Cognitive performance is central to health and quality of life. Studying the factors that sustain performance may offer insights into maintaining cognitive function into advanced ages and may inform strategies to promote healthy cognitive aging. To identify single nucleotide polymorphisms (SNPs) underlying cognitive function, we performed genome-wide association studies (GWAS) of nine neuropsychological test scores capturing performance in three cognitive domains in 2,455 participants of the Long Life Family Study (LLFS). We identified 12 variants in seven tests and three domains that reached genome-wide significance (p < 5e-8). Three rare (minor allele frequency, European population MAF < 0.01) protective, intronic variants, rs190287985 (CCSER1), rs75730801 (FHOD3), and rs552842447 (LINC00508), were uniquely associated with semantic fluency, phonemic fluency and number span forward, respectively. Two rare deleterious variants, rs556333682 and rs188304645, were associated with performance on the Hopkins Verbal Learning Test-Revised (HVLT-R) learning trials and lie in ischemia-related genes SH3TC1 and RPH3A. Another variant, rs180691759, associated with HVLT-R delayed recall, was proximal to RSPO3 and linked to decreased ECHDC1 expression, implicating ischemic and unexplained Ethylmalonic acid (EMA) pathways. We compared the results with GWASs of a general cognitive factor (GCF) and reaction time (RT) in the UK Biobank and meta-analysis results of the UK Biobank, CHARGE and COGENT by Davies et al. We found that rs535509651 associates with HVLT-R delayed recall in the LLFS and nominally associates (p < 0.05) with GCF, and that rs10424537 associates with Immediate Logical Memory in the LLFS and nominally associates with RT. Furthermore, we identified 5 genome-wide significant loci in Davies et al. that reached loci adjusted significance in the LLFS (GCF p < 0.05/128 and RT p < 0.05/39). Each locus was associated with a single cognitive domain in the LLFS. We annotated the genome-wide significant results with quantitative trait loci (QTL) analyses of whole blood transcriptomic, serum metabolomic data, and gene set enrichment analyses (GSEA) using all nominally significant transcripts (p < 0.05/12). QTL analyses discovered 1 SNP-transcript (ECHDC1, p < 3e-6), no SNP-lipid (p < 2e-4), and no SNP-polar metabolite (p < 2 x 10-4) associations. Gene set enrichment analyses identified three pathways at FDR < 0.05. Our findings provide insight into the domain-specific genetic architecture of cognitive function. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, NIA cooperative agreement, U19-AG063893, UH2/UH3-AG064704

OBJECTIVE:Alcohol use plays a role in college sexual assaults. Given that more restrictive state alcohol policy environments have been associated with less binge drinking we tested whether these environments were associated with reduced risk of sexual assault victimization in college students. METHOD:Repeated cross-sectional National College Health Assessment surveys of 876,326 students (ages 18-24) from 2008-2019 were linked to time-varying, state-level Alcohol Policy Scale (APS) scores indexing the efficacy and implementation of 29 policies. Students reported five past-year sexual victimization experiences, formed into a binary composite, as well as 2-week binge drinking. RESULTS:Binge drinking was associated with significantly higher odds of sexual assault (OR = 2.22, p<0.0001 for the composite measure). In states with higher APS scores (more restrictive) students had lower odds of experiencing unwanted sexual touching [OR = .93 for women; OR = .81 (stronger) for men, p<.0001] and men had lower odds of experiencing attempted non-consensual penetration (OR = .81, p<.0001). CONCLUSIONS:State alcohol policies that reduce the prevalence of binge drinking may play a role in preventing some forms of sexual assault. Findings are consistent with the importance of multi-level (state-, community-, campus-level) and multi-target (e.g., alcohol misuse, bystander training) prevention approaches.

OBJECTIVES:Depression is a risk factor for cannabis use, an association that may change as state cannabis policies evolve. The present study uses individual-level data on college students and a continuous measure of state cannabis policy restrictiveness to examine this question. METHODS:Undergraduates (n = 902,486) ages 18-24 years from 591 four-year institutions in 47 states completed a cross-sectional survey between 2008 and 2019, including items assessing significant 30-day depressive symptoms, 12-month depression diagnosis or treatment, and 30-day cannabis use and frequent (20 + days) use. Time-varying, state-level cannabis policy restrictiveness was measured with the Cannabis Policy Scale (CPS). RESULTS:From 2008-2019 prevalence increased for 30-day depressive symptoms (15.3-26.7%) and frequent cannabis use (3.3-5.2%). Depression measures were associated with cannabis use outcomes [odds ratios (OR) ranged from 1.54 to 2.13, p < 0.0001]. Effects were modestly but significantly weaker in less restrictive than in more restrictive state cannabis policy environments. For example, depressive symptoms were less associated with increased odds of 30-day cannabis use in the least restrictive states [OR (95% CI) = 1.47 (1.42-1.52), p < 0.0001] than in the most restrictive states [OR (95% CI) = 1.57 (1.54-1.59), p < 0.0001; interaction p = 0.0017]. There was no evidence that depression prevalence was higher among students exposed to less restrictive cannabis policies. CONCLUSIONS:Depression and frequent cannabis use co-occurred across restrictive and liberal state cannabis policy environments, and both conditions increased in prevalence across the study period. Depression was a somewhat weaker risk factor for cannabis use when and where cannabis was more legal and accessible.

INTRODUCTION:Cannabis policies differ between states that have legalized cannabis use and within states over time after legalization milestones. A continuous measure of state cannabis policy environments was examined in relation to college students' cannabis and alcohol use, accounting for concurrent state alcohol policies. METHODS:Undergraduates (N=902,486) aged 18-24 years from 591 four-year institutions in 47 states completed a cross-sectional survey between 2008 and 2019. Time-varying, state-level Cannabis Policy Scale and Alcohol Policy Scale scores were sums of 17 and 29 policies, respectively, weighted by efficacy and state-level implementation. Outcomes were any 30-day use and frequent use (≥20 days) of cannabis and alcohol, 2-week binge drinking (≥5 drinks in a sitting), and co-use (binge drinking and frequent cannabis use). Data were analyzed in 2024-2025. RESULTS:Higher Cannabis Policy Scale scores (greater restrictiveness) were associated with significantly lower odds of cannabis use, frequent cannabis use, and co-use (OR=0.97 [0.96-0.98]; 0.93 [0.91-0.94]; and 0.94 [0.92-0.96], respectively) but not significantly associated with alcohol use outcomes. Higher Alcohol Policy Scale scores were significantly associated with lower odds of every cannabis, alcohol, and co-use outcome. Cannabis Policy Scale and Alcohol Policy Scale effects generally were significant for underage students (aged 18-20 years) but stronger for older students (aged 21-24 years). CONCLUSIONS:Under less restrictive state cannabis and alcohol policy regimes, college students were more apt to use cannabis and alcohol frequently and concurrently. To improve students' well-being, campus- and community-level policymakers can build on strong state policy environments or compensate for weak ones, using Alcohol Policy Scale and Cannabis Policy Scale as tools to identify these needs.

INTRODUCTION:State-level alcohol policies reduce excessive drinking and related harms in the general population, but their effectiveness may vary by policy type and age group. This study examined the associations that mutually exclusive policy subgroups of the Alcohol Policy Scale had with alcohol use and alcohol-related negative consequences among U.S. college students. METHODS:Data were from repeated cross-sectional surveys of 902,486 college students aged 18-24 years from 591 four-year institutions in 47 states during 2008-2019. Outcomes were past 2-week binge drinking, 30-day frequent alcohol use, 30-day driving after drinking, 12-month use of designated drivers, and a series of 12-month negative consequences after drinking. Three sets of mutually exclusive Alcohol Policy Scale policy subgroups were used to evaluate their independent effects: consumption-oriented versus impaired driving-oriented policies, general population versus youth-specific policies, and tax versus nontax policies. Multilevel logistic and negative binomial models were adjusted for individual- and institution-level covariates and time trends. Data analyses were conducted in 2025. RESULTS:Stronger general population-oriented, consumption-oriented, and tax and nontax policies were associated with lower odds of negative alcohol-related consequences, binge drinking, and frequent alcohol use. More restrictive youth-specific policies were associated with lower odds of binge drinking among students aged 21-24 years but not among those aged 18-20 years (i.e., underage students). The effects of impaired driving policies were specific to lower odds of driving after drinking, whereas the effects of consumption-oriented policies were specific to lower alcohol use and alcohol-related negative consequences. CONCLUSIONS:Population-based alcohol policies, including taxation, appear to protect against risky drinking patterns and alcohol-related harms among college students.

Binge drinking remains a serious issue among college students. While prior works showed more restrictive state alcohol policy environments are associated with less binge drinking in college students, the association may depend on individual, contextual, and institutional factors specific to this population. Data were from repeated cross-sectional surveys among 902,486 college students ages 18-24 years from 591 four-year institutions in 47 states during 2008-2019. Time-varying, state-level Alcohol Policy Scale (APS) scores and fourteen moderators were examined in relation to students' past 2-week binge drinking (5+ drinks in a sitting). Associations between higher APS scores (more restrictive state policies) and lower odds of binge drinking were moderated by several factors representing contextual features of college. For example, higher APS scores were associated with lower odds of binge drinking among students living on campus or with their parents and by those unaffiliated with the Greek system, but not among students in off-campus or Greek housing or members of the Greek system. Negative associations between APS and binge drinking were stronger for dating and cohabitating than single students. Additionally, APS scores were significantly more negatively associated with binge drinking for Asian than for non-Asian students. At the institution level, APS scores were negatively associated with students' binge drinking at institutions in medium to large, but not small population centers. The identification of factors that moderate effects of alcohol policy environment on college binge drinking informs potential prevention approaches that are more culturally tailored and targeted to subgroups of interest.

Objective: National College Health Assessment (NCHA) and Campus Safety and Security (CSS) data on sexual assault and alcohol misuse are potentially informative, but evidence of convergence is needed. Method: NCHA prevalence data from 73 four-year colleges on female students' sexual assault experiences and students' binge drinking were matched with each institution's CSS data on rape and fondling offenses, and alcohol-related arrests and discipline. Results: More rape offenses (CSS) occurred on campuses where female students reported higher rates of sexual touching, attempted penetration, and penetration on NCHA (Spearman's rho = 0.39, 0.40, and 0.34, respectively; p < 0.01). Institutions with a higher prevalence of binge drinking on NCHA recorded more alcohol-related arrests and discipline, and rapes on CSS (rho = 0.35, 0.64, and 0.32 respectively, p < 0.01). Conclusions: Indicators of sexual assault and alcohol misuse from NCHA and CSS may have utility in future research, evaluation, and prevention.

A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank using antibody-based Olink serum proteomics. This analysis replicated the association between APOB and the e2 allele of APOE, detected a new, robust pattern of association between APOE genotypes and the serum level of APOE, and discovered new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC2, APOC3, APOC4, APOE, APOF, and APOL1. In addition, 13 new proteins correlated with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease.

We previously identified a signature of 16 serum proteins that highlighted a role of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE), and in inflammation. The serum proteins were profiled using the aptamer-based Somalogic technology. Here, we validate and expand the serum protein signature of APOE using a combination of mass-spectrometry, ELISA, Luminex, antibody-based Olink proteomics, and blood transcriptomics. We replicate the association between APOB and the e2 allele of APOE, we correct the pattern of association between APOE genotypes and serum level of APOE, and we detect new associations between APOE genotypes and the complex of apolipoproteins APOC1, APOC4, APOC2, APOC3, APOE, APOF and APOL1. In addition, we discover 13 new proteins that correlate with APOE genotypes. This extended signature includes granule proteins CAMP, CTSG, DEFA3, and MPO secreted from neutrophils and points to olfactomedin 4 (OLFM4) as a new target for the prevention of Alzheimer's disease.

Cognitive impairment is a growing healthcare and quality-of-life challenge as more individuals reach older ages. Without effective interventions, the prevalence of decline will continue to rise. To identify genetic factors underlying cognitive function, we performed GWAS on nine neuropsychological test scores in the Long Life Family Study (LLFS). We then compared results with UK Biobank GWAS of general cognitive ability and reaction time, conducted quantitative trait locus (QTL) analyses of whole blood transcriptomic and serum metabolomic data for genome-wide significant variants (p < 5e-8), and performed gene set enrichment analyses of nominally significant transcripts. We identified 12 genome-wide significant variants across 7 tests in LLFS. Comparison with UK Biobank data revealed test-specific replication patterns, suggesting that loci for general cognitive function and reaction time reflect distinct cognitive domains. QTL analyses identified one SNP–transcript association (p < 0.05/16,300) but no significant SNP–lipid or SNP–polar metabolite associations. Three rare protective variants—rs190287985, rs75730801, and rs552842447—were linked to semantic fluency (animal), phonemic fluency (FAS), and digit span forward, respectively. Two rare deleterious variants, rs556333682 and rs188304645, associated with performance on the Hopkins Verbal Learning Test (HVLT) total recall, lie in ischemia-related genes SH3TC1 and RPH3A. Another variant, rs180691759, associated with HVLT delayed recall, was proximal to RSPO3 and linked to decreased ECHDC1 expression, implicating ischemic and unexplained ethylmalonic acid pathways. Gene set enrichment identified three pathways (FDR < 0.05), including KEGG JAK-STAT signaling and oxidative phosphorylation. These findings highlight domain-specific mechanisms of cognitive resilience and decline.

Using whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not statistically significant, cancer risk. The association with cancer risk was replicated in the UK Biobank and FinnGen. Metabolomic analyses linked the rs6543176 longevity allele to higher serine levels, potentially associated with delayed mortality. Our findings warrant further investigation of SLC9A2’s role in both longevity and cancer susceptibility, and they highlight the need for careful evaluation in developing anti-aging therapies based on EL-associated alleles.

OBJECTIVE:The prevalence of binge drinking among U.S. college students has decreased over the last two decades but remains high. We examined the extent to which state-level alcohol policies and drinking environments are associated with excessive and underage alcohol use among college students. METHOD:Repeated cross-sectional surveys were administered to 902,486 college students ages 18-24 years from 591 4-year institutions in 47 states biannually from 2008 to 2019. Time-varying, state-level Alcohol Policy Scale (APS) scores and population-level binge drinking and alcohol consumption rates were examined in relation to students' 30-day alcohol use (1+ days) and frequent use (20+ days), and 2-week binge drinking (5+ drinks in a sitting). RESULTS:More restrictive state-level policy environments were associated with lower odds of students' alcohol use, frequent use, and binge drinking; for a 10-point increase in APS, odds ratios [95% confidence interval] were .92 [.88, .95], .91 [.87, .96], and .94 [.91, .98], respectively (p < .01). Associations were significant for underage students (ages 18-20 years) but significantly stronger for older students (ages 21-24 years). State population levels of binge drinking and alcohol consumption were only positively associated with drinking outcomes for students age 21 years and older. CONCLUSIONS:Alcohol use and binge drinking were less prevalent among young adults attending college in states with more restrictive alcohol policies and among students age 21 and older in states with lower state rates of binge drinking and alcohol consumption. Lifelong patterns of alcohol use can begin in college, and findings indicate that state alcohol policies are a foundation on which community- and campus-level preventive efforts can build.

We constructed a polygenic protective score specific to Alzheimer’s disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the USA, Europe, and Asia. This AD PPS did not include variants on apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality. Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.

Introduction: Binge drinking and sexual assault are serious inter-related public health problems faced by college students. State-level alcohol policy restrictiveness has been found to decrease binge drinking among college students and, therefore, may also reduce occurrences of alcohol-related criminal offenses. It was hypothesized that more restrictive state alcohol policy environments would be associated with fewer liquor law violations and sexual assault offenses on U.S. college campuses. Methods: Data were aggregated across 3 academic years (2016-2017, 2017-2018, and 2018-2019) and represented n=1,290 institutions. Zero-inflated negative binomial regression modeling was performed in 2022-2023 to evaluate associations of state-level young adult binge drinking and the Alcohol Policy Scale (APS) with the numbers of campus-level alcohol-related arrests, alcohol-related disciplinary actions, rape offenses, and fondling offenses reported in national Campus Safety and Results: Higher APS scores had direct associations with fewer alcohol-related arrests (1.79% decrease per one-unit increase in APS, p=0.05), alcohol-related disciplinary actions (2.27% decrease per one-unit increase in APS, p=0.027), and rape offenses (0.85% decrease per one-unit increase in APS, p=0.021). The associations APS scores had with disciplinary actions and rape offenses were partially and fully mediated, respectively, by state-level young adult binge drinking. No associations were found between APS and fondling offenses. Conclusions: This cross-sectional study presents evidence that more restrictive state alcohol policies are associated with fewer alcohol-related arrests and disciplinary actions, and rape offenses on college campuses. Future research should identify the alcohol policy domains that are most protective against these outcomes. Am J Prev Med 2024;66(1):1-9. (c) 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Prevalence estimates of mental health problems including suicidal thoughts and behaviors among college students have increased over the last decade, but time trends for sexual and gender minority (SGM) students remain undocumented. We compared trends in the adjusted prevalence of these outcomes by gender and sexual orientation in college students (n = 816,461) ages 18-24 years sampled from 4-year colleges that self-selected to participate in the cross-sectional National College Health Assessment in 2008-2018. Prevalence of 30-day depressive and anxiety symptoms increased significantly for every group examined-cisgender women, cisgender women, transgender students, and heterosexual, gay/lesbian, bisexual/pansexual, and unsure/questioning students-and 30-day suicidal ideation increased significantly for all but transgender and unsure/questioning students. Disparities that sexual minority and transgender students showed relative to heterosexual and cisgender peers widened for depressive and anxiety symptoms, and the narrowing of disparities on suicidal ideation and past-year suicide attempt were explained by increases in prevalence among cisgender women and heterosexual students. A redoubling of prevention efforts, particularly for SGM young people, is needed to reverse recent trends in psychological distress and suicide risk. Public Significance Statement In this sample of more than 800,000 young adult college students in the United States, we found increases from 2008-2018 in the proportions of students reporting serious depressed mood, overwhelming anxiety, suicidal thoughts, self-harm, and suicide attempt. Moreover, we found increases across subpopulations defined by sexual orientation and gender, including transgender.

In previous work, we used a SomaLogic platform targeting approximately 5000 proteins to generate a serum protein signature of centenarians that we validated in independent studies that used the same technology. We set here to validate and possibly expand the results by profiling the serum proteome of a subset of individuals included in the original study using liquid chromatography tandem mass spectrometry (LC-MS/MS). Following pre-processing, the LC-MS/MS data provided quantification of 398 proteins, with only 266 proteins shared by both platforms. At 1% FDR statistical significance threshold, the analysis of LC-MS/MS data detected 44 proteins associated with extreme old age, including 23 of the original analysis. To identify proteins for which associations between expression and extreme-old age were conserved across platforms, we performed inter-study conservation testing of the 266 proteins quantified by both platforms using a method that accounts for the correlation between the results. From these tests, a total of 80 proteins reached 5% FDR statistical significance, and 26 of these proteins had concordant pattern of gene expression in whole blood generated in an independent set. This signature of 80 proteins points to blood coagulation, IGF signaling, extracellular matrix (ECM) organization, and complement cascade as important pathways whose protein level changes provide evidence for age-related adjustments that distinguish centenarians from younger individuals. The comparison with blood transcriptomics also highlights a possible role for neutrophil degranulation in aging.

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609, p = 7.13 × 10−8) that almost reached genome-wide significance and four additional loci that were suggestively significant. Among these, a novel rare variant (rs145265196) on chromosome 11 had much higher longevity allele frequencies in cases of Ashkenazi Jewish and Southern Italian ancestry compared to cases of other European ancestries. We also correlated EL-associated SNPs with serum proteins to link our findings to potential biological mechanisms that may be related to EL and are under genetic regulation. The findings from the proteomic analyses suggested that longevity-promoting alleles of significant genetic variants either provided EL cases with more youthful molecular profiles compared to controls or provided some form of protection from other illnesses, such as Alzheimer’s disease, and disease progressions.

Objective: We considered the utility of National College Health Assessment (NCHA) data relative to other national data for studying college students' cannabis use and binge drinking, and drug policy effects. Participants: Survey data on 18-22-year old college students were drawn from the 2008-2018 NCHA, National Survey on Drug Use and Health (NSDUH), Monitoring the Future (MTF), and Healthy Minds Study (HMS). Methods: Prevalence estimates were compared across data sources in terms of level and change from 2008-2018 using linear regressions, separately for men and women. Results: Mean prevalence estimates for 30-day cannabis use and 2-week binge drinking, and linear time trends did not differ significantly among NCHA, NSDUH, and MTF. Conclusions: NCHA prevalence estimates are similar to those from NSDUH and MTF, NCHA has unique strengths, and some weaknesses can be offset. Findings support the value of NCHA for studying college students' substance use and effects of drug policy.