Epigenetics

INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer's disease and related dementias (ADRD) and prospective cognitive ability remains unclear. METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers. RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083-.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (beta=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g. DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.

Background Preterm birth (PTB) rates among Hispanic/Latina individuals in the United States have risen over the past decade. Data suggests this rise may be driven in part by psychosocial stress. Leukocyte telomere length (LTL), a marker of cumulative cellular aging that shortens under chronic stress, may capture stress-related biological vulnerability, but has not been examined as a potential population-level contributor to PTB in Hispanic/Latina pregnancies. Objective To examine the association between mid-pregnancy maternal LTL and PTB in a population-based Hispanic/Latina cohort. Methods In a case-control study nested within a California singleton birth cohort (n = 436 Hispanic/Latina individuals; 215 PTB, 221 term births), LTL was measured by quantitative PCR from biobank specimens collected from 15 to 20 weeks of gestation. Covariates from linked birth certificate and hospital discharge records were included. Logistic regression estimated ORs and 95% CIs of PTB by LTL examined continuously and by percentile category (<=10th, 11th-89th, >=90th) with and without adjustment for covariates. Results Mean and median LTL did not differ between PTB and term births. LTL at or below the 10th percentile was associated with elevated odds of PTB relative to full-term birth (12.6% versus 4.3%; ORc = 3.2, 95% CI 1.3-7.9), persisting after partial (ORadj1 = 3.2, 95% CI 1.3-8.3) and full covariate adjustment (ORadj2 = 3.4, 95% CI 1.3-9.3). Subgroup analyses showed consistent directional patterns across PTB subgroups and for early term birth (ORadj2 = 5.1, 95% CI 1.5-17.0). Conclusions Mid-pregnancy maternal LTL <=10th percentile was associated with more than three times the odds of PTB, with risk concentrated at the extreme low tail of the distribution. Consistent with a cumulative allostatic load model, markedly short LTL at mid-gestation may reflect elevated stress-related biological risk for preterm delivery. These findings support upstream investment in stress reduction and prospective LTL research in high-burden populations.

Background: It is well-established that males have a higher mortality risk than females. Immune cells and their function are known to undergo characteristic changes during aging, and immune cells are known to have sex differences. Immune cells and their function have been linked to mortality risk, but no studies have investigated to what degree, if at all, Immune Cell Biomarkers (ICBs) contribute to the known differences in mortality risk by sex. Methods: Using participant data from the Health and Retirement Study (n = 8,822), we applied multivariable linear regressions adjusting for age, cytomegalovirus (CMV) serostatus, sex, and race/ethnicity to identify differences by sex in 48 immune cell biomarker (ICB, e.g. T cells, B cells, Monocytes, etc.) percentages and counts (measured in 2016). We studied how the associations between ICBs and mortality risk differ by sex using stratified Cox Proportional Hazard (CPH) models. We estimated how inclusion of sex explained the relationship between ICBs and all-cause mortality, and conversely, how inclusion of individual and all ICBs combined explain the relationship between sex and all-cause mortality using multivariable modeling approaches. Results: Differences in ICBs by sex range between 2-38% (39/48 statistically significant). 9 ICBs were significantly associated with mortality risk in the entire sample. While different ICBs were significantly associated with mortality risk in the stratified analyses, particularly with respect to monocyte, B cell, and NK cell populations, adjusting for sex modestly influenced the hazard ratios of the ICBs (sex: 8 ICBs, percent change <5.4%). Furthermore, individual and cumulative contributions of ICBs in explaining the differences in mortality risk by sex were not significant.

Background: Despite the success of combination antiretroviral therapy (cART), vascular comorbidities, including cerebrovascular disease, are more prominent in people living with HIV (PLWH) compared to people without HIV (PWOH). However, quantitative assessments of cerebrovascular morphometry and their associations with cognitive outcomes in the context of HIV are still limited. In this study, we explore this missing link. Methods: Magnetic Resonance Angiography (MRA) data, blood markers, and neurocognitive assessments were collected from 73 PWOH subjects (male: 57, female: 16; age: 53 {+/-} 16) and 99 PLWH subjects (male: 66, female: 30, age: 53 {+/-} 11). Vessel morphometric features were quantified using intraCranial Artery Feature Extraction (iCafe) to investigate associations between vessel morphometry, markers of monocytes, endothelial cell activation, and cognitive performance. Results: HIV status predicted a lower total number of branches ({beta} = -0.224, p = 0.001, d = -0.517) and shorter total distal length ({beta} = -0.173, p = 0.021, d = -0.370) with a moderate effect size. Total branch number was found to be negatively associated with plasma levels of monocyte markers (sCD14: r = -0.167, p = 0.033; sCD163: r = -0.157, p = 0.045) and positively correlated with white matter cerebral blood flow (r = 0.550; p [&le;] 0.05). HIV status was the strongest predictor of overall cognitive performance in ANCOVA model ({beta} = -0.219, p = 0.006, d = -0.453). Conclusions: Our results suggest that cognitive impairment in PLWH is associated with vessel morphology metrics. Monocyte immune activation may contribute to changes in vessel morphology.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women?s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] [&ge;] 2%) and large CHIP (VAF [&ge;] 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non-DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non-DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

Objective: To characterize genome-wide DNA methylation patterns associated with sepsis using the Infinium Methylation EPIC v2.0 platform and to evaluate the feasibility of pooled methylation profiling in a pilot critical care cohort. Design: Single-center pilot epigenome-wide association study using pooled whole-blood genomic DNA and pool-level bioinformatic analysis. Setting: Academic medical center. Patients: Fifty critically ill adults enrolled within 48 hours of illness onset and 20 healthy controls. Interventions: None. Measurements and Main Results: Critically ill patients required mechanical ventilation and/or vasopressor support. Sepsis was defined according to Sepsis-3 criteria. Seventy individual samples were organized into 14 intended pools of 5 individuals each: 7 sepsis pools, 3 critically ill non-septic pools, and 4 healthy-control pools. One critically ill non-septic pool was excluded because of poor DNA quality, yielding 13 analyzable pools. For the primary pooled comparison, 7 sepsis pools were compared with 6 non-sepsis comparator pools comprising 2 critically ill non-septic and 4 healthy-control pools. After quality control and preprocessing with SeSAMe, 876,094 CpG sites were retained. The initial pool-level screen identified 170,897 candidate differentially methylated regions. Application of stringent secondary filters (false discovery rate <= 1%, absolute delta-beta >= 7.5%, and >= 5 CpGs per region) yielded a high-confidence subset with marked directional skewing, including 155 hypomethylated and 32 hypermethylated regions in sepsis. Differentially methylated region-associated genes were enriched in myeloid leukocyte activation, myeloid leukocyte-mediated immunity, defense response to bacterium, neutrophil granule biology, and hematopoietic cell lineage pathways. Additional signals involved microRNA-associated targets, ribosome biogenesis, RNA processing, long noncoding RNAs, and previously uncharacterized loci. Conclusions: In this pilot pooled EPIC v2.0 study, sepsis was associated with a biologically coherent, predominantly hypomethylated methylation signature enriched in myeloid and host-defense pathways. These findings support the feasibility of pooled methylation profiling for discovery-oriented sepsis biobank studies but should be interpreted as hypothesis-generating given the pool-level design, limited effective sample size, heterogeneous comparator group, and lack of direct validation against individual-level methylation profiles.

INTRODUCTION: Alzheimers disease (AD) is a multifactorial disorder, yet current research largely focuses on downstream biomarkers with limited attention to environmental contributors. Experimental studies suggest that per and polyfluoroalkyl substances (PFAS) may contribute to neuroimmune and neurodegenerative pathways relevant to AD. OBJECTIVE: To examine associations between PFAS exposure and neuroimmune and AD related plasma biomarkers in cognitively unimpaired rural adults. METHODS: In a cross sectional pilot study (n=48), serum concentrations of 33 PFAS were measured, including four legacy compounds (PFOS, PFHxS, PFOA, PFNA). Plasma neuroimmune related (ITGB2, SMOC1, TREM2, GFAP) and AD related biomarkers (Ab42/40, ptau217) were detected using proteomic analysis. RESULTS: PFOS showed moderate associations with ITGB2, SMOC1, and Ab42/40 in unadjusted analyses, which attenuated after adjustment for age. PFOA and PFNA demonstrated consistent inverse associations with TREM2 before and after adjustment. DISCUSSION: Findings suggest possible compound specific PFAS associations with immune and amyloid related biomarkers, supporting further investigation in longitudinal and PFAS mixture based studies.

Lead is a toxic metal ubiquitous in our environment. While dramatic reductions in lead sources have paralleled equivalent decreases in lead-poisoning rates, chronic lead exposure remains a critical public health concern. Childhood lead exposure (at its lowest levels) is liked to changes in cognitive development but less is known about lead's effects on children's brain structure, especially as a result of in utero exposure. We measured prenatal and early-postnatal lead exposure in shed deciduous teeth of 448 9- and 10-year-old children (from 20 United States cities) and linked those lead levels to childhood brain structure, cognition/behavior, and neighborhood- and family-level socioeconomic characteristics. Here we show negative associations between tooth-lead levels and the thickness of the brain's cortex, particularly in regions linked to language processing. With increasing tooth-lead levels, children of lower-income (versus higher-income) families showed steeper declines in receptive vocabulary. Caregiver-reported behavioral problems exhibited similar associations. With in utero exposure linked to adverse neurodevelopmental outcomes (well before lead exposure and its risks are evaluated by healthcare professionals), prenatal screening of maternal lead levels/exposure, coupled with recommended strategies to reduce its placental transmission, may help reduce lead's effects on future generations.

Atherosclerosis is a systemic vascular process linked to cardiovascular, cognitive and renal outcomes. DNA methylation (DNAm)-based scores of atherosclerosis may capture cumulative biological processes underlying vascular aging. Here, we examined associations of DNAm scores for coronary artery calcification (DNAm-CAC) and carotid plaque (DNAm-cPlaque), derived from a large study of imaging-based subclinical atherosclerosis, with prevalent and incident outcomes in two population-based cohorts of older adults: the Health and Retirement Study (HRS; n = 3,875) and The Irish Longitudinal Study on Ageing (TILDA; n = 487). Higher DNAm scores were associated with adverse cardiometabolic profiles and socioeconomic indicators. In HRS, higher DNAm-CAC was associated with prevalent cardiovascular disease (odds ratio per SD, 1.16; 95% confidence interval (CI), 1.07-1.26), lower cognitive function ({beta} = -0.50, 95% CI -0.68 to -0.32) and lower estimated glomerular filtration rate (eGFR; -1.7 ml min-1 1.73 m-2, 95% CI -2.6 to -0.8) in unadjusted models. After adjustment for demographic and clinical risk factors, DNAm-CAC ({beta} = -0.29, 95% CI -0.46 to -0.13) and DNAm-cPlaque ({beta} = -0.24, 95% CI -0.42 to -0.06) remained associated with lower cognitive function, and DNAm-cPlaque was associated with incident cognitive impairment or dementia (hazard ratio per SD, 1.16; 95% CI, 1.01-1.32). Associations were attenuated after further adjustment for race/ethnicity and socioeconomic indicators. In TILDA, higher DNAm-cPlaque was associated with worse cognitive performance (incidence rate ratio, 1.11; 95% CI, 1.01-1.21), increased risk of incident cardiovascular disease (hazard ratio, 1.18; 95% CI, 1.00-1.42) and lower eGFR, with consistent associations observed for DNAm-CAC. These findings suggest that DNAm-based scores of atherosclerosis capture systemic vascular processes linked to multiple age-related outcomes across populations. Further work is needed to clarify the biological pathways reflected by these scores and their relation to cumulative and socially patterned vascular risk.

Background: Progressive multiple sclerosis (MS) is characterized by ongoing neurodegeneration and limited therapeutic options. Circulating metabolites provide insight into disease biology, yet biomarkers that predict disability progression and reflect treatment response are lacking. We aimed to identify metabolomic signatures associated with longitudinal MRI measures of brain atrophy and to evaluate whether ibudilast treatment was associated with metabolite trajectories over time. Methods: We repeatedly profiled 1,726 plasma metabolites using untargeted UPLC-MS/MS in 244 participants from the 96-week SPRINT-MS randomized trial of oral ibudilast, up to 100 mg daily, versus placebo. Weighted gene co-expression network analysis was used to derive groups of related metabolites. Associations between baseline metabolite groups and longitudinal MRI outcomes were evaluated using linear mixed-effects models adjusted for demographic, clinical, and treatment covariates. The primary outcome was the rate of whole-brain atrophy measured by brain parenchymal fraction (BPF), defined as the proportion of intracranial volume occupied by brain tissue. Secondary outcomes included white matter fraction (WMF), gray matter fraction (GMF), and cortical thickness (CTH). Metabolite groups nominally associated with MRI outcomes, defined as p < 0.05, were followed by individual metabolite analyses to identify potential drivers. Significant metabolites were tested for replication in a comparable real-world observational HEAL-MS cohort with longitudinal MRI data. Lastly, we tested whether ibudilast treatment was associated with metabolite trajectories and performed metabolite set enrichment analysis. Findings: Higher baseline levels of glycerophospholipids were associated with slower decline in both BPF and WMF, and sphingomyelins were similarly associated with slower BPF decline. For example, higher 1-palmityl-2-stearoyl-GPC (O-16:0/18:0) levels were associated with slower BPF decline in SPRINT-MS (beta = 0.016 [95% CI: 0.008, 0.024]; p = 4.35 x 10^-5) and replicated in HEAL-MS (beta = 0.108 [95% CI: 0.006, 0.211]; p = 3.90 x 10^-2). Metabolites associated with GMF preservation were enriched in androgenic steroids and steroid sulfates, with consistent positive associations observed in the replication cohort, whereas metabolites inversely associated with CTH were predominantly xenobiotic-related. Ibudilast treatment was associated with increased sphingomyelin species, such as palmitoyl sphingomyelin (d18:1/16:0; beta = 0.185 [95% CI: 0.085, 0.286]; FDR = 1.79 x 10^-2), and decreased levels of amino acid-related metabolites, such as anthranilate (beta = -0.270 [95% CI: -0.403, -0.137]; FDR = 3.87 x 10^-2). Pathway-based analyses corroborated these findings, highlighting glycerophospholipid and sphingolipid metabolism as key pathways implicated in brain atrophy in MS. Interpretation: Distinct lipid subsets were associated with slower brain atrophy in people with MS, and ibudilast treatment was associated with metabolite alterations in potentially neuroprotective directions. Metabolomics may provide prognostic and pharmacodynamic biomarkers for progressive MS.

The course of multiple sclerosis (MS) is highly heterogeneous, yet the biological mechanisms underlying this variability remain incompletely understood. Although metabolic alterations have increasingly been associated with disease progression, existing observational evidence is limited by confounding, reverse causation, and an inability to establish causal mechanisms. To bridge this gap, we used a metabolome-wide Mendelian Randomization (MR) framework, including thorough sensitivity analyses, to identify metabolites genetically linked to MS severity that can causally affect it. Bidirectional MR analyses revealed a subset of amino acid and lipid pathways with strong, consistent effects across different MR approaches, confirmed by tests for heterogeneity, horizontal pleiotropy, and LD confounding. For metabolites prioritized by metabolome-wide MR with evidence of causal effects, we conducted genetic colocalization at loci encompassing proximal enzyme-encoding genes, leveraging the corresponding instrumental variants to assess shared underlying genetic signals. This process revealed shared genetic signals between metabolite levels and MS severity, mapped to the FADS1/2 and CYP4F2 loci. A subsequent pathway-resolved set of cis-MR analyses across FADS1/2-derived polyunsaturated fatty acid (PUFA) metabolites, using a functional variant that proxies reduced {triangleup}5-desaturase activity, showed consistent effects indicating that FADS1 perturbation is associated with MS severity. Collectively, these results highlight FADS1 as a key driver of PUFA-related causal effects on MS severity in both systemic (circulating metabolites) and brain cell-specific contexts. Additional supportive cis-MR evidence implicates the disruption of CYP4F2 as another PUFA-metabolizing enzyme.

Objectives. Despite the body of literature on genetic risk factors for dementia, little is known on protective genetic factors associated with favourable cognitive ageing in the oldest population. In Europe, Italy has a leading position with a swelling population of centenarians, and the urban area of Genoa in the Liguria region has one of the highest prevalence of centenarians. The COOL study is a not-for-profit, multicentric study involving a cohort of centenarians (aged >99) living in the Genoa area. The ultimate aim is the identification of genomic biomarkers associated with cognition in the oldest old population. Results. Participants underwent a semi-structured interview on personal, disease and family history, and a neuropsychological assessment of the main cognitive domains. As of July 2025, we enrolled 88 centenarians (age range: 99-108, median 100.56) with and without cognitive impairment; 32 subjects were followed up. All participants were of Italian ancestry, 81% were female. The cognitive profile in assessed subjects showed a wide range of cognitive health measures (CDR 0-5; MMSE 3-30, median 24). Whole peripheral blood and DNA samples from 67 participants were stored. Conclusions. We demonstrated that the protocol is feasible, and acceptable by participants and their families. A comprehensive phenotype dataset was established, and DNA samples were stored. Centenarians exhibited a broad spectrum of cognitive profiles, from preserved cognition to severe dementia. These findings will eventually allow to interpret the profiles of genomic variants as associated with variability of cognitive performance in centenarians. The molecular underpinnings of healthy cognitive ageing could inform health policy strategies in the general population.

Background: Maternal micronutrient deficiencies (MNDs) and inflammation contribute to adverse birth outcomes While the individual effects of MNDs have been studied, the consequence of co-occurring MNDs remains unclear. Objectives: To examine the associations between maternal micronutrient deficiencies and inflammation with adverse birth outcomes (ABOs). Methods: Data from 5,408 pregnant women across 11 datasets from 10 countries were analyzed. Descriptive analyses explored the distribution of MNDs (iron, vitamin A, zinc, serum folate, vitamin D, and vitamin B12) and inflammation (c-reactive protein >5 mg/L or -(1)-acid glycoprotein > 1g/L) by maternal characteristics (age, height, education, socioeconomic status [SES]) using chi-square tests. Associations of 1) single MNDs and inflammation and 2) co-occurring MNDs (2 deficiencies at a time) with low birth weight (LBW, < 2500 g), preterm birth (PTB, < 37 wks), and small-for-gestational age (SGA, < 10th percentile for gestational age), were examined using modified Poisson regression to estimate relative risk (RR), adjusting for age, SES, and dataset. Results: Young maternal age and short height were associated with up to 9.7% and 25% higher prevalence of MNDs and inflammation, respectively. Lower education and SES level were associated with higher prevalence of Vitamin B12 deficiency. Women with folate deficiency had an increased risk of LBW (RR [95% CI]: 1.22 [1.06, 1.39]). Co-occurring MNDs for folate and vitamin B12 were also associated with increased LBW risk (1.38 [1,1.9]) as was folate deficiency without iron (1.28 [1.09, 1.51]) or vitamin B12 deficiency (1.67 [1.09, 2.56]) compared with mothers without either deficiency. Iron deficiency without vitamin B12 deficiency was associated with a reduced LBW risk (0.4 [0.2, 0.79]). Conclusion: Maternal MNDs, especially folate and vitamin B12, are linked to adverse birth outcomes. Complex nutrient interactions highlight the need to explore these relationships to improve maternal and neonatal health interventions.

1. Background: With the rising prevalence of hypertension, especially among younger populations, there is a critical need to better assess health status and predict associated complications. This study developed a biological age model ("hypertension age") for hypertensive patients to predict the risk and timing of major complications. 2. Methods: Using South Korea's NHIS-NHID data, researchers analyzed 4,535,041 hypertensive patients who underwent health examinations between 2009 and 2010. Patients were followed for an average of 12.40 years (until 2022). Principal Component Analysis (PCA) was used to develop the biological age (cBA) model. The risk and onset timing of complications were analyzed using Cox proportional hazards and multiple regression models, adjusting for variables like medication use and baseline diseases. 3. Results: A 1-standard deviation (SD) increase in the age gap?where biological age exceeds chronological age (cBA - CA)?was significantly associated with an elevated risk for all major complications in both sexes (p < 0.001). Furthermore, a 1-SD increase in this gap significantly accelerated the time to complication onset for nearly all conditions (p < 0.001), with the exception of dementia in women. The impacts of medication use, hypertension duration, and baseline comorbidities varied by specific complication. 4. Conclusions: Lowering "hypertension age" relative to chronological age can significantly reduce the risk and delay the onset of major cardiovascular and related complications. Quantifying this biological age gap serves as a powerful motivational tool for personalized health management and complication prevention in hypertensive patients.

Abstract Importance: Irregular sleep-wake patterns have been associated with poor health and cognitive outcomes, yet evidence linking 24-hour sleep-wake regularity to cognitive decline or dementia remains inconsistent. Particularly, regularity can be measured as regularity of rest-wake, sleep-wake or overall 24-hour activity, but it is unclear which aspects are most relevant for cognitive aging. Objective: To assess associations of rest-wake, sleep-wake, and 24-hour activity regularity with cognitive decline and dementia risk. Design: Observational prospective study comprised of six US and European cohorts: MrOS (sleep study between 2003-2005, mean follow-up: 7.1 years), Rotterdam Study (2004-2007, 11.6 years), MESA (2010-2013, 8.2 years), MAP (2005-2018, 7.2 years), Whitehall II (2012-2013, 6.9 years), and UKB (2013-2015, 7.9 years). Setting: Cohort-specific estimates were pooled using random-effects meta-analysis. Analyses were done between June 2025 and March 2026. Participants 74,733 dementia-free adults with multi-day actigraphy were included across cohorts: MrOS (age: 67-96 years, female:0%), MESA (54-95y, female:54.6%), Rotterdam Study (46-98y, female:55.0%), MAP (56-100y, female:77.1%), Whitehall II (59-83y, female:25.9%), and UKB (55-78y, female:55.5%). Exposure: Day-to-day rest-wake regularity (Rest Regularity Index, RRI), day-to-day sleep-wake regularity (Sleep Regularity Index, SRI), and 24-hour activity regularity (Interdaily Stability, IS) were derived from multi-day actigraphy. Main Outcome: Outcomes were risk of dementia and changes in global cognition. Results: Across six cohorts, 1,906 dementia cases occurred among 74,733 participants. After adjusting for demographics, health behaviors, depressive symptoms and cardiovascular comorbidities, each 1-SD higher regularity score was associated with an 9-14% lower dementia risk (pooled hazard ratios: RRI 0.86 95%CI: [0.79-0.95]; SRI 0.87[0.79-0.97]; IS: 0.91[0.88-0.95]). Associations were approximately linear. Age-stratified analyses showed directionally stronger associations among adults aged < 65, although meta-regression did not support an interaction(p > 0.55). Greater regularity was associated with modestly slower decline in global cognition (pooled {beta} per 1-SD higher score of RRI per year: 0.003, 95%CI [0.001-0.006]). Conclusions & Relevance: Greater regularity of rest-wake, sleep-wake, and 24-hour activity rhythms was associated with lower dementia risk and modestly slower global cognitive decline. These findings suggest that 24-hour sleep-wake regularity is a relevant behavioral marker of cognitive aging and may inform future efforts to identify or intervene on early risk.

INTRODUCTION: Postmenopausal estrogen decline may contribute to Alzheimer's disease (AD) risk, but longitudinal evidence linking circulating estrogens to cerebrospinal fluid (CSF) biomarkers is lacking. METHODS: We analyzed 866 female participants from the European Prevention of AD Longitudinal Cohort Study with baseline serum estradiol and estrone measured by liquid chromatography tandem mass spectrometry and repeated CSF measurements of amyloid-beta (A{beta})42, phosphorylated (p) Tau181, and total (t) Tau. RESULTS: Neither estradiol nor estrone was associated with longitudinal A{beta}42. Higher estradiol was associated with lower baseline tau and slower tau increases over time. Baseline estradiol-tau associations were stronger in apolipoprotein E (APOE) {epsilon}4 carriers, though APOE{epsilon}4 did not modify longitudinal associations. Amyloid positivity did not moderate hormone-tau associations but was associated with steeper tau increases over time. Estrone showed no significant associations. DISCUSSION: These findings suggest a more consistent relationship between estradiol and tau-related rather than amyloid-related pathology.

Background: Circadian rest-activity rhythms weaken with age, but whether sleep disorders modify this trajectory is unknown. Methods: We analyzed wrist accelerometry data from 4,386 participants aged 6-80 years in the 2011-2012 National Health and Nutrition Examination Survey (NHANES). Circadian features were extracted using cosinor analysis and nonparametric methods; a Circadian Disruption Index (CDI) was constructed from five standardized components. Survey-weighted regression with natural cubic splines and Wald F-tests tested age-by-sleep-disorder interactions using Taylor series linearization for variance estimation. Results: Doctor-diagnosed sleep disorder (N = 360, 8.2%) was associated with significantly different age-related trajectories of amplitude (F(2,17) = 11.24, p = 0.0008) and MESOR (F(2,17) = 8.22, p = 0.0032), both surviving Bonferroni correction (p < 0.006). CDI was higher in those with a sleep disorder (0.290 vs. 0.131, p < 0.001) and was independently associated with higher BMI (beta = 1.33 kg/m2, p < 0.001), higher HbA1c (beta = 0.089%, p = 0.004), greater diabetes prevalence (beta = 3.8 percentage points, p < 0.001), and worse depressive symptoms (beta = 0.43 PHQ-9 points, p = 0.020). Sensitivity analyses using a broader sleep problem exposure did not replicate these interactions. Conclusions: Doctor-diagnosed sleep disorders are associated with an altered age-related decline in circadian amplitude and mean activity level. CDI was independently linked to cardiometabolic and depressive outcomes, supporting a mechanistic connection between clinically significant sleep pathology and circadian disruption across the lifespan.

Background and Objectives In ADHD, a heterogeneous neurodevelopmental condition, behavioral and motor manifestations may reflect multiple inefficient or perturbed inhibitory systems. To evaluate Transcranial Magnetic Stimulation (TMS) evoked cortical silent period (CSP) duration, an indicator of GABA(B) receptor-mediated inhibition in motor cortex, as a potential biomarker of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Method We retrospectively analyzed TMS data, obtained using both round and figure-of-8 coils, from three cross-sectional studies conducted in 8- to 12-year-old children with ADHD (n=79; 10.7 +/- 1.5 years old) and age-and-sex-matched typically developing controls (n=96; 10.5 +/- 1.4 years old). Results Median CSP was 32% shorter in ADHD (p=0.02). Regression analysis demonstrated a relationship between shorter CSP and both lower active motor thresholds (p < 0.0001) and more severe hyperactivity symptom rating (p = 0.026). Test-retest CSP measures in 83 children showed moderate reliability (intraclass correlation 0.77 [ADHD], 0.75 [controls]). Conclusion TMS-evoked CSP may be a useful biomarker in future investigations of ADHD subtypes, domains of impaired function, or treatment outcomes.

The Asian population in Los Angeles is among the largest and most heterogeneous in the U.S. This is true culturally and health-wise. Older Asians have differing risks for cardiovascular and cardiometabolic disease, depending on their ethnicity, health literacy, and lifestyle choices. This pilot examines several of these factors in a small but diverse group of older Asian adults who attended community health events from 2024-2025. Self-reported and biometric data were collected at five such events hosted by the Asian Pacific Health Corps at UCLA. The pilot generated health literacy and lifestyle (HLL) scores for all participating attendees and explored how they relate to their socio-demographics, healthcare habits, and predictions of their own health data. Overall, there were significantly more females than males with higher HLL scores (p = 0.027). College education (p = 0.028) and "normal" ranges for biometric data (e.g., blood pressure, BMI, blood glucose, cholesterol) were related to higher median HLL scores. With a few exceptions, fewer than 50% accurately predicted their biometric numbers regardless of HLL scores, suggesting a disconnect between perception and reality, and that better provider-patient communication may help foster greater patient understanding about their chronic conditions. These HLL score distributions indicate that educational attainment, better awareness of one's health, and high health literacy are individual factors that may influence older Asians' understanding and potential approach to managing their health conditions.

Background: Immune-mediated mechanisms are increasingly implicated in childhood arterial ischemic stroke (AIS), but the associated inflammatory pathways and how they differ by stroke subtype and outcome remain poorly understood. Understanding immune responses to AIS may identify subtype-specific mechanisms and inform targeted strategies to reduce ischemic injury. Methods: We conducted a prospective cohort study with cross-sectional transcriptomic analysis through the Vascular Effects of Infection in Pediatric Stroke Study Part II (VIPS II) at 22 academic centers in the United States, Canada, and Australia between December 2016 and January 2022. Children aged 28 days to 18 years with centrally confirmed AIS were enrolled within 72 hours of stroke onset, in addition to enrollment of stroke-free well children. Peripheral blood RNA sequencing was performed on samples collected within 72 hours of stroke or at enrollment for controls. Differential gene expression (DGE) and pathway analyses were performed comparing all AIS cases to stroke-free well children. Additional cross-sectional analyses stratified by stroke subtype and neurological outcomes were performed. Results: Transcriptomes were available in 190/205 AIS cases (median age 11.7 years) and 91/100 stroke-free children (11.8 years). Stroke subtypes included 67 definite arteriopathic, 74 probable arteriopathic, 23 cardioembolic, and 26 idiopathic, with similar demographics but smaller infarct size for idiopathic cases. 47 genes (false discovery rate (FDR) <0.05 and log2 fold-change (log2FC)>1) were differentially expressed in AIS versus stroke-free well children, with upregulated pathways reflecting innate immune responses. Stratification by subtype revealed these inflammatory responses occurred after arteriopathic and cardioembolic AIS, but not idiopathic AIS; in sensitivity analyses, these findings were not explained by infarct size. Four immune-related genes were differentially expressed in children with good versus poor neurological outcomes at hospital discharge or 12 months; upregulation of one (Joining Chain; JCHAIN) correlated with poor outcomes at both timepoints. Conclusions: Compared with stroke-free children, children with AIS, particularly arteriopathic and cardioembolic subtypes, have upregulated innate immune pathways, including neutrophil activation and interleukin-1 signaling. Differential expression of immune-related genes also correlated with neurological outcomes. These findings support immune dysregulation as a key feature of early pediatric AIS while highlighting differences across subtypes and clinical outcomes, with implications for targeted immunomodulatory therapies and future biomarker development.