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BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Growing evidence has linked inflammatory processes to cognitive decline and dementia. This work examines whether an epigenetic marker of C-reactive protein (CRP), a common clinical inflammatory biomarker, may mediate the relationship between educational attainment and cognition. We first evaluated whether 53 previously reported CRP-associated DNA methylation sites (CpGs) are associated with CRP, both individually and aggregated into a methylation risk score (MRSCRP), in 3 298 participants from the Health and Retirement Study (HRS, mean age = 69.7 years). Forty-nine CpGs (92%) were associated with the natural logarithm of CRP in HRS after adjusting for age, sex, smoking, BMI, genetic ancestry, and white blood cell counts (p  < .05), and each standard deviation increase in MRSCRP was associated with a 0.38 unit increase in lnCRP (p  = 4.02E-99). In cross-sectional analysis, for each standard deviation increase in MRSCRP, total memory score and total cognitive score decreased, on average, by 0.28 words and 0.43 items, respectively (p  < .001). Further, MRSCRP mediated 6.9% of the relationship between high school education and total memory score in a model adjusting for age, sex, and genetic ancestry (p  < .05); this was attenuated to 2.4% with additional adjustment for marital status, APOE ε4 status, health behaviors, and comorbidities (p  < .05). Thus, CRP-associated methylation may partially mediate the relationship between education and cognition at older ages. Further research is warranted to determine whether DNA methylation at these sites may improve current prediction models for cognitive impairment in older adults. [ABSTRACT FROM AUTHOR]

INTRODUCTION: In observational studies, the association between alcohol consumption and dementia is mixed. METHODS: We performed two‐sample Mendelian randomization (MR) using summary statistics from genome‐wide association studies of weekly alcohol consumption and late‐onset Alzheimer's disease and one‐sample MR in the Health and Retirement Study (HRS), wave 2012. Inverse variance weighted two‐stage regression provided odds ratios of association between alcohol exposure and dementia or cognitively impaired, non‐dementia relative to cognitively normal. RESULTS: Alcohol consumption was not associated with late‐onset Alzheimer's disease using two‐sample MR (odds ratio [OR] = 1.15, 95% confidence interval [CI]: [0.78, 1.72]). In HRS, doubling weekly alcohol consumption was not associated with dementia (African ancestries, n = 1,322, OR = 1.00, 95% CI [0.45, 2.25]; European ancestries, n = 7,160, OR = 1.37, 95% CI [0.53, 3.51]) or cognitively impaired, non‐dementia (African ancestries, n = 1,322, OR = 1.17, 95% CI [0.69, 1.98]; European ancestries, n = 7,160, OR = 0.75, 95% CI [0.47, 1.22]). DISCUSSION: Alcohol consumption was not associated with cognitively impaired, non‐dementia or dementia status. Highlights: Cross‐sectionally in a large, diverse sample, alcohol appears protective for dementia.We apply two‐ and one‐sample Mendelian randomization to test inferred causality.Mendelian randomization approaches show no association with alcohol and dementia.We conclude that alcohol consumption should not be considered protective. [ABSTRACT FROM AUTHOR]

Background and Objectives Spouses with concordant (i.e. similar) drinking behaviors often report better quality marriages and are married longer compared with those who report discordant drinking behaviors. Less is known regarding whether concordant or discordant patterns have implications for health, as couples grow older. The present study examined whether drinking patterns among older couples are associated with mortality over time. Research Design and Methods The Health and Retirement Study (HRS) is a nationally representative sample of individuals and their partners (married/cohabiting) over age 50 in the United States, in which participants completed surveys every 2 years. Participants included 4,656 married/cohabiting different-sex couples (9,312 individuals) who completed at least 3 waves of the HRS from 1996 to 2016. Participants reported whether they drank alcohol at all in the last 3 months, and if so, the average amount they drank per week. Mortality data were from 2016. Results Analyses revealed concordant drinking spouses (both indicated they drank in the last 3 months) survived longer than discordant drinking spouses (1 partner drinks and the other does not) and concordant nondrinking spouses. Analysis of average drinks per week showed a quadratic association with mortality such that light drinking predicted better survival rates among individuals and their partners compared with abstaining and heavy drinking. Further, similar levels of drinking in terms of the amount of drinking were associated with greater survival, particularly among wives. Discussion and Implications This study moves the field forward by showing that survival varies as a function of one's own and one's partner's drinking. [ABSTRACT FROM AUTHOR]

Background and objectives: Elevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia. Methods: In a pooled cross-sectional sample of the Health and Retirement Study (n = 9,923), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24 vs. ≤1.24 mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, other biomarkers, and chronic conditions. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity. Results: Overall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.2; 95% CI: 1.0, 1.5). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 0.7 (95% CI: −0.1, 2.4), the attributable proportion was 0.1 (95% CI: −0.2, 0.4), and the synergy index was 1.1 (95% CI: 0.8, 1.8) in a fully adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: −0, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 8% (95% CI: −5, 22%). Analyses for Hispanic relative to non-white participants suggested moderation by race/ethnicity, but not mediation. Discussion: Elevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White. [ABSTRACT FROM AUTHOR]

The prevalence and severity of many diseases differs by sex, potentially due to sex-specific patterns in DNA methylation. Autosomal sex-specific differences in DNA methylation have been observed in cord blood and placental tissue but are not well studied in saliva or in diverse populations. We sought to characterize sex-specific DNA methylation on autosomal chromosomes in saliva samples from children in the Future of Families and Child Wellbeing Study, a multi-ethnic prospective birth cohort containing an oversampling of Black, Hispanic and low-income families. DNA methylation from saliva samples was analysed on 796 children (50.6% male) at both ages 9 and 15 with DNA methylation measured using the Illumina HumanMethylation 450k array. An epigenome-wide association analysis of the age 9 samples identified 8,430 sex-differentiated autosomal DNA methylation sites (P < 2.4 × 10-7), of which 76.2% had higher DNA methylation in female children. The strongest sex-difference was in the cg26921482 probe, in the AMDHD2 gene, with 30.6% higher DNA methylation in female compared to male children (P < 1 × 10-300). Treating the age 15 samples as an internal replication set, we observed highly consistent results between the ages 9 and 15 measurements, indicating stable and replicable sex-differentiation. Further, we directly compared our results to previously published DNA methylation sex differences in both cord blood and saliva and again found strong consistency. Our findings support widespread and robust sex-differential DNA methylation across age, human tissues, and populations. These findings help inform our understanding of potential biological processes contributing to sex differences in human physiology and disease. [ABSTRACT FROM AUTHOR]

Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7–16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10−8). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10−5). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10−4), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions. [ABSTRACT FROM AUTHOR]

Background: The number of older adults remaining in the workforce is growing, but little is known about how physical and mental work demands jointly affect cognitive health. This study assessed whether self‐rated physical and mental work demands were associated with cognition among older working adults and whether their associations were dependent. Methods: Our cross‐sectional sample consisted of 6,376 working older adults in the 2004 wave of the Health and Retirement Study. Self‐rated work demands were summarized from four questions about frequency of mental or physical demands in the respondent's current job. Cognition was assessed using a subset of the Telephone Interview for Cognitive Status. We used multivariable linear regression to test for associations and additive interaction between physical and mental work demands and cognition, adjusted for age, sex, race, education, and practice effect. Result: Independently, higher physical work demands were associated (P<0.001) with poorer cognition and higher mental work demands were associated (P<0.001) with better cognition. In an interaction analysis, the effect of one work demand measure became more negative as level of the other increased (B for interaction = ‐0.22, 95% CI: ‐0.42, ‐0.02). A one‐point increase in mental work demands was associated with 0.69 (95% CI: 0.40, 0.99) points higher cognition score when physical work demands were lowest. At the highest level of physical work demands, mental work demands were not associated with cognition (0.11, 95% CI: ‐0.28, 0.49). A one‐point increase in physical work demands was not associated with cognition (0.09, 95% CI: ‐0.30, 0.48) when mental work demands were lowest. At the highest level of mental work demands, physical work demands were associated with ‐0.53 (95% CI: ‐0.78, ‐0.29) points lower cognition score. The highest predicted cognition score was for the highest mental and lowest physical work demands. Results were robust to additional adjustment for health and behavior covariates. Conclusion: The associations of self‐rated mental and physical work demand with cognition were dependent. Beneficial cognitive effects of mental work demands may not apply to workers with physically demanding jobs. Future studies should strongly consider examining interactions to capture the range of work demand effects. [ABSTRACT FROM AUTHOR]

This article examines the relationship between social determinants of health (SDOH), inflammation, and postoperative delirium in older adults. The study finds that individual-level SDOH, such as household income and private health insurance, are associated with an increased risk of delirium. However, neighborhood-level SDOH, such as area deprivation, do not show a significant association with delirium. The findings suggest that different biological pathways may be triggered by different levels of SDOH, highlighting the need for further research to better understand the mechanisms underlying the impact of SDOH on delirium. The study emphasizes the importance of identifying interventions to prevent delirium, which can significantly affect the quality of life for older adults. [Extracted from the article]

Major depressive disorder accelerates DNA methylation age, a biological aging marker. Subclinical depressive symptoms are common, but their link to DNA methylation aging in older adults remains unexplored. This study analyzed the cross-sectional relationship between depressive symptoms and accelerated DNA methylation aging, considering gender and race/ethnicity in U.S. adults aged over 50. We used data from 3,882 diverse participants in the 2016 Health and Retirement Study wave, measuring blood DNA methylation age against chronologic age for acceleration. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Multiple linear regression evaluated the association between depressive symptoms and DNA methylation age acceleration, adjusting for sociodemographic factors, blood cell proportions, and health behaviors (physical activity, alcohol use, smoking, and chronic conditions). Gender and race/ethnicity modifications were also tested. Depressive symptoms, measured by continuous CES-D score, high depressive symptoms (CES-D ≥ 4), or any symptoms (CES-D ≥ 1), significantly correlated with increased GrimAge DNA methylation age acceleration (all p ≤ .001) in unadjusted and sociodemographic-adjusted models but were nonsignificant in fully adjusted models. No significant gender or race/ethnicity effect modifications were found in fully adjusted models. Health behaviors significantly influence DNA methylation age acceleration and depressive phenotypes, underscoring the need to understand their roles in assessing psychological factors related to DNA methylation age acceleration. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not., Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts., Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD., Conclusion: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts., (© 2024. The Author(s).)

Background: DNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the link between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity., Objective: Our study aimed to investigate the longitudinal associations between DNA methylation clocks and incident cognitive impairment using a larger sample size encompassing a US nationally representative sample from the Health and Retirement Study., Methods: We measured DNA methylation age acceleration in 2016 by comparing the residuals of DNA methylation clocks, including GrimAge, against chronological age. Cognitive decline was determined by the change in Langa-Weir cognition status from 2016 to 2018. Using multivariable logistic regression, we evaluated the link between DNA methylation age acceleration and cognitive decline, adjusting for cell-type proportions, demographic, and health factors. We also conducted an inverse probability weighting analysis to address potential selection bias from varying loss-to-follow-up rates., Results: The analytic sample (N=2,713) at baseline had an average of 68 years old, and during the two years of follow-up, 12% experienced cognitive decline. Participants who experienced cognitive decline during follow-up had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those who maintained normal cognitive function (mean = -0.8 years, p < 0.001). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive decline during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11)., Conclusion: Our study offers insights into DNA methylation age acceleration associated with cognitive decline, suggesting avenues for improved prevention, diagnosis, and treatment.

Background: Dementia susceptibility likely begins years before symptoms. Early life has not been comprehensively tested for dementia associations., Method: In the US Health and Retirement Study (normal baseline cognition; n=16,509; 2008-2018 waves), 31 exposures before age 16 were retrospectively assessed with ten-year incident cognitive status (dementia, impaired, normal). Using parallel logistic models, each exposure was tested with incident cognition, adjusting for sex, baseline age, follow-up, race/ethnicity, personal/parental education., Result: 14.5% had incident impairment and 5.3% had dementia. Depression was associated with 1.71 (95%CI:1.28,2.26) times higher odds of incident impairment, relative to normal cognition. Headaches/migraines were associated with 1.63 (95%CI:1.18,2.22) times higher odds of incident impairment. Learning problems were associated with 1.75 (95%CI:1.05,2.79) times higher odds of incident impairment. Childhood self-rated health of fair (1.86, 95%CI:1.27,2.64) and poor (3.39, 95%CI:1.91,5.82) were associated with higher incident dementia odds, relative to excellent., Conclusion: Early life factors may be important for impairment or dementia, extending the relevant risk window.

Background: Chronic inflammation and DNA methylation are potential mechanisms in dementia etiology. The linkage between inflammation and DNA methylation age acceleration in shaping dementia risk is understudied. We explored the association of inflammatory cytokines with cognitive impairment and whether DNA methylation age acceleration mediates this relationship., Methods: In a subset of the 2016 wave of the Health and Retirement Study (n=3,346, age>50), we employed logistic regression to estimate the associations between each inflammatory cytokine (interleukin-6 (IL-6), C-reactive protein (CRP), and insulin-like growth factor-1 (IGF-1)), and both Langa-Weir classified cognitive impairment non-dementia and dementia, respectively. We calculated DNA methylation age acceleration residuals by regressing GrimAge on chronologic age. We tested if DNA methylation age acceleration mediated the relationship between systemic inflammation and cognitive impairment, adjusting for sociodemographic, behavioral factors, chronic conditions, and cell type proportions., Results: The prevalence of cognitive impairment was 16%. In the fully-adjusted model, participants with a doubling of IL-6 levels had 1.12 (95% CI: 1.02-1.22) times higher odds of cognitive impairment. Similar associations were found for CRP and IGF-1. Participants with a doubling of IL-6 levels had 0.77 (95% CI: 0.64, 0.90) years of GrimAge acceleration. In mediation analyses with each cytokine as predictor separately, 17.7% (95% CI: 7.0%, 50.9%) of the effect of IL-6 on cognitive impairment was mediated through DNA methylation age acceleration. Comparable mediated estimates were found for CRP and IGF-1., Conclusions: Systemic inflammation is associated with cognitive impairment, with suggestive evidence that this relationship is partially mediated through DNA methylation age acceleration.

Cognitive impairment among older adults is a growing public health challenge and environmental chemicals may be modifiable risk factors. A wide array of chemicals has not yet been tested for association with cognition in an environment-wide association framework. In the US National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2011-2014 cross-sectional cycles, cognition was assessed using the Digit Symbol Substitution Test (DSST, scores 0-117) among participants aged 60 years and older. Concentrations of environmental chemicals measured in blood or urine were log 2 transformed and standardized. Chemicals with at least 50% of measures above the lower limit of detection were included (n chemicals =147, n classes =14). We tested for associations between chemical concentrations and cognition using parallel survey-weighted multivariable linear regression models adjusted for age, sex, race/ethnicity, education, smoking status, fish consumption, cycle year, urinary creatinine, and cotinine. Participants with at least one chemical measurement (n=4,982) were mean age 69.8 years, 55.0% female, 78.2% non-Hispanic White, and 77.0% at least high school educated. The mean DSST score was 50.4 (standard deviation (SD)=17.4). In adjusted analyses, 5 of 147 exposures were associated with DSST at p-value<0.01. Notably, a SD increase in log 2 -scaled cotinine concentration was associated with 2.71 points lower DSST score (95% CI -3.69, -1.73). A SD increase in log 2 -scaled urinary tungsten concentration was associated with 1.34 points lower DSST score (95% CI -2.11, -0.56). Exposure to environmental chemicals, particularly heavy metals and tobacco smoke, may be modifiable factors for cognition among older adults.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions., Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress., Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB . Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels., Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD., Competing Interests: Competing interests CYC is an employee of Biogen. NPD has served on scientific advisory boards for BioVie Pharma, Circular Genomics and Sentio Solutions for unrelated work. NRN serves as an unpaid member of the Ilumivu advisory board. SAMR receives support from the Wounded Warrior Project (WWP), Department of Veterans Affairs (VA), National Institute of Health (NIH), McCormick Foundation, Tonix Pharmaceuticals, Woodruff Foundation, and Department of Defense (DOD). Dr. Rauch receives royalties from Oxford University Press and American. KJR serves as a consultant for Acer, Bionomics, and Jazz Pharma; SABs for Sage, Boehringer Ingelheim, and Senseye. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. MBS has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Delix Therapeutics, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. MBS has stock options in Oxeia Biopharmaceuticals and EpiVario. MBS has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). MBS has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. MBS is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America.

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of the racialization process in incident dementia., Methods: In the US Health and Retirement Study (n = 6,908), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic white) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates)., Results: The 6-year cumulative incidence of dementia is 12%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels ( ≥ 75 th percentile or 4.73μg/mL) are associated with 1.26 (95%CI: 0.98, 1.62) times greater risk of incident dementia than low CRP ( < 4.73μg/mL). Decomposition analysis comparing minoritized versus non-Hispanic white participants shows that the mediating effect of CRP accounts for 3% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounts for 14% (95% CI: 1%, 27%) of the disparity. Findings are robust to potential violations of causal mediation assumptions., Conclusions: Minoritized group membership modifies the relationship between systemic inflammation and incident dementia., (© 2024. The Author(s).)

Introduction: In observational studies, the association between alcohol consumption and dementia is mixed., Methods: We performed two-sample Mendelian randomization (MR) using summary statistics from genome-wide association studies of weekly alcohol consumption and late-onset Alzheimer's disease and one-sample MR in the Health and Retirement Study (HRS), wave 2012. Inverse variance weighted two-stage regression provided odds ratios of association between alcohol exposure and dementia or cognitively impaired, non-dementia relative to cognitively normal., Results: Alcohol consumption was not associated with late-onset Alzheimer's disease using two-sample MR (odds ratio [OR] = 1.15, 95% confidence interval [CI]: [0.78, 1.72]). In HRS, doubling weekly alcohol consumption was not associated with dementia (African ancestries, n  = 1,322, OR = 1.00, 95% CI [0.45, 2.25]; European ancestries, n  = 7,160, OR = 1.37, 95% CI [0.53, 3.51]) or cognitively impaired, non-dementia (African ancestries, n  = 1,322, OR = 1.17, 95% CI [0.69, 1.98]; European ancestries, n  = 7,160, OR = 0.75, 95% CI [0.47, 1.22])., Discussion: Alcohol consumption was not associated with cognitively impaired, non-dementia or dementia status., Highlights: Cross-sectionally in a large, diverse sample, alcohol appears protective for dementia.We apply two- and one-sample Mendelian randomization to test inferred causality.Mendelian randomization approaches show no association with alcohol and dementia.We conclude that alcohol consumption should not be considered protective., Competing Interests: The authors declare no conflicts of interest/competing interests in the production of this work. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: Elevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia., Methods: In a pooled cross-sectional sample of the Health and Retirement Study ( n = 9,923), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24 vs. ≤1.24 mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, other biomarkers, and chronic conditions. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity., Results: Overall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.2; 95% CI: 1.0, 1.5). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 0.7 (95% CI: -0.1, 2.4), the attributable proportion was 0.1 (95% CI: -0.2, 0.4), and the synergy index was 1.1 (95% CI: 0.8, 1.8) in a fully adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: -0, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 8% (95% CI: -5, 22%). Analyses for Hispanic relative to non-white participants suggested moderation by race/ethnicity, but not mediation., Discussion: Elevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Higgins Tejera, Ware, Kobayashi, Fu, Hicken, Zawistowski, Mukherjee and Bakulski.)