1555 adults who completed at least 1 follow-up assessment found evidence for the heritability of subjective memory concern, which was associated with genetic risk indicators of Alzheimer disease and anxiety and remained relatively stable across 3 decades. Meaning: The findings in this study suggest that assessment of subjective memory concern will need to develop ways to distinguish longstanding memory concerns from concerns that reflect recent memory changes so as to more accurately measure the more relevant statelike component for the improvement of dementia risk evaluation. This cohort study evaluates the heritability of subjective memory concern and its association with certain genetic risk indicators. 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. [ABSTRACT FROM AUTHOR]