Background: Fibrinogen is a critical coagulation factor that plays an essential role in thrombosis and is elevated in individuals with chronic inflammation. Objectives: Here, we used fibrinogen as a representative quantitative measure of procoagulant risk and evaluated metabolites associated with fibrinogen levels using nontargeted plasma metabolomics profiling (Broad and Metabolon platforms). Methods: Our analysis included 10 533 individuals across 6 United States-based cohorts representing diverse population groups. The cross-sectional relationship between each of the 789 metabolites tested and plasma fibrinogen concentration was assessed after adjustment for relevant covariates, including age, cohort-reported sex, body mass index, and circulating lipoprotein levels. Results: Meta-analysis of per-cohort results revealed 270 metabolites significantly associated with fibrinogen levels (false discovery rate-adjusted P value < .05). Lipid species, such as glycerophospholipids, sphingolipids, and fatty acyls, were among the most significantly associated metabolites; some of these may capture effects of inflammation, as supported by sensitivity analyses adjusted for C-reactive protein. Significant associations between fibrinogen levels and serotonin, thyroxine, and sex hormone derivatives may capture endogenous influences on fibrinogen levels. Exogenous compounds and microbial cometabolites were significantly associated with fibrinogen, also implicating lifestyle and microbiome risk factors. Only a portion of fibrinogen-associated metabolites (30%) has been associated with cardiovascular disease outcomes in a prior study, suggesting that the associations discovered here may provide insights into vascular biology that case-control studies may not yet be powered to detect. Conclusion: These findings contribute to the growing list of metabolite biomarkers that may influence coagulation and inflammation pathways and, thereby, vascular risk.

Abnormal cardiac atrial structure and function (atrial cardiopathy) 1 typically precedes atrial fibrillation (AF) and predicts other cardiovascular complications, yet detection is limited by the cost and limited accessibility of high-quality cardiac imaging. We trained a deep learning model (ECG-AI) using 12-lead electrocardiograms paired with 21,749 cardiac magnetic resonance scans to predict left atrial structure and function. ECG-AI measures of atrial cardiopathy were strongly associated with new-onset AF, heart failure, and ischemic stroke after adjustment for clinical risk factors and biomarkers in two external cohorts, outperforming imaging measures and clinical risk factors. The risk of cardioembolic stroke, the hallmark complication of AF, was 66% greater per SD left atrial volume. In a screening population, ECG-AI predicted subclinical AF from 14-day cardiac monitoring better than a clinical risk prediction tool. Our ECG-AI is an inexpensive, accessible tool that identifies individuals at high-risk for AF and related complications.

Higher Mediterranean- DASH for Neurodegenerative Delay (MIND) diet scores have previously been associated with larger total brain volume (TBV) in the Framingham Offspring Study (FOS) community-based cohort. We investigated cross-sectional relationships between the MIND diet and structural brain imaging volumes and white matter hyperintensity volume (WMHV) across six community-based cohorts. We analyzed data from 3130 dementia-, stroke- and other neurological disease free adults (aged 65 to 74) who participated in the Atherosclerosis Risk in Communities (ARIC) cohort, Cardiovascular Health Study (CHS), Three City (3C) cohort, FOS cohort, Rotterdam Study (RS) or the Study of Health in Pomerania (SHIP) cohort. Individuals completed a brain magnetic resonance imaging (MRI) scan, and a validated food frequency questionnaire (FFQ) (ARIC, CHS, FOS, RS), 24h dietary recall (3C), or an extensive food list (SHIP). The MIND diet consists of ten healthy (e.g. green leafy vegetables, berries and fish) and five unhealthy (e.g. cheese, red meat and products and fast fried foods) components. Outcomes from brain MRI included TBV, total grey matter volume (TGMV), hippocampal volume (HPV), and WMHV. We used multivariable linear regression to relate MIND diet adherence to the outcomes. Results were combined in meta-analysis using fixed effects and random effects models. Higher MIND diet scores (score range: 0-15) were associated with larger HPV (beta = 0.015, 95% confidence interval = 0.004 to 0.026, cm³ per one unit MIND diet score increase) after adjustment for age, age squared, sex, time from clinical exam to brain MRI exam, total intracranial volume and energy intake, but not with TBV, TGMV and WMHV. Heterogeneity between studies was low (I 2 = 0% TBV, TGMV, HPV) to moderate (I 2 = 44% WMHV). In cross-sectional analyses, higher MIND diet scores were associated with larger HPV, but not with other brain volume measures. It might be that HPV was a more sensitive marker of brain health in the populations under study. Future studies are encouraged to examine the associations between the MIND diet and amyloid and tau positron emission tomography (PET) imaging to elucidate whether a relationship between the MIND diet and dementia pathologies exists.

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Findings from observational studies which examined relationships between Mediterranean- DASH for Neurodegenerative Delay(MIND) diet scores and risk of dementia are promising. We investigated whether MIND diet scores are associated with incident all-cause dementia and being alive and dementia free at age 80 across six community-based cohorts. We analyzed data from 8714 dementia free adults (mean age range across cohorts: 67 to 73) who participated in the Atherosclerosis Risk in Communities (ARIC) cohort, Cardiovascular Health Study (CHS), Three City (3C) cohort, Framingham Offspring Study (FOS) cohort, Rotterdam Study (RS) or the Study of Health in Pomerania (SHIP) cohort. Individuals had incident all-cause dementia surveillance data available and completed a validated food frequency questionnaire (FFQ) (ARIC, CHS, FOS, RS, 3C), 24h dietary recall (3C), or an extensive food list (SHIP). The MIND diet score is derived from ten healthy and five unhealthy components. We used Cox regression and logistic regression. Results were combined in meta-analysis using fixed effects and random effects models. Higher MIND diet scores (score range: 0-15) and MIND diet scores ≥6 were associated with decreased risk for all-cause dementia (Hazard ratio(HR) = 0.96,95% confidence interval(CI)=0.93-0.99; 0.86,95%CI=0.78-0.94, respectively) after adjustment for age at dietary intake assessment visit, sex, and total energy intake. Further, higher MIND diet scores and MIND diet scores ≥6 related to higher odds of being alive and dementia free at age 80 (Odds ratio(OR) = 1.11,95%CI=1.07-1.15;OR=1.37,95%CI=1.22-1.54, respectively). Heterogeneity between studies ranged between 0-30%. Higher MIND diet scores associated with decreased all-cause dementia risk and being alive and dementia free at age 80. We encourage clinical trials to examine the MIND diet in relation to dementia related outcomes such as amyloid and tau to elucidate whether a causal relationship between the MIND diet and dementia pathologies exists.

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

The MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort. Plasma NfL was measured using HD-X and HD-1 Simoa instruments. Samples from the MarkVCID consortium were used to evaluate intra- and inter-plate reliability, test-retest repeatability, and inter-site reproducibility. We used linear regression models to assess the association of NfL in MarkVCID with general cognitive function (GCF) as the primary outcome (n=331). In secondary analyses we assessed NfL associations with white matter hyperintensities (WMH). Models were adjusted for potential confounders, including eGFR as renal function influences NfL clearance. We replicated our findings using cohorts from the CHARGE consortium (CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196). We found the Quanterix Simoa platform to be reliable with low coefficients of variation (average CV<12%), high inter-site reproducibility (overall ICC = 0.93) and high repeatability in test-retest samples drawn within 30 days (ICC=0.968). There was strong consistency across Quanterix instruments (HD-X and HD-1; R 2 ≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in MarkVCID (β=-0.23; [95% CI -0.41; -0.01), CHARGE cohorts (meta-analysis β=-0.11; [95% CI -0.17; -0.06]), the UKY ADRC (β=-0.16; [95% CI -0.27; -0.05]) and the UCD ADRC (UCD: β=-0.28; [95% CI -0.48; -0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in MarkVCID (when controlled for eGFR), CHARGE, and the UCD ADRC. We have found that NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi-site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH in MarkVCID and across independent samples, providing evidence that it can be a useful biomarker for stratification in VCID trials.

Glial fibrillary acidic protein (GFAP) is an astrocytic cytoskeletal protein and a promising blood biomarker for Alzheimer's disease (AD) and other neurodegenerative diseases. To date, the genetic architecture of plasma GFAP has not been characterized. We conducted a multi-ancestry meta-analyses of genome-wide association studies (GWAS) in diverse population-based cohorts to identify genetic variants associated with plasma levels of GFAP and to investigate their implication for neurological diseases. Circulating GFAP levels were assayed by ultrasensitive single molecule array (Simoa) immunoassay. We performed ancestry-specific and ancestry-combined meta-analyses of GWAS in 17,028 individuals (mean age: 64.5 years; 60% women) of diverse ancestry (African (AA), N=1163; Hispanic (HA), N=7405; European (EA), N=8460) from 12 community-based cohorts. In the combined sample, we identified 7 loci associated with plasma GFAP. These were located in or near genes encoding APOE, CAPN1, CAPN2, GFAP, TMEM106B, PPP1R3C, and LOC105375672. The strongest association was with the APOE4 variant rs429358 (P=2.6x10 -40 ). However, this association was heterogeneous by ancestry, with stronger effects in EA, weaker in HA, and no association in AA. Ancestry-specific meta-analyses identified additional loci, including ZFAND3 in EA (Figure 1) and CAPN2 in HA (Figure 2), which were not observed in the other ancestries. No locus reached genome-wide significance in AA. Using fine-mapping methods incorporating functional annotation, gene expression, and linkage disequilibrium, we further prioritized potential causal variants and genes at the identified loci and investigated their implication for major neurological diseases, including AD. Our GWAS of plasma GFAP has identified multiple loci with ancestry-specific or cross-ancestry effects. Our multi-ancestry, integrative approach extends knowledge about the biology of GFAP and its shared genetic architecture with neurological disease.

BACKGROUND:Limited data exist on associations of immune cell subsets with longitudinal changes in subclinical coronary artery disease. METHODS:In the MESA (Multi-Ethnic Study of Atherosclerosis) study, we used a case-cohort approach to explore associations of 28 immune cell subsets measured at baseline (2000-2002) with longitudinal changes in coronary artery calcium (CAC). We examined incident CAC from examination 2 (2002-2004) through examination 5 (2010-2012) in participants with 0 CAC at baseline using multivariable-adjusted Cox regression. In participants with CAC >0 at baseline, we analyzed changes in CAC through examination 5 using multivariable-adjusted linear mixed models. Because no studies have investigated immune cells and longitudinal CAC changes, analyses were considered exploratory, with P<0.05 as the threshold for possible significance. RESULTS:Of 975 participants with immune cells subsets and CAC measurements at baseline, 378 had CAC 0 at baseline (mean age, 58.4; 37.0% men) and 597 had CAC >0 at baseline (mean age, 65.7; 57.6% men). Natural killer cells were associated with higher incident CAC (hazard ratio [HR], 1.26 per SD higher natural killer cell proportion; P=0.03), whereas T helper type cells were associated with lower incident CAC (HR, 0.81; P=0.04). B cells were associated with CAC progression (β=53.1 Agatston units per SD higher B-cell proportion, P=0.04), whereas CD14+CD16+ monocytes (β=-71.6; P=0.03) and T regulatory cells (β=-61.9; P=0.03) were associated with lower CAC progression. CONCLUSIONS:Natural killer cells may be associated with incident CAC and T regulatory cells may be associated with attenuated CAC progression, among other findings. These warrant replication and experimental investigation.

Introduction: Atrial cardiomyopathy precedes atrial fibrillation (AF) and is a strong risk factor for downstream adverse clinical outcomes, but there is no census about the optimal method for assessing it. Cardiac magnetic resonance imaging (CMR) is the most accurate tool to assess atrial function and structure. Our objective was to evaluate the association between CMR measures of atrial cardiomyopathy, incident AF, and AF-related clinical complications. Hypothesis: We hypothesized that CMR measures of atrial cardiomyopathy are associated with AF, ischemic stroke, heart failure, and dementia, independent of established risk factors. Methods: In 44,591 participants who underwent CMR as part of UK Biobank Imaging Study and had no history of AF, we assessed atrial minimal and maximal volumes (indexed to body surface area) and ejection fraction. Cox proportional hazard models were used to evaluate the association of these CMR measures with incident AF, ischemic stroke, heart failure, and dementia, adjusting for established risk factors. Results: During a median follow-up time of 4.0 [IQR 2.9-5.4] years, 834 (2%) participants developed AF, 197 (0.4%) developed ischemic stroke, 278 (0.6%) developed heart failure, and 61 (0.1%) developed dementia. The mean [standard deviation] age was 65 [8] years and 51% were female. When evaluated as continuous variables, left atrial ejection fraction (LAEF) was significantly associated with the risk of new-onset AF, ischemic stroke, and heart failure, while left atrial minimal volume (LAVI min ) and maximal volume (LAVI max ) were associated with these outcomes as well as the risk of dementia (Table). In comparison, right atrial measures were associated with only AF and heart failure, and the magnitude of the associations was generally smaller. After further adjustment for time-varying AF, these associations remained significant. When categorized by quintiles, participants in the highest LAVI min group had a HR of 3.67(95%CI 2.93-4.60) for AF, 1.51(95%CI 1.02-2.25) for ischemic stroke, 2.71(95%CI 1.86-3.96) for heart failure, and 2.43 (95%CI 1.11-5.31) for dementia, compared to those in the lowest. Conclusion: CMR measures of atrial structure and function were associated with AF-associated clinical outcomes independent of risk of AF. These findings suggest that atrial cardiomyopathy may be an important target of future research efforts, with potential implications for screening patients at high risk for cardiovascular disease.

BACKGROUND AND OBJECTIVES:Cardiac dysfunction and heart failure are linked to cognitive impairment, but the underlying brain pathology remains undetermined. We investigated associations between cardiac function (measured by echocardiography or cardiac MRI), clinical heart failure, and structural markers on brain MRI, including volumes of gray and white matter (WM), the hippocampus, and white matter hyperintensities (WMHs). METHODS:We leverage data from 7 prospective, community-based cohorts across Europe and the United States, all part of the Cross-Cohort Collaboration. The included cohorts were the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in Communities study, Austrian Stroke Prevention Study, Cardiovascular Health Study, Framingham Heart Study, Rotterdam Study, and Study of Health in Pomerania (SHIP-START and SHIP-TREND). Each cohort performed cross-sectional multivariable linear regression analyses, after which estimates were pooled through random-effects meta-analysis. Heterogeneity was assessed by the I2 index (%). RESULTS:Among 10,889 participants (mean age: 66.8 years, range 52.0-76.0; 56.7% women), markers of systolic dysfunction were consistently associated with smaller total brain volume (TBV) (e.g., adjusted standardized mean difference for moderate to severe dysfunction -0.19, 95% CI -0.31 to -0.07, I2 = 20%). Impaired relaxation and restrictive diastolic dysfunction were also associated with smaller TBV (e.g., for impaired relaxation -0.08, 95% CI -0.15 to -0.01, I2 = 32%) and hippocampal volume (-0.18, 95% CI -0.33 to -0.03, I2 = 0%), with similar results for the E/A-ratio. Systolic and diastolic dysfunction was not consistently associated with volume of WMHs. Among 5 cohorts with available data, 302 (3.4%) participants had clinical heart failure, which was associated with smaller brain volumes, particularly in the hippocampus (-0.13, 95% CI -0.23 to -0.02, I2 = 1%). DISCUSSION:In this large study among community-dwelling adults, subclinical cardiac dysfunction was associated with brain imaging markers of neurodegeneration. These findings encourage longitudinal investigations on the effect of maintaining cardiac function on brain health.

Circulating lipid concentrations are clinically associated with cardiometabolic diseases. The phenotypic variance explained by identified genetic variants remains limited, highlighting the importance of searching for additional factors beyond genetic sequence variants. DNA methylation has been linked to lipid concentrations in previous studies, although most of the studies harbored moderate sample sizes and exhibited underrepresentation of non-European ancestry populations. In addition, knowledge of nongenetic factors on lipid profiles is extremely limited. In the Population Architecture Using Genomics and Epidemiology (PAGE) Study, we performed methylome-wide association analysis on 9,561 participants from diverse race and ethnicity backgrounds for HDL-c, LDL-c, TC, and TG levels, and also tested interactions between smoking or alcohol intake and methylation in their association with lipid levels. We identified novel CpG sites at 16 loci (P < 1.18E-7) with successful replication on 3,215 participants. One additional novel locus was identified in the self-reported White participants (P = 4.66E-8). Although no additional CpG sites were identified in the genome-wide interaction analysis, 13 reported CpG sites showed significant heterogeneous association across smoking or alcohol intake strata. By mapping novel and reported CpG sites to genes, we identified enriched pathways directly linked to lipid metabolism as well as ones spanning various biological functions. These findings provide new insights into the regulation of lipid concentrations.

Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease. Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595). Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. Here we show that 49 proteins are associated with MRI markers of cSVD, most prominently in cerebrospinal fluid. We highlight associations that are consistent across platforms and ancestries, and supported by complementary observational analyses, and we explore differences between fluids. The proteins are enriched in pathways related to the extracellular matrix, immune response and microglial activity. Many also associate with stroke and dementia, and several correspond to existing drug targets. Together, these findings reveal a robust biological fingerprint of cSVD and highlight opportunities for biomarker and drug discovery and repositioning.

Background:Gene-environment interactions may enhance our understanding of hypertension. Our previous study highlighted the importance of considering psychosocial factors in gene discovery for blood pressure (BP) but was limited in statistical power and population diversity. To address these challenges, we conducted a multi-population genome-wide association study (GWAS) of BP accounting for gene-depressive symptomatology (DEPR) interactions in a larger and more diverse sample. Results:Our study included 564,680 adults aged 18 years or older from 67 cohorts and 4 population backgrounds (African (5%), Asian (7%), European (85%), and Hispanic (3%)). We discovered seven novel gene-DEPR interaction loci for BP traits. These loci mapped to genes implicated in neurogenesis (TGFA, CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), and synaptic activity (CNTN6, DBI). We also identified evidence for gene-DEPR interaction at nine known BP loci, further suggesting links between mood disturbance and BP regulation. Of the 16 identified loci, 11 loci were derived from African, Asian, or Hispanic populations. Post-GWAS analyses prioritized 36 genes, including genes involved in synaptic functions (DOCK4, MAGI2) and neuronal signaling (CCK, UGDH, SLC01A2). Integrative druggability analyses identified 11 druggable candidate gene targets, including genes implicated in pathways linked to mood disorders as well as gene products targeted by known antihypertensive drugs. Conclusions:Our findings emphasize the importance of considering gene-DEPR interactions on BP, particularly in non-European populations. Our prioritized genes and druggable targets highlight biological pathways connecting mood disorders and hypertension and suggest opportunities for BP drug repurposing and risk factor prevention, especially in individuals with DEPR.

Background: Understanding how circulating biomarkers of brain injury correlate with cognitive function and magnetic resonance imaging. (MRI) findings of vascular brain injury is critical for developing early interventions. We aimed to elucidate the associations of change in circulating blood-based biomarkers of brain injury with change in cognitive measures and MRI findings in a cohort of older adults from the Cardiovascular Health Study. Methods: Four biomarkers (glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total tau, and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1)) were measured twice over 4 years in up to 780 participants. Biomarkers were log-transformed, and multiple linear regression was applied, adjusting for age and eGFR. Changes in residuals from year 5 to year 9 were the primary exposure variable. Cognitive changes (DSST and 3MSE) were calculated over the same period. MRI at the second biomarker measurement assessed cerebrovascular markers (WMH, lacunar/non-lacunar infarcts). Multivariable regression, adjusting for key covariates, examined associations between biomarker changes, cognitive outcomes, and MRI findings. Results: Rising NfL levels were associated with a decline in processing speed and executive function (DSST change: β = -0.63 points per standard deviation (SD) increase, 95% CI [-1.24, -0.02]). Changes in GFAP, total tau, and UCH-L1 were not significantly associated with cognitive change. A direct association was observed between change in total tau and WMH grade (β = 0.17 points per SD increase, 95% CI [0.00, 0.35]). In logistic regression models, NfL change was marginally associated with lacunar infarcts (OR = 0.82, 95% CI [0.68, 1.00]), but not with non-lacunar infarcts. Conclusion: Our findings suggest that changes in circulating NfL may serve as a biomarker for predicting decline in processing speed and executive function, whereas NfL and total tau appears to be linked to the burden cerebrovascular disease. Further research should investigate how these biomarkers can inform early risk stratification and personalized interventions to maximize brain health and cognition in older adults.

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P < 0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P < 0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.

Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Brain deposition of transactive response DNA-binding protein 43 (TDP-43) is a feature of neurodegenerative syndromes. We evaluated TDP-43 plasma concentrations in 1058 participants in the Cardiovascular Health Study (CHS), a population-based longitudinal cohort. The cohort was 38% male, 11% Black, had a mean age 75 years, and 261 people developed dementia over a mean of 5.5 years of follow up. Median TDP-43 levels were 211.0 pg/mL (IQR: 134.0–341.0 pg/mL). TDP-43 levels were not associated with cross-sectional or longitudinal change in cognitive scores, with plasma AD biomarkers, with brain MRI volumes, with incident dementia, or with demographic characteristics.