Associations of plasma neurofilament light chain with cognition and neuroimaging measures in community-dwelling early old age men.

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

Changes in affect longitudinally mediate associations between emotion regulation strategy use and disordered eating.

BACKGROUND: Trait-level emotion regulation (ER) difficulties are associated with eating disorders (EDs) transdiagnostically. However, little research has examined whether within-person fluctuations in ER longitudinally predict ED behaviors in daily life or the mechanisms of ER effects. Investigating daily ER could help us better understand why people experience ED behaviors at a given time. We examined whether day-to-day changes in adaptive (e.g., cognitive reappraisal) and maladaptive (e.g., rumination) ER longitudinally predicted core ED behaviors (binge eating, purging, dieting) and whether changes in affect mediated effects. METHOD: Female participants (N = 688) ages 15-30 from the Michigan State University Twin Registry reported their adaptive and maladaptive ER use, negative affect (NA), positive affect (PA), binge eating, purging, and dieting on 49 consecutive days. Using structural equation modeling, we examined whether within-person fluctuations in ER predicted same- and next-day ED behaviors and whether changes in affect mediated longitudinal ER effects. RESULTS: Greater maladaptive ER predicted increased likelihood of same-day binge eating and next-day binge eating and purging. The association between maladaptive ER and next-day binge eating and purging was mediated by increased next-day NA. In contrast, dieting was more closely related to changes in PA. Adaptive ER did not predict reduced likelihood of any ED behavior. CONCLUSIONS: Maladaptive ER may longitudinally increase risk for binge eating and purging by amplifying NA. Interventions focused on decreasing maladaptive ER and subsequent NA might help disrupt binge eating-purging cycles. Conversely, results add to evidence that PA fluctuations may play a unique role in maintaining restrictive behaviors. PUBLIC SIGNIFICANCE: Little is known about how daily changes in emotion regulation may impact disordered eating. We found that maladaptive emotion regulation (e.g., rumination) was associated with a higher likelihood of binge eating and purging on the next day because it predicted increased next-day negative affect. In contrast, dieting was more closely tied to fluctuations in positive affect. Targeting daily emotion regulation and affective processes may help disrupt cycles of disordered eating.

Using Instrumental Variables to Measure Causation over Time in Cross-Lagged Panel Models.

Cross-lagged panel models (CLPMs) are commonly used to estimate causal influences between two variables with repeated assessments. The lagged effects in a CLPM depend on the time interval between assessments, eventually becoming undetectable at longer intervals. To address this limitation, we incorporate instrumental variables (IVs) into the CLPM with two study waves and two variables. Doing so enables estimation of both the lagged (i.e., "distal") effects and the bidirectional cross-sectional (i.e., "proximal") effects at each wave. The distal effects reflect Granger-causal influences across time, which decay with increasing time intervals. The proximal effects capture causal influences that accrue over time and can help infer causality when the distal effects become undetectable at longer intervals. Significant proximal effects, with a negligible distal effect, would imply that the time interval is too long to estimate a lagged effect at that time interval using the standard CLPM. Through simulations and an empirical application, we demonstrate the impact of time intervals on causal inference in the CLPM and present modeling strategies to detect causal influences regardless of the time interval in a study. Furthermore, to motivate empirical applications of the proposed model, we highlight the utility and limitations of using genetic variables as IVs in large-scale panel studies.

The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

INTRODUCTION: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS: Plasma amyloid beta 40 (Aß40), Aß42, the Aß42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (µ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS: Additive genetics explained 44% to 52% of Aß42, Aß40, t-tau, and NfL. The Aß42/40 ratio was not heritable. Aß40 and Aß42 were genetically near identical (rg  = 0.94). Both Aß40 and Aß42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION: Except for Aß42/40, plasma biomarkers are heritable. Aß40 and Aß42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aßs and t-tau is not consistent with the amyloid cascade hypothesis.

Power, measurement error, and pleiotropy robustness in twin-design extensions to Mendelian Randomization.

Mendelian Randomization (MR) has become an important tool for causal inference in the health sciences. It takes advantage of the random segregation of alleles to control for background confounding factors. In brief, the method works by using genetic variants as instrumental variables, but it depends on the assumption of exclusion restriction, i.e., that the variants affect the outcome exclusively via the exposure variable. Equivalently, the assumption states that there is no horizontal pleiotropy from the variant to the outcome. This assumption is unlikely to hold in nature, so several extensions to MR have been developed to increase its robustness against horizontal pleiotropy, though not eliminating the problem entirely (Sanderson et al. 2022). The Direction of Causation (DoC) model, which affords information from the cross-twin cross-trait correlations to estimate causal paths, was extended with polygenic scores to explicitly model horizontal pleiotropy and a causal path (MR-DoC, Minica et al 2018). MR-DoC was further extended to accommodate bidirectional causation (MR-DoC2 ; Castro-de-Araujo et al. 2023). In the present paper, we compared the power of the DoC model, MR-DoC, and MR-DoC2. We investigated the effect of phenotypic measurement error and the effect of misspecification of unshared (individual-specific) environmental factors on the parameter estimates.

Effects of smoking on genome-wide DNA methylation profiles: A study of discordant and concordant monozygotic twin pairs.

Background: Smoking-associated DNA methylation levels identified through epigenome-wide association studies (EWASs) are generally ascribed to smoking-reactive mechanisms, but the contribution of a shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for. Methods: We exploited a strong within-family design, that is, the discordant monozygotic twin design, to study reactiveness of DNA methylation in blood cells to smoking and reversibility of methylation patterns upon quitting smoking. Illumina HumanMethylation450 BeadChip data were available for 769 monozygotic twin pairs (mean age = 36 years, range = 18-78, 70% female), including pairs discordant or concordant for current or former smoking. Results: In pairs discordant for current smoking, 13 differentially methylated CpGs were found between current smoking twins and their genetically identical co-twin who never smoked. Top sites include multiple CpGs in CACNA1D and GNG12, which encode subunits of a calcium voltage-gated channel and G protein, respectively. These proteins interact with the nicotinic acetylcholine receptor, suggesting that methylation levels at these CpGs might be reactive to nicotine exposure. All 13 CpGs have been previously associated with smoking in unrelated individuals and data from monozygotic pairs discordant for former smoking indicated that methylation patterns are to a large extent reversible upon smoking cessation. We further showed that differences in smoking level exposure for monozygotic twins who are both current smokers but differ in the number of cigarettes they smoke are reflected in their DNA methylation profiles. Conclusions: In conclusion, by analysing data from monozygotic twins, we robustly demonstrate that DNA methylation level in human blood cells is reactive to cigarette smoking. Funding: We acknowledge funding from the National Institute on Drug Abuse grant DA049867, the Netherlands Organization for Scientific Research (NWO): Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, NWO 184.033.111) and the BBRMI-NL-financed BIOS Consortium (NWO 184.021.007), NWO Large Scale infrastructures X-Omics (184.034.019), Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (ZonMw Middelgroot 911-09-032); Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO-Groot 480-15-001/674); the Avera Institute, Sioux Falls (USA), and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995); epigenetic data were generated at the Human Genomics Facility (HuGe-F) at ErasmusMC Rotterdam. Cotinine assaying was sponsored by the Neuroscience Campus Amsterdam. DIB acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635).

The genetic information of people who smoke present distinctive characteristics. In particular, previous research has revealed differences in patterns of DNA methylation, a type of chemical modification that helps cells switch certain genes on or off. However, most of these studies could not establish for sure whether these changes were caused by smoking, predisposed individuals to smoke, or were driven by underlying genetic variation in the DNA sequence itself. To investigate this question, van Dongen et al. examined DNA methylation data from the blood cells of over 700 pairs of identical twins. These individuals share the exact same genetic information, making it possible to better evaluate the impact of lifestyle on DNA modifications. The analyses identified differences in methylation at 13 DNA locations in pairs of twins where one was a current smoker and their sibling had never smoked. Two of the genes code for proteins involved in the response to nicotine, the primary addictive chemical in cigarette smoke. The differences were smaller if one of the twins had stopped smoking, suggesting that quitting can help to reverse some of these changes. These findings confirm that DNA methylation in blood cells is influenced by cigarette smoke, which could help to better understand smoking-associated diseases. They also demonstrate how useful identical twins studies can be to identify methylation changes that are markers of lifestyle.

Environment-by-PGS Interaction in the Classical Twin Design: An Application to Childhood Anxiety and Negative Affect.

One type of genotype-environment interaction occurs when genetic effects on a phenotype are moderated by an environment; or when environmental effects on a phenotype are moderated by genes. Here we outline these types of genotype-environment interaction models, and propose a test of genotype-environment interaction based on the classical twin design, which includes observed genetic variables (polygenic scores: PGSs) that account for part of the genetic variance of the phenotype. We introduce environment-by-PGS interaction and the results of a simulation study to address statistical power and parameter recovery. Next, we apply the model to empirical data on anxiety and negative affect in children. The power to detect environment-by-PGS interaction depends on the heritability of the phenotype, and the strength of the PGS. The simulation results indicate that under realistic conditions of sample size, heritability and strength of the interaction, the environment-by-PGS model is a viable approach to detect genotype-environment interaction. In 7-year-old children, we defined two PGS based on the largest genetic association studies for 2 traits that are genetically correlated to childhood anxiety and negative affect, namely major depression (MDD) and intelligence (IQ). We find that common environmental influences on negative affect are amplified for children with a lower IQ-PGS.

Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

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

A Traitlike Dimension of Subjective Memory Concern Over 30 Years Among Adult Male Twins.

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.

Associations between resting state functional brain connectivity and childhood anhedonia: A reproduction and replication study.

BACKGROUND: Previously, a study using a sample of the Adolescent Brain Cognitive Development (ABCD)® study from the earlier 1.0 release found differences in several resting state functional MRI (rsfMRI) brain connectivity measures associated with children reporting anhedonia. Here, we aim to reproduce, replicate, and extend the previous findings using data from the later ABCD study 4.0 release, which includes a significantly larger sample. METHODS: To reproduce and replicate the previous authors' findings, we analyzed data from the ABCD 1.0 release (n = 2437), from an independent subsample from the newer ABCD 4.0 release (excluding individuals from the 1.0 release) (n = 6456), and from the full ABCD 4.0 release sample (n = 8866). Additionally, we assessed whether using a multiple linear regression approach could improve replicability by controlling for the effects of comorbid psychiatric conditions and sociodemographic covariates. RESULTS: While the previously reported associations were reproducible, effect sizes for most rsfMRI measures were drastically reduced in replication analyses (including for both t-tests and multiple linear regressions) using the ABCD 4.0 (excluding 1.0) sample. However, 2 new rsfMRI measures (the Auditory vs. Right Putamen and the Retrosplenial-Temporal vs. Right-Thalamus-Proper measures) exhibited replicable associations with anhedonia and stable, albeit small, effect sizes across the ABCD samples, even after accounting for sociodemographic covariates and comorbid psychiatric conditions using a multiple linear regression approach. CONCLUSION: The most statistically significant associations between anhedonia and rsfMRI connectivity measures found in the ABCD 1.0 sample tended to be non-replicable and inflated. Contrastingly, replicable associations exhibited smaller effects with less statistical significance in the ABCD 1.0 sample. Multiple linear regressions helped assess the specificity of these findings and control the effects of confounding covariates.

Genetic and Cultural Transmission of Alcohol Use Disorder in Swedish Twin Pedigrees.

OBJECTIVE: Using Swedish nationwide registry data, we investigated the contribution of genetic and environmental risk factors to the etiology of alcohol use disorder (AUD) by extended twin pedigree modeling. METHOD: AUD was defined using public inpatient, outpatient, prescription, and criminal records. Three-generational pedigrees were selected for index individuals born between 1980 and 1990, obtained from the national twin and genealogical registers, whose parents were twins. Relatives of the twins included in the pedigrees were their parents, siblings, spouses, and children. Genetic structural equation modeling was applied to the population-based data on AUD, using OpenMx, with age used as a covariate. RESULTS: Analyses including up to 162,469 individuals in 18,971 pedigrees estimated AUD prevalence at 5%-12% in men and 2%-5% in women. Results indicated substantial heritability (about 50%-60%), of which a portion upwards of 5% was attributable to the consequences of assortative mating. Contributions of shared environmental factors to AUD, which represent a mix of within- and cross-generational effects, appeared to be moderate (about 10%-20%). Unique environment accounted for the remaining variance (about 20%-30%). Sex differences in the magnitude of the variance components suggested higher heritability in men and correspondingly higher shared environmental contributions in women. CONCLUSIONS: Using objective registry data, we found that AUD is highly heritable. Furthermore, shared environmental factors contributed significantly to the liability of AUD in both men and women.

A cotwin control study of associations between financial hardship and binge eating phenotypes during COVID-19.

BACKGROUND: COVID-19 was associated with significant financial hardship and increased binge eating (BE). However, it is largely unknown whether financial stressors contributed to BE during the pandemic. We used a longitudinal, cotwin control design that controls for genetic/environmental confounds by comparing twins in the same family to examine whether financial hardship during COVID-19 was associated with BE. METHODS: Female twins (N = 158; Mage  = 22.13) from the Michigan State University Twin Registry rated financial stressors (e.g., inability to afford necessities) daily for 49 consecutive days during COVID-19. We first examined whether financial hardship was associated with BE phenotypes across the full sample. We then examined whether cotwins who differed on financial hardship also differed in BE. RESULTS: Participants who experienced greater mean financial hardship across the study had significantly greater dimensional BE symptoms, and participants who experienced greater financial hardship on a given day reported significantly more emotional eating that day. These results were replicated in cotwin control analyses. Twins who experienced more financial hardship than their cotwin across the study reported greater dimensional BE symptoms than their cotwin, and participants who experienced more financial hardship than their cotwin on a given day reported greater emotional eating that day. Results were identical when restricting analyses to monozygotic twins, suggesting associations were not due to genetic confounds. CONCLUSIONS: Results suggest that BE-related symptoms may be elevated in women who experienced financial hardship during COVID-19 independent of potential genetic/environmental confounds. However, additional research in larger samples is needed. PUBLIC SIGNIFICANCE: Little is known regarding how financial difficulties during the COVID-19 pandemic may have contributed to increased binge eating (BE). We found preliminary evidence that financial hardship during COVID-19 may be associated with greater rates of BE-related symptoms even when comparing twins from the same family. While additional research is needed, results suggest that people who experienced financial hardship during COVID-19 may be at increased risk for BE.

MR-DoC2: Bidirectional Causal Modeling with Instrumental Variables and Data from Relatives.

Establishing causality is an essential step towards developing interventions for psychiatric disorders, substance use and many other conditions. While randomized controlled trials (RCTs) are considered the gold standard for causal inference, they are unethical in many scenarios. Mendelian randomization (MR) can be used in such cases, but importantly both RCTs and MR assume unidirectional causality. In this paper, we developed a new model, MRDoC2, that can be used to identify bidirectional causation in the presence of confounding due to both familial and non-familial sources. Our model extends the MRDoC model (Minica et al. in Behav Genet 48:337-349,  https://doi.org/10.1007/s10519-018-9904-4 , 2018), by simultaneously including risk scores for each trait. Furthermore, the power to detect causal effects in MRDoC2 does not require the phenotypes to have different additive genetic or shared environmental sources of variance, as is the case in the direction of causation twin model (Heath et al. in Behav Genet 23:29-50,  https://doi.org/10.1007/BF01067552 , 1993).

Genetic and Environmental Variation in Continuous Phenotypes in the ABCD Study®.

Twin studies yield valuable insights into the sources of variation, covariation and causation in human traits. The ABCD Study® (abcdstudy.org) was designed to take advantage of four universities known for their twin research, neuroimaging, population-based sampling, and expertise in genetic epidemiology so that representative twin studies could be performed. In this paper we use the twin data to: (i) provide initial estimates of heritability for the wide range of phenotypes assessed in the ABCD Study using a consistent direct variance estimation approach, assuring that both data and methodology are sound; and (ii) provide an online resource for researchers that can serve as a reference point for future behavior genetic studies of this publicly available dataset. Data were analyzed from 772 pairs of twins aged 9-10 years at study inception, with zygosity determined using genotypic data, recruited and assessed at four twin hub sites. The online tool provides twin correlations and both standardized and unstandardized estimates of additive genetic, and environmental variation for 14,500 continuously distributed phenotypic features, including: structural and functional neuroimaging, neurocognition, personality, psychopathology, substance use propensity, physical, and environmental trait variables. The estimates were obtained using an unconstrained variance approach, so they can be incorporated directly into meta-analyses without upwardly biasing aggregate estimates. The results indicated broad consistency with prior literature where available and provided novel estimates for phenotypes without prior twin studies or those assessed at different ages. Effects of site, self-identified race/ethnicity, age and sex were statistically controlled. Results from genetic modeling of all 53,172 continuous variables, including 38,672 functional MRI variables, will be accessible via the user-friendly open-access web interface we have established, and will be updated as new data are released from the ABCD Study. This paper provides an overview of the initial results from the twin study embedded within the ABCD Study, an introduction to the primary research domains in the ABCD study and twin methodology, and an evaluation of the initial findings with a focus on data quality and suitability for future behavior genetic studies using the ABCD dataset. The broad introductory material is provided in recognition of the multidisciplinary appeal of the ABCD Study. While this paper focuses on univariate analyses, we emphasize the opportunities for multivariate, developmental and causal analyses, as well as those evaluating heterogeneity by key moderators such as sex, demographic factors and genetic background.

Genetic and Environmental Influences on Structural and Diffusion-Based Alzheimer's Disease Neuroimaging Signatures Across Midlife and Early Old Age.

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

Alzheimer's Disease Polygenic Scores Predict Changes in Episodic Memory and Executive Function Across 12 Years in Late Middle Age.

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

Alcohol use and cognitive aging in middle-aged men: The Vietnam Era Twin Study of Aging.

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

Association of neurofilament light chain with renal function: mechanisms and clinical implications.

BACKGROUND: Blood-based neurofilament light chain (NfL) is a promising biomarker of neurodegeneration across multiple neurodegenerative diseases. However, blood-based NfL is highly associated with renal function in older adults, which leads to the concern that blood-based NfL levels may be influenced by renal function, rather than neurodegeneration alone. Despite growing interest in using blood-based NfL as a biomarker of neurodegeneration in research and clinical practices, whether renal function should always be accounted for in these settings remains unclear. Moreover, the mechanisms underlying this association between blood-based measures of NfL and renal function remain elusive. In this study, we first evaluated the effect of renal function on the associations of plasma NfL with other measures of neurodegeneration. We then examined the extent of genetic and environmental contributions to the association between plasma NfL and renal function. METHODS: In a sample of 393 adults (mean age=75.22 years, range=54-90), we examined the associations of plasma NfL with cerebrospinal fluid (CSF) NfL and brain volumetric measures before and after adjusting for levels of serum creatinine (an index of renal function). In an independent sample of 969 men (mean age=67.57 years, range=61-73) that include monozygotic and dizygotic twin pairs, we replicated the same analyses and leveraged biometrical twin modeling to examine the genetic and environmental influences on the plasma NfL and creatinine association. RESULTS: Plasma NfL's associations with cerebrospinal fluid NfL and brain volumetric measures did not meaningfully change after adjusting for creatinine levels. Both plasma NfL and creatinine were significantly heritable (h2=0.54 and 0.60, respectively). Their phenotypic correlation (r=0.38) was moderately explained by shared genetic influences (genetic correlation=0.46) and unique environmental influences (unique environmental correlation=0.27). CONCLUSIONS: Adjusting for renal function is unnecessary when assessing associations between plasma NfL and other measures of neurodegeneration but is necessary if plasma NfL is compared to a cutoff for classifying neurodegeneration-positive versus neurodegeneration-negative individuals. Blood-based measures of NfL and renal function are heritable and share common genetic influences.