A twin analysis to estimate genetic and environmental factors contributing to variation in weighted gene co-expression network module eigengenes.

Multivariate network-based analytic methods such as weighted gene co-expression network analysis are frequently applied to human and animal gene-expression data to estimate the first principal component of a module, or module eigengene (ME). MEs are interpreted as multivariate summaries of correlated gene-expression patterns and network connectivity across genes within a module. As such, they have the potential to elucidate the mechanisms by which molecular genomic variation contributes to individual differences in complex traits. Although increasingly used to test for associations between modules and complex traits, the genetic and environmental etiology of MEs has not been empirically established. It is unclear if, and to what degree, individual differences in blood-derived MEs reflect random variation versus familial aggregation arising from heritable or shared environmental influences. We used biometrical genetic analyses to estimate the contribution of genetic and environmental influences on MEs derived from blood lymphocytes collected on a sample of N = 661 older male twins from the Vietnam Era Twin Study of Aging (VETSA) whose mean age at assessment was 67.7 years (SD = 2.6 years, range = 62-74 years). Of the 26 detected MEs, 14 (56%) had statistically significant additive genetic variation with an average heritability of 44% (SD = 0.08, range = 35%-64%). Despite the relatively small sample size, this demonstration of significant family aggregation including estimates of heritability in 14 of the 26 MEs suggests that blood-based MEs are reliable and merit further exploration in terms of their associations with complex traits and diseases.

Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins.

INTRODUCTION: The amyloid cascade hypothesis predicts that amyloid-beta (Aß) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aß40 and Aß42 and total Tau (t-Tau) plasma biomarkers. METHODS: Plasma Aß40, Aß42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aßs and t-Tau. RESULTS: No clear evidence that Aß40 or Aß42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aß biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSION: Plasma Aß40 or Aß42 do not appear to have a direct causal impact on t-Tau. In contrast, Aß aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

The genetic and environmental etiology of novel frequency-driven regional parcellations of abnormal white matter.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

Comorbidity and sex differences in functional disorders and internalizing disorders.

OBJECTIVE: In the current exploratory study we estimate comorbidity rates between FDs [fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and irritable bowel syndrome (IBS)]-and IDs-[major depressive disorder (MDD) and generalized anxiety disorder (GAD)] by using self-reported diagnostic criteria. METHOD: We analyzed data from 107,849 participants (mean age = 49.3 (SD = 13.0), 58.6% women) of the Lifelines Cohort Study. Lifelines is a prospective population-based cohort study in the northeast of the Netherlands. Current IDs were assessed using the Mini-International Neuropsychiatric Interview. Current FM, ME/CFS, and IBS were assessed according to the 2010 American College of Rheumatology criteria, the 1994 Centers for Disease Control and Prevention criteria and the ROME IV criteria, respectively. We estimated tetrachoric correlations between diagnoses and tested for sex differences. Additionally, we estimated the ratio of observed-to-expected frequency for combinations of diagnoses. RESULTS: FDs and IDs are highly comorbid (odds ratios: 3.2-12.6) with associations stronger among men. Participants with at least three disorders/diagnoses were more prevalent than expected by chance. CONCLUSION: Studies that aim to explain sex differences and the comorbidity of specific combinations of IDs and FDs will be an important contribution to understanding the etiology of these conditions.

Brain reserve in midlife is associated with executive function changes across 12 years.

We examined how brain reserve in midlife, measured by brain-predicted age difference scores (Brain-PADs), predicted executive function concurrently and longitudinally into early old age, and whether these associations were moderated by young adult cognitive reserve or APOE genotype. 508 men in the Vietnam Era Twin Study of Aging (VETSA) completed neuroimaging assessments at mean age 56 and six executive function tasks at mean ages 56, 62, and 68 years. Results indicated that greater brain reserve at age 56 was associated with better concurrent executive function (r=.10, p=.040) and less decline in executive function over 12 years (r=.34, p=.001). These associations were not moderated by cognitive reserve or APOE genotype. Twin analysis suggested associations with executive function slopes were driven by genetic influences. Our findings suggest that greater brain reserve allowed for better cognitive maintenance from middle- to old age, driven by a genetic association. The results are consistent with differential preservation of executive function based on brain reserve that is independent of young adult cognitive reserve or APOE genotype.

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.

Midlife cumulative deficit frailty predicts Alzheimer's disease-related plasma biomarkers in older adults.

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 (Aß40, Aß42), 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), Aß40 (P = 0.001) and Aß42 (P = 0.023), but not t-tau. Age 62 FI predicted all biomarkers at age 68: NfL (P = 0.023), Aß40 (P = 0.002), Aß42 (P = 0.001) and t-tau (P = 0.001). Age 68 FI scores were associated with age 68 levels of NfL (P = 0.027), Aß40 (P < 0.001), Aß42 (P = 0.001) and t-tau (P = 0.003). Genetic influences accounted for 45-48% of the variance in frailty and significantly contributed to its stability across 11 years. CONCLUSIONS: Frailty during one's 50s doubled the risk of mortality by age 68. A mechanism linking frailty and ADRD may be through its associations with biomarkers related to neurodegeneration. Cumulative deficit frailty increases with age but remains moderately heritable across the age range studied. With environmental factors accounting for about half of its variance, early interventions aimed at reducing frailty may help to reduce risk for ADRD.

The 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.

A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Polygenic risk scores and the prediction of onset of mood and psychotic disorders in adolescents and young adults.

AIM: To examine whether polygenic risk scores (PRS) for neuroticism, depression, bipolar disorder and schizophrenia are higher in individuals manifesting trans-diagnostic risk factors for the development of major mental disorders and whether PRS enhance prediction of early onset full-threshold disorders. METHODS: Using data from the Brisbane Longitudinal Twin Study, we examined individual PRS for neuroticism, depression, bipolar disorder and schizophrenia, recorded evidence of subthreshold syndromes and family history of mood and/or psychotic disorders and noted progression to trans-diagnostic clinical caseness (onset of major mental disorders) at follow-up. We undertook multivariate, receiver operating curve and logistic regression analyses that were adjusted for known variables of influence (age, twin status, and so on). RESULTS: Of 1473 eligible participants (female = 866, 59%; mean age 26.3 years), 28% (n = 409) met caseness criteria for a mood and/or psychotic disorder. All PRS were higher in cases versus non-cases but associations with different levels of risk were inconsistent. The prediction of caseness (reported as area under the curve with 95% confidence intervals [CI]) improved from 0.68 (95% CI: 0.65, 0.71) when estimated using clinical risk factors alone up to 0.71 (95% CI: 0.69, 0.73) when PRS were added to the model. Logistic regression identified five variables that optimally classified individuals according to caseness: age, sex, individual risk characteristics, PRS for depression and mental health case status of cotwins or siblings. CONCLUSIONS: The findings need replication. However, this exploratory study suggests that combining PRS with other risk factors has the potential to improve outcome prediction in youth.

Associations of polygenic risk scores for smoking heaviness and lifetime cannabis use with tobacco and cannabis co-use trajectories among African Americans.

BACKGROUND: We aimed to identify distinct trajectories of tobacco, cannabis, and their co-use among African Americans, and to investigate whether these patterns were associated with polygenic risk scores (PRS) for tobacco and cannabis use. METHOD: Participants (N=428 participants; 50.9% male) were initially recruited for an elementary school-based prevention in a Mid-Atlantic city when they were in first grade. From ages 14-26, participants reported on their frequency of tobacco and cannabis use in the past year during annual assessments. DNA was collected from participants at age 21. PRS for smoking heaviness (i.e., cigarettes per day) and lifetime cannabis use were created based on genome-wide association study results derived from Liu et al. (2019) and Pasman et al. (2018), respectively. RESULTS: We identified five distinct trajectories of tobacco and cannabis co-use, including (1) Low Tobacco and Cannabis Use, (2) Adolescent Limited Tobacco and Cannabis Use, (3) Experimental Cannabis, Young Adult Increasing Tobacco, (4) Experimental Tobacco, Young Adult Increasing Cannabis, and (5) High, Chronic Tobacco and Cannabis Use. Compared to the Low Tobacco and Cannabis Use subgroup, individuals in the High, Chronic Tobacco and Cannabis Use subgroup had greater PRS for smoking heaviness, and individuals in the Experimental Cannabis, Young Adult Increasing Tobacco subgroup had higher PRS for lifetime cannabis use. CONCLUSIONS: Polygenic risk for lifetime cannabis use and smoking heaviness is associated with the developmental progression of tobacco and cannabis co-use among African Americans, furthering knowledge on the etiology of co-use in this population.

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.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

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.

Is pre-college interpersonal trauma associated with cannabis use?

OBJECTIVE: To examine the prevalence and correlates of lifetime cannabis use (i.e., experimental [use 1-5 times] and non-experimental [use ≥ 6 times]) in relation to interpersonal trauma (IPT) above and beyond relevant covariates. PARTICIPANTS: A large (n = 9,889) representative sample of college students at an urban university in the southeastern part of the United States. METHODS: Participants were 4 cohorts of first-year college students who completed measures of demographics, cannabis, alcohol, nicotine, and IPT. Associations were estimated using multinomial logistic regressions. RESULTS: The prevalence of lifetime cannabis use was 28.1% and 17.4% for non-experimental and experimental cannabis use, respectively. IPT was significantly associated with experimental and non-experimental cannabis use above and beyond effects of sex, race, cohort, alcohol, and nicotine. CONCLUSIONS: Results show that cannabis use is prevalent among college students and is associated with IPT above and beyond associations with sex, race, and other substance use.

A longitudinal mediational investigation of risk pathways among cannabis use, interpersonal trauma exposure, and trauma-related distress.

OBJECTIVE: College students are at high risk for cannabis use, interpersonal trauma (IPT) exposure, and trauma-related distress (TRD). Two phenotypic etiologic models posited to explain associations between cannabis use and trauma-related phenotypes are the self-medication (trauma/TRD → cannabis use) and high-risk (cannabis use → trauma/TRD) hypotheses. The primary objective of the present study was to investigate direct and indirect associations among cannabis use, IPT exposure, and TRD above and beyond established covariates. METHOD: The current study used data from the first assessment (i.e., baseline survey at Year 1 Fall) and two follow-up assessments (i.e., Year 1 Spring and Year 2 Spring) from an ongoing longitudinal study on college behavioral health. Participants were 4 cohorts of college students (n = 9,889) who completed measures of demographics, substance use, IPT, and TRD. Indirect effects of IPT on cannabis through TRD (i.e., self-medication) and cannabis on TRD through IPT (i.e., high-risk), including tests of covariate effects (e.g., gender, age, race, cohort, alcohol, nicotine), were simultaneously estimated using a longitudinal mediation modeling framework. RESULTS: Results suggest that more IPT exposure increases risk for TRD and subsequent nonexperimental (use 6+ times) cannabis use, and that experimental (use 1-5 times) and nonexperimental cannabis use increases risk for IPT exposure and subsequent TRD. CONCLUSIONS: Both the self-medication and high-risk hypotheses were supported. Findings support a bidirectional causal relationship between cannabis use and trauma-related phenotypes. Additionally, results highlight areas for colleges to intervene among students to help reduce cannabis use and create a safer environment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.