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Abnormal tau, a hallmark Alzheimer’s disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations.
We examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation.
For participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains.
Lower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.
To determine associations of alcohol use with cognitive aging among middle-aged men.
1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003–2007 to 2016–2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1–4 drinks in past 14 days), light (5–14 drinks), moderate (15–28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors.
Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by –0.21 SD (95% CI –0.35, –0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, –0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association.
Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.
Alzheimer’s disease (AD) is highly heritable, and AD polygenic risk scores (AD-PRSs) have been derived from genome-wide association studies. However, the nature of genetic influences very early in the disease process is still not well known. Here we tested the hypothesis that an AD-PRSs would be associated with changes in episodic memory and executive function across late midlife in men who were cognitively unimpaired at their baseline midlife assessment..
We examined 1168 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively normal (CN) at their first of up to three assessments across 12 years (mean ages 56, 62, and 68). Latent growth models of episodic memory and executive function were based on 6–7 tests/subtests. AD-PRSs were based on Kunkle et al. (Nature Genetics, 51, 414–430, 2019), p < 5×10−8 threshold.
AD-PRSs were correlated with linear slopes of change for both cognitive abilities. Men with higher AD-PRSs had steeper declines in both memory (r = −.19, 95% CI [−.35, −.03]) and executive functioning (r = −.27, 95% CI [−.49, −.05]). Associations appeared driven by a combination of APOE and non-APOE genetic influences.
Memory is most characteristically impaired in AD, but executive functions are one of the first cognitive abilities to decline in midlife in normal aging. This study is among the first to demonstrate that this early decline also relates to AD genetic influences, even in men CN at baseline.
Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.
The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse (‘baseline’) and the longitudinal Vietnam Era Twin Study of Aging (‘follow-up’). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)].
Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07–1.57), erectile dysfunction (OR 1.32, 95% CI 1.10–1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04–1.53), and sleep apnea (OR 1.40, 95% CI 1.13–1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09–1.60).
A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.
Heavy alcohol consumption is associated with poorer cognitive function in older adults. Although understudied in middle-aged adults, the relationship between alcohol and cognition may also be influenced by genetics such as the apolipoprotein (ApoE) ε4 allele, a risk factor for Alzheimer’s disease. We examined the relationship between alcohol consumption, ApoE genotype, and cognition in middle-aged adults and hypothesized that light and/or moderate drinkers (≤2 drinks per day) would show better cognitive performance than heavy drinkers or non-drinkers. Additionally, we hypothesized that the association between alcohol use and cognitive function would differ by ApoE genotype (ε4+ vs. ε4−).
Participants were 1266 men from the Vietnam Era Twin Study of Aging (VETSA; M age = 56; range 51–60) who completed a neuropsychological battery assessing seven cognitive abilities: general cognitive ability (GCA), episodic memory, processing speed, executive function, abstract reasoning, verbal fluency, and visuospatial ability. Alcohol consumption was categorized into five groups: never, former, light, moderate, and heavy.
In fully adjusted models, there was no significant main effect of alcohol consumption on cognitive functions. However, there was a significant interaction between alcohol consumption and ApoE ε4 status for GCA and episodic memory, such that the relationship of alcohol consumption and cognition was stronger in ε4 carriers. The ε4+ heavy drinking subgroup had the poorest GCA and episodic memory.
Presence of the ε4 allele may increase vulnerability to the deleterious effects of heavy alcohol consumption. Beneficial effects of light or moderate alcohol consumption were not observed.
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.
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.
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).
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.
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 impact of dementia-related stressors and strains have been examined for their potential to threaten the well-being of either the person with dementia or the family care partner, but rarely have studies considered the dyadic nature of well-being in dementia. The purpose of this study was to examine the dyadic effects of multiple dimensions of strain on the well-being of dementia care dyads.
Using multilevel modeling to account for the inter-relatedness of individual well-being within dementia care dyads, we examined cross-sectional responses collected from 42 dyads comprised of a hospitalized patient diagnosed with a primary progressive dementia (PWD) and their family care partner (CP). Both PWDs and CPs self-reported on their own well-being using measures of quality of life (QOL-Alzheimer’s Disease scale) and depressive symptoms (Center for Epidemiological Studies Depression Scale).
In adjusted models, the PWD’s well-being (higher QOL and lower depressive symptoms) was associated with significantly less strain in the dyad’s relationship. The CP’s well-being was associated with significantly less care-related strain and (for QOL scale) less relationship strain.
Understanding the impact of dementia on the well-being of PWDs or CPs may require an assessment of both members of the dementia care dyad in order to gain a complete picture of how dementia-related stressors and strains impact individual well-being. These results underscore the need to assess and manage dementia-related strain as a multi-dimensional construct that may include strain related to the progression of the disease, strain from providing care, and strain on the dyad’s relationship quality.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
The semiconductor industry has seen tremendous progress over the last few decades with continuous reduction in transistor size to improve device performance. Miniaturization of devices has led to changes in the dopants and dielectric layers incorporated. As the gradual shift from two-dimensional metal-oxide semiconductor field-effect transistor to three-dimensional (3D) field-effect transistors (finFETs) occurred, it has become imperative to understand compositional variability with nanoscale spatial resolution. Compositional changes can affect device performance primarily through fluctuations in threshold voltage and channel current density. Traditional techniques such as scanning electron microscope and focused ion beam no longer provide the required resolution to probe the physical structure and chemical composition of individual fins. Hence advanced multimodal characterization approaches are required to better understand electronic devices. Herein, we report the study of 14 nm commercial finFETs using atom probe tomography (APT) and scanning transmission electron microscopy–energy-dispersive X-ray spectroscopy (STEM-EDS). Complimentary compositional maps were obtained using both techniques with analysis of the gate dielectrics and silicon fin. APT additionally provided 3D information and allowed analysis of the distribution of low atomic number dopant elements (e.g., boron), which are elusive when using STEM-EDS.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
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.
The Interplay of Genes and Environment across Multiple Studies (IGEMS) group is a consortium of eight longitudinal twin studies established to explore the nature of social context effects and gene-environment interplay in late-life functioning. The resulting analysis of the combined data from over 17,500 participants aged 25–102 at baseline (including nearly 2,600 monogygotic and 4,300 dizygotic twin pairs and over 1,700 family members) aims to understand why early life adversity, and social factors such as isolation and loneliness, are associated with diverse outcomes including mortality, physical functioning (health, functional ability), and psychological functioning (well-being, cognition), particularly in later life.
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. It comprises a subset of over 1,200 twins from the Vietnam Era Twin Registry. Like many other studies of aging, the VETSA includes many different phenotypes, but there are some key features that distinguish it from most other behavioral genetic aging studies. First, the initial assessment was conducted when all participants were middle-aged. Second, the age range of participants is narrow; all were in their 50s at the time of the initial recruitment. Third, the study includes an extensive and demanding neurocognitive test battery that was designed to provide good coverage of different cognitive abilities and avoid ceiling effects in middle-aged adults. Fourth, young adult cognitive test data (at an average age of 20 years) are available to provide a gauge of cognitive change. 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.