BACKGROUND:Previous cohort studies of physical activity and cognitive health have often been limited by small sample sizes, short follow-up durations, absence of long-term assessments of physical activity, and potential reverse causation. We aimed to prospectively examine the associations between long-term physical activity and multiple cognitive outcomes. METHODS:In this study, we used data from two ongoing US prospective cohorts: the Nurses' Health Study (established in 1976, comprising 121 700 female registered nurses aged 30-55 years at enrolment) and the Health Professionals Follow-Up Study (HPFS; established in 1986, comprising 51 492 male health professionals aged 40-75 years at enrolment). Discretionary physical activity was assessed approximately every 2-4 years using self-report questionnaires, beginning in 1986 for both cohorts. Total physical activity, walking, and vigorous aerobic exercise were each expressed as the summed metabolic equivalent of task hours per week. We ascertained incident dementia cases (a composite endpoint of self-reported physician-diagnosed dementia and deaths due to dementia) in eligible Nurses' Health Study participants (1990-2023) and HPFS participants (1990-2023); deaths due to dementia were confirmed using medical records, death certificates, and autopsy reports. Objective cognitive function was assessed in Nurses' Health Study participants only (1995-2008) using the Telephone Interview for Cognitive Status (TICS). Subjective cognitive decline was self-reported by Nurses' Health Study participants (followed up in 2012 and 2014) and HPFS participants (followed up in 2008, 2012, 2016, 2018, and 2020) via questionnaires with binary questions that assessed subjective cognitive concerns across multiple domains. Participants were excluded from the analysis if they had dementia, stroke, cancer, were missing total physical activity or walking data, or reported difficulties with walking at baseline. Outcomes were analysed using multivariable-adjusted regression models. We used a 4-year lag approach in our main analyses to minimise the potential for reverse causation. FINDINGS:Our final samples comprised 63 596 Nurses' Health Study participants and 43 440 HPFS participants for the dementia endpoints, 13 647 Nurses' Health Study participants for assessing objective cognitive function, and 29 801 Nurses' Health Study participants and 17 162 HPFS participants for assessing subjective cognitive decline. Compared with participants in the lowest quartile for total physical activity, those in the highest quartile had a lower risk of dementia (hazard ratio [HR] 0·72, 95% CI 0·68-0·76; p<0·0001 for trend) and subjective cognitive decline (relative risk [RR] 0·77, 95% CI 0·73-0·80; p<0·0001 for trend). Being in the highest versus the lowest tertile for walking or vigorous aerobic exercise was also associated with lower risk for dementia (HR 0·76, 95% CI 0·72-0·80 for walking and 0·89, 0·85-0·93 for vigorous aerobic exercise; p<0·0001 for trend for both activities) and subjective cognitive decline (RR 0·82, 95% CI 0·79-0·86 for walking and 0·89, 0·86-0·93 for vigorous aerobic exercise; p<0·0001 for trend for both activities). Additionally, being in the highest quartile of total physical activity versus the lowest quartile was associated with fewer years of age-related cognitive differences in global cognition (mean difference -1·15, 95% CI -1·69 to -0·60; p<0·0001 for trend), verbal memory (-1·27, -1·86 to -0·68; p<0·0001 for trend), and TICS score (-0·79, -1·36 to -0·23; p=0·016 for trend). Similar decreases were observed for vigorous aerobic exercise but not for walking. INTERPRETATION:Higher levels of physical activity were associated with a lower risk of dementia and better cognitive performance. These findings support physical activity as a potential strategy to promote long-term cognitive health. FUNDING:US National Institutes of Health.

Abstract Background and objectives Residence in the United States Stroke Belt has been linked to a higher stroke mortality rate, raising the question of whether this increased risk is also associated with other brain health outcomes, such as cognitive change, defined as within-person changes in cognitive performance over time. This study aimed to investigate if residing in the Stroke Belt is associated with cognitive decline compared to residing outside this region in a large cohort of women. Methods We used data from the cognitive cohort of the Women’s Health Study, a U.S.-based cohort of predominantly White women currently or formerly employed in health professions. Our analyses included 6,362 women aged ≥65 years at baseline who underwent cognitive assessments. The exposure was residency in the Stroke Belt. Cognitive change was assessed as the primary outcome using repeated measures of a global cognitive composite score. Linear mixed-effects models were applied, adjusted for age, education, and lifestyle factors, measured by Life’s Simple 7 score with random effects for each of the participating women (fully adjusted model). Secondary analyses used logistic regression to examine the association between Stroke Belt residency and the odds of belonging to the first quintile or first decile of the cognitive change distribution (secondary outcome), representing women with the greatest cognitive decline. Results Of the participating women, 1,131 (17.8%) resided within the Stroke Belt. Compared to women residing outside the Stroke Belt, women residing in the Stroke Belt did not have significantly different rates of cognitive decline. The fully adjusted difference in change in the global cognitive composite score from the first to the last assessment between women living inside and outside the Stroke Belt was β = -0.03, SE = 0.02, p = 0.233. Women residing in the Stroke Belt had higher odds of being in the first quintile (adjusted odds ratio (OR) 1.20, 95% confidence interval (CI) 1.00–1.42) and in the first decile (adjusted OR 1.43, 95% CI 1.14–1.78) of the cognitive change distribution. Discussion Residence in the U.S. Stroke Belt was not associated with overall differences in cognitive decline trajectories, although secondary analyses suggested a possible increase in more pronounced decline among women living in the region. Trial Registration Information ClinicalTrials.gov Identifier: NCT00000479; retrospectively submitted: October 27, 1999.

OBJECTIVES:Higher endogenous estrogen may be associated with better cognition, but associations with menopausal hormone therapy (MHT) have been inconsistent, possibly due to differences in the timing of use. This prospective cohort study aimed to evaluate the associations between reproductive span, as a proxy for endogenous estrogen history, MHT use, and cognitive function. METHODS:We assessed cognitive change (1995-2008) with four telephone interviews (primary outcome: global composite score average of six test z-scores) in 14,217 Nurses' Health Study participants (mean age 74.3 y) and examined associations with reproductive span ([age at menopause]-[age at menarche]), and MHT use duration, separately by 0-10 years, and 11+ years after menopause. RESULTS:A longer reproductive span was associated with better cognitive trajectories (mean annual rate of change difference [95% CI]41-46 vs. ≤33 y=0.008 [0.00005, 0.015]; P-trend=0.02). MHT use 0-10 years postmenopause was associated with faster decline (mean difference8-10 vs. 0 y=-0.007 [-0.016, 0.002]; P-trend=0.02); use during 11+ years postmenopause was not associated. CONCLUSIONS:Although MHT use was not inversely associated, a longer reproductive span was associated with better cognitive trajectories.

PURPOSE:To evaluate whether a polygenic risk score (PRS) for primary open-angle glaucoma (POAG) is associated with open-angle glaucoma (OAG) progression and treatment burden in a multiancestry population. DESIGN:Longitudinal cohort study. SUBJECTS:A total of 950 individuals with OAG and serial Humphrey visual field (VF) testing were included, comprising 713 participants from the Mass General Brigham Biobank and 237 from the Mount Sinai BioMe Biobank. METHODS:A POAG PRS was generated using summary statistics from a cross-ancestry genome-wide association study. Association between PRS and VF progression, defined as a mean deviation slope worse than -0.25 dB/year, was tested with logistic regression models adjusted for age, sex, and ancestry. Associations with treatment burden, defined by a weighted score of medications, laser, and surgical interventions, were analyzed using logistic regression. Association between PRS and surgical interventions were assessed using Cox proportional hazards models. MAIN OUTCOME MEASURES:OAG progression described by mean deviation slope and treatment intensity. RESULTS:Among 950 individuals with OAG, the mean age at baseline was 71.2 ± 10.5 years; 54.7% were female, and 65.5% were of European descent. The median follow-up duration was 6.5 years. Each standard deviation (SD) increase in PRS was associated with a faster rate of VF decline (β = -0.02 dB/year per SD higher PRS; 95% confidence interval [CI], -0.04 to -0.01; P = 0.007) and 22% higher odds of progression (odds ratio = 1.22 per SD higher PRS; 95% CI, 1.04-1.42; P = 0.014). Higher PRS was also associated with greater treatment burden (odds ratio = 1.47 per SD; 95% CI, 1.27-1.71; P < 0.001). In the Mass General Brigham cohort, higher PRS predicted shorter time to glaucoma procedures (hazard ratio = 1.34 per SD; 95% CI, 1.12-1.59; P = 0.001), and this association persisted among eyes with normal or mild baseline disease severity (hazard ratio = 1.33 per SD; 95% CI, 1.10-1.60; P = 0.003). CONCLUSIONS:In 2 independent biobank cohorts, higher POAG PRS was associated with faster VF progression and greater treatment burden in OAG. These findings support the potential utility of genetic risk profiling for prognostication of disease trajectory and management intensity in glaucoma. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

INTRODUCTION:Associations of adherence to and changes in Mediterranean (MedDiet) and Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diets with cognitive outcomes are unclear. METHODS:We prospectively followed 86,740 women (Nurses' Health Study, 1980-2023) and 43,500 men (Health Professionals Follow-Up Study, 1986-2023). Diet was assessed repeatedly using food frequency questionnaires. Dementia cases were identified from self-reported physician diagnoses and death records. Cognitive function was assessed by telephone tests, and subjective cognitive decline (SCD) was self-reported. RESULTS:Participants in the highest versus lowest MedDiet and MIND categories had 21% (hazard ratio [HR] = 0.79, 95% confidence interval [CI]: 0.73-0.84) and 14% (HR = 0.86, 95% CI: 0.81-0.91) lower dementia risk, respectively. Higher adherence was associated with 0.75 to 1.59 fewer years of cognitive aging, and 40% to 42% lower risk of SCD. Similar inverse associations were observed for improved adherence over 4 or 8 years. DISCUSSION:Adherence to Mediterranean and MIND diets was associated with cognitive benefits.

Importance:Evidence linking coffee and tea to cognitive health remains inconclusive, and most studies fail to differentiate caffeinated from decaffeinated coffee. Objective:To investigate associations of coffee and tea intake with dementia risk and cognitive function. Design, Setting, and Participants:Prospective cohort study that included female participants from the Nurses' Health Study (NHS; n = 86 606 with data from 1980-2023) and male participants from the Health Professionals Follow-up Study (HPFS; n = 45 215 with data from 1986-2023) who did not have cancer, Parkinson disease, or dementia at study entry (baseline) in the US. Exposures:The primary exposures were intakes of caffeinated coffee, decaffeinated coffee, and tea. Dietary intake was collected every 2 to 4 years using validated food frequency questionnaires. Main Outcomes and Measures:The primary outcome was dementia, which was identified via death records and physician diagnoses. The secondary outcomes included subjective cognitive decline assessed by a questionnaire-based score (range, 0-7; higher scores indicate greater perceived decline; cases defined as those with a score ≥3) and objective cognitive function assessed only in the NHS cohort using telephone-based neuropsychological tests such as the Telephone Interview for Cognitive Status (TICS) score (range, 0-41) and a measure of global cognition (a standardized mean z score for all 6 administered cognitive tests). Results:Among 131 821 participants (mean age at baseline, 46.2 [SD, 7.2] years in the NHS cohort and 53.8 [SD, 9.7] years in the HPFS cohort; 65.7% were female) during up to 43 years of follow-up (median, 36.8 years; IQR, 28-42 years), there were 11 033 cases of incident dementia. After adjusting for potential confounders and pooling results across cohorts, higher caffeinated coffee intake was significantly associated with lower dementia risk (141 vs 330 cases per 100 000 person-years comparing the fourth [highest] quartile of consumption with the first [lowest] quartile; hazard ratio, 0.82 [95% CI, 0.76 to 0.89]) and lower prevalence of subjective cognitive decline (7.8% vs 9.5%, respectively; prevalence ratio, 0.85 [95% CI, 0.78 to 0.93]). In the NHS cohort, higher caffeinated coffee intake was also associated with better objective cognitive performance. Compared with participants in the lowest quartile, those in the highest quartile had a higher mean TICS score (mean difference, 0.11 [95% CI, 0.01 to 0.21]) and a higher mean global cognition score (mean difference, 0.02 [95% CI, -0.01 to 0.04]); however, the association with global cognition was not statistically significant (P = .06). Higher intake of tea showed similar associations with these cognitive outcomes, whereas decaffeinated coffee intake was not associated with lower dementia risk or better cognitive performance. A dose-response analysis showed nonlinear inverse associations of caffeinated coffee and tea intake levels with dementia risk and subjective cognitive decline. The most pronounced associated differences were observed with intake of approximately 2 to 3 cups per day of caffeinated coffee or 1 to 2 cups per day of tea. Conclusions and Relevance:Greater consumption of caffeinated coffee and tea was associated with lower risk of dementia and modestly better cognitive function, with the most pronounced association at moderate intake levels.

Abstract Background Impaired cognitive function has been linked to an elevated risk of stroke. However, the effect of cognitive change, conceptualized as a dynamic process, has received limited attention. We therefore aimed to estimate the effect of cognitive decline on the risk of stroke in older women. Methods Our analyses were based on data from the cognitive cohort of the Women’s Health Study composed of 6,377 US female health professionals aged 65 years and older at baseline. We included women without a history of stroke who had complete information on global cognitive performance change. Women were categorized into quintiles based on their 4-year global cognitive performance change and followed for self-reported incident stroke confirmed by a physician Endpoints Committee through December 31, 2022. We used multivariable-adjusted Cox proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of the association between cognitive change and stroke. Secondary analyses assessed the risk for stroke subtypes, lowest 10% and 20% of the cognitive change distribution, and changes in verbal memory. Results 5,093 women with a mean age of 66 years (SD = 3.93) were analyzed. The mean follow-up time was 11.6 years per person during which 302 incident stroke cases were reported. Compared to the 5th quintile (greatest improvement), the adjusted HR for stroke was 0.76 (95%CI [0.53–1.10]) for the 4th, 0.91 (95%CI [0.64–1.29]) for the 3rd, 0.95 (95%CI [0.67–1.34]) for the 2nd, and 1.02 (95%CI [0.72–1.45]) for the 1st quintile characterized by the greatest decline. Similar patterns were observed in secondary analyses. Women in the lowest 10% of global cognitive change exhibited a non-significant increase in the risk of stroke compared to the rest of the distribution (HRadj = 1.25 (95%CI [0.86–1.82]). Conclusions Large declines in cognitive performance were not strongly associated with stroke risk in this cohort of older female health professionals. However, future studies should further explore whether cognitive trajectories may influence risk of stroke and assess the generalizability of our findings, particularly to men.

We analyzed free-text narratives about recent bereavement experiences from 1997 women aged 55-73 years (M = 65.9, SD = 4.4) enrolled in the Nurses' Health Study II to identify associations between text characteristics and postbereavement mental health. We applied covariate-adjusted linear mixed effects models to assess the association between word count and expression of positive vs negative sentiment (emotional valence) in first-person bereavement narratives and standardized Patient Health Questionnaire-4 (PHQ-4) total, anxiety, and depression symptom scores over 6 months, stratified by loss of a partner or child vs a close other. Emotional valence was quantified using the Valence Aware Dictionary and sEntiment Reasoner (VADER) algorithm. Among women bereaved of a close other, word count was positively associated with log PHQ-4 total (0.06 SD [95% CI, 0.02-0.09]), anxiety (0.05 SD [95% CI, 0.02-0.09]), and depression (0.06 SD [95 % CI, 0.03-0.09]) symptom scores. Negatively scored emotional valence was associated with elevated log PHQ-4 total (-0.05 SD [95% CI, -0.08 to -0.01]), anxiety (-0.04 SD [95% CI, -0.08 to 0.00]), and depression (-0.04 SD [95% CI, -0.07 to -0.01]) symptom scores. Estimated associations among women bereaved of a partner or child were elevated but underpowered. Qualitative approaches in epidemiologic cohorts offer promise in identifying novel characteristics associated with bereavement outcomes among older women.

Purpose:Exfoliation glaucoma (XFG) is the most common secondary glaucoma. Prior studies suggest a higher incidence in women and links to reproductive history, implying estrogen-related pathways. Metabolomic data also indicated inverse associations with steroid-related plasma metabolites, suggesting steroid involvement in XFG pathogenesis. Methods:We conducted a nested case-control study within the Nurses' Health Study (NHS) (1980-2018), NHSII (1989-2019), and Health Professionals Follow-up Study (1986-2018), with 217 XFG suspect (XFGS)/XFG cases and 217 matched controls (62 men and 372 women). We evaluated 18 endogenous steroids and five steroid classes using conditional logistic regression. Secondary analyses examined effect modifications by age and residential latitude, and heterogeneity by disease severity (XFGS vs. XFG). Metabolite set enrichment analysis (MSEA) was used for class-level associations. Multiple comparisons were addressed using the number of effective tests (NEF) for individual steroids and false discovery rate (FDR) for steroid classes. Results:No individual steroid or steroid class met NEF- or FDR-adjusted significance thresholds, overall or by sex. Nonetheless, across both sexes, MSEA demonstrated a non-significant inverse trend between androgen levels and XFG/XFGS risk (FDR=0.22), with 11-ketotestosterone showing a nominal inverse association (OR=0.54; 95%CI=0.31-0.93; P=0.03). Progestogens showed enrichment scores in the positive trend (FDR=0.31), with a borderline positive association between progesterone and XFG/XFGS (OR=2.21; 95%CI=1.00-4.87; P=0.05). Conclusions:Although we observed no statistically significant associations with steroids after correction for multiple testing, the suggestive patterns for androgens and progestogens support the possibility of steroid-related pathways in XFG etiology and support further evaluation in larger studies.

Importance:Healthier diets are generally believed to benefit cognitive health; however, the evidence remains inconsistent, and a systematic examination of multiple healthy dietary patterns within the same context is lacking. Objective:To evaluate the associations of 6 healthy patterns with subjective cognitive decline (SCD) and objective cognitive function. Design, Setting, and Participants:This was a prospective cohort study based on the Nurses' Health Study (NHS, 1986-2014), NHSII (1991-2017), and the Health Professionals Follow-Up Study (HPFS, 1986-2012). Included were adults with available data on diet and cognitive function. Data analyses were performed from September 2024 to November 2025. Exposures:Six dietary pattern scores, including the Alternate Healthy Eating Index 2010 (AHEI-2010), the Dietary Approaches to Stop Hypertension (DASH) diet score, the Healthful Plant-Based Diet Index (hPDI), the Planetary Health Diet Index (PHDI), and the reversed empirical dietary indices for hyperinsulinemia (rEDIH) and inflammatory pattern (rEDIP). Main Outcomes and Measures:SCD was assessed using 7 questions on perceived cognitive changes. Cognitive function was objectively measured via telephone in the NHS. Results:A total of 159 347 individuals (mean [SD] age, 44.3 [9.3] years; 131 560 female [82.6%]) were included in this analysis. Among the study participants, higher adherence to all 6 dietary patterns was associated with a lower SCD risk. The DASH diet showed the strongest magnitude (risk ratio [RR] comparing 90th vs 10th percentile of adherence: 0.59; 95% CI, 0.57-0.62), followed by the hPDI (RR, 0.76; 95% CI, 0.65-0.85), rEDIH (RR, 0.76; 95% CI, 0.73-0.80), PHDI (RR, 0.80; 95% CI, 0.75-0.86), AHEI-2010 (RR, 0.84; 95% CI, 0.80-0.89), and rEDIP (RR, 0.89; 95% CI, 0.85-0.93). Higher DASH diet score at ages 45 to 54 years showed the strongest association with SCD. Higher adherence to the DASH diet also showed the strongest association with a higher objectively measured global cognition (mean z score difference comparing 90th vs 10th percentile: 0.05; 95% CI, 0.02-0.09). Key food groups associated with better cognitive function included higher vegetable and fish intake and lower red and processed meats intake. Conclusions and Relevance:Results reveal that healthy diets, exemplified by the DASH diet for blood pressure control and diets with lower hyperinsulinemia and inflammation potentials, were associated with a lower SCD risk and better cognitive function. These findings underscore the importance of a healthy diet for maintaining long-term cognitive health.

Abstract Background With global population aging and an increasing prevalence of cognitive decline, the association between cognitive change as a dynamic process and all-cause mortality remains insufficiently investigated. We therefore aimed to assess the association of cognitive decline on all-cause mortality in older women. Methods We analyzed data originating from the cognitive cohort of the Women’s Health Study established in 1998. 6,377 US-based women aged ≥ 65 years and currently or formerly employed in health-related professions were enrolled at baseline. Women with complete information on 4-year global cognitive performance change were eligible for our analysis and assigned to quintiles according to change in global cognitive performance. Follow-up for all-cause mortality was administered until December 31, 2022. Multivariable adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of the effect of cognitive change on the risk of all-cause mortality. Secondary analyses evaluated the risk in the lowest 20% and 10% of the cognitive change distribution, and according to verbal memory changes. Results 5,214 women with a mean age of 66.1 years (SD 4.0) were included in the analyses. Women were followed for an average of 13.4 person years and 3,333 deaths were observed. When compared to the 5th quintile with the greatest improvement, the adjusted HR for all-cause mortality was 0.96 (95%CI [0.86–1.08]) for the 4th, 1.04 (95%CI [0.93–1.16]) for the 3rd, 1.15 (95%CI [1.04–1.29]) for the 2nd, and 1.37 (95%CI [1.23–1.52]) for the 1st quintile characterized by the greatest decline. Similar patterns were observed for verbal memory change. Risk was further elevated when comparing the worst 20% (HR: 1.32 (95%CI [1.21–1.43])) and 10% (HR: 1.44 (95%CI [1.29–1.60])) to all other participants. Conclusion Cognitive decline over four years was associated with an increased risk of mortality among older women. Further studies should explore whether declines earlier in life or among men are also associated with an increased risk of mortality.

OBJECTIVES:Practice effects (PEs), improvements in cognitive test performance with repeated exposure, must be addressed in longitudinal studies of cognitive aging. Although many cognitive assessments are marketed as robust to PEs, evidence is limited. Randomizing testing features enables direct quantification of PEs but remains underutilized. METHODS:Among Nurses' Health Study II participants (N=14,802), we examined PEs in the Cogstate Brief Battery arising from increased testing repetition and frequency using conditionally randomized 6- or 12-month regimens (2014 to 2019). RESULTS:Taking the assessment twice previously, compared with once previously, at the 12-month assessment (defined as frequency PEs) was associated with 0.13 SD-higher global cognitive scores (95% CI: 0.10-0.16), corresponding to between-person age differences of 4.3 to 6.8 years. Taking the second assessment 6-months compared with 12-months after baseline (defined as frequency of PEs) was associated with 0.04 SD-higher global cognitive scores ( P <0.01), corresponding to between-person 1.3 to 1.6-year age differences. Repetition and frequency PEs both appeared to be greater in magnitude for participants who were older at baseline, but uncertainty was high in formal tests of effect modification. CONCLUSIONS:Over short follow-up periods, repetition PEs may obscure age-related cognitive decline using Cogstate. Randomizing testing features can be used to strengthen cognitive aging research.

BACKGROUND:Underlying metabolic perturbations may offer insight into etiological factors related to liver cancer development. The objective of this study was to explore associations between pre-diagnostic metabolites and risk of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS:We conducted a nested case-control study within 12 prospective U.S. cohort studies, including 727 HCC cases and 126 ICC cases with matched controls. Metabolomic profiling was performed on pre-diagnostic blood samples using the Metabolon platform. Multivariable conditional logistic regression estimated adjusted odds ratios and 95% confidence intervals for associations between metabolites (per doubling in levels) and liver cancer risk. Elastic net regression selected metabolites predictive of HCC and ICC, with predictive performance assessed by area under the curve (AUC). RESULTS:Median time from blood collection to diagnosis was 11.6 years. Of 1,485 pre-diagnostic metabolites, 600 were associated with HCC risk after false discovery rate correction (366 positively, 234 negatively); no metabolites were significantly associated with ICC. Enriched pathways among HCC cases included methylhistidine metabolism, amino acid metabolism, and bile acid biosynthesis; ICC showed enrichment in valine, leucine, and isoleucine pathways. Elastic net models for HCC selected 38 metabolites with strong predictive performance (AUC = 0.87; 95% CI: 0.83 to 0.91), while eight metabolites were selected for ICC with modest discrimination (AUC = 0.64; 95% CI: 0.49 to 0.80). CONCLUSIONS:Numerous pre-diagnostic metabolites were associated with HCC risk, potentially reflecting underlying liver dysfunction. Enrichment patterns suggest distinct metabolic perturbations between HCC and ICC. Larger studies are needed to characterize metabolic risk factors for ICC and evaluate metabolites as predictors of HCC risk.

Endogenous estrogen history across the life course may be associated with better cognitive maintenance. Few large longitudinal studies have evaluated this prospectively, and results have been inconsistent. We assessed the association of reproductive span, an indicator of endogenous estrogen history, with cognitive change in older women. We followed 13,419 Nurses’ Health Study participants who were free of stroke, were ≥70 years old as of 1995-2001, reported natural menopause or bilateral oophorectomy and had information on ages at menarche and menopause. Reproductive span was defined as age at menopause minus age at menarche. Four telephone-based cognitive assessments were administered (at 1.5-2 year intervals). The primary outcome was the global composite score, averaging z-scores of 6 tests measuring general cognition (the Telephone Interview of Cognitive Status, TICS), verbal memory, category fluency, and attention. Linear mixed-effects models, adjusted for age, education, depression, menopausal hormone therapy (MHT) within 10 years of menopause, surgical menopause, and other lifestyle and health variables, were used to estimate the differences in annual rate of change over time by quintiles (Qs) of reproductive span. We examined interactions with menopause type, MHT duration and apolipoprotein E ( APOE ) e4 allele (among 5,434 women). The mean baseline age was 74.3 years, the mean follow-up was 6.6 years, and the mean reproductive span was 36.4 years (range = 7-46 years). Longer reproductive span was significantly associated with more favorable cognitive change: compared with women with the shortest reproductive span (Q1: ≤33 years), women with the longest reproductive span (Q5: ≥41 years) demonstrated better maintenance in global cognition (difference in annual rate of change Q5vs.Q1 = 0.007; 95% CI: 0.00001, 0.01; p-trend = 0.02); this difference was equivalent to that observed in women 1.4 years apart in age. We observed similar trends with TICS and verbal memory (p-trends≤0.04), but not category fluency (longer reproductive span was associated with better baseline performance, p≤0.01; but not differences in rates of decline) and attention (no associations found). We observed no interactions with surgical menopause, MHT, or APOE e4. Longer reproductive span, an indicator of greater endogenous estrogen history, was significantly associated with more favorable cognitive maintenance in older women.

Previous studies yielded inconsistent results regarding the association between red meat intake and cognitive health. We aimed to prospectively examine the associations between processed and unprocessed red meat intakes and various cognitive outcomes. We assessed diet intake every 2-4 years using food-frequency questionnaires and ascertained incident dementia cases through self-report and death records in 87,424 participants free from Parkinson’s disease or baseline dementia, stroke, cancer from the Nurses' Health Study (NHS). In a subset of 17,458 NHS participants, cognitive function was assessed using the Telephone Interview for Cognitive Status (1995-2008). We longitudinally collected information on subjective cognitive decline from 33,908 NHS participants and 10,058 participants in the Health Professionals Follow-Up Study. During a follow-up of 38 years (1980-2018) in the NHS, we documented 6,856 dementia cases. Participants with processed red meat intake ≥ 0.25 serving/day, as compared to < 0.10 serving/day, had 15% higher risk of dementia (HR = 1.15; 95% CI: 1.08-1.23; P linearity <0.001). We found significant associations between higher processed red meat intake and accelerated aging in global cognition [1.61 years per 1 serving/day increment (95% CI: 0.20, 3.03)] and verbal memory [1.69 years per 1 serving/day increment (95% CI: 0.13, 3.25), both P linearity = 0.03]. Participants with processed red meat intake ≥ 0.25 serving/day had a 14% higher likelihood of subjective cognitive decline compared to those with intake < 0.10 serving/day (OR = 1.14; 95% CI: 1.04–1.24; P linearity = 0.004), while unprocessed red meat intake of ≥ 1.00 serving/day compared to < 0.50 serving/day was associated with a 16% higher likelihood of subjective cognitive decline (OR = 1.16; 95% CI: 1.04–1.30; P linearity = 0.02). In substitution analyses, replacing 1 serving/day of processed red meat with 1 serving/day of nuts and legumes was associated with a 23% lower risk of dementia (HR = 0.77, 95% CI: 0.69–0.86), 1.37 fewer years of cognitive aging (95% CI: -2.49—0.25), and a 20% lower odds of subjective cognitive decline (OR = 0.80, 95% CI: 0.69–0.92). Higher intake of red meat, particularly processed red meat, is associated with a higher risk of developing dementia and worse cognition.

Posttraumatic stress disorder (PTSD) is associated with mortality and increased risk of diseases of aging, but underlying mechanisms remain unclear. We examine associations of PTSD with one potential pathway, accelerated epigenetic aging. In a longitudinal cohort of trauma-exposed middle-aged women (n = 831, n observations = 1,516), we examined cross-sectional and longitudinal associations between PTSD, with and without comorbid depression, and epigenetic aging measured by six clocks at two time points approximately 13.5 years apart: Hannum, Horvath, PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE. We further examined associations of 3 well-established predictors of aging and mortality also linked with PTSD, namely, body mass index (BMI), diet quality, and physical activity, with epigenetic aging. Cross-sectionally, across all six clocks, epigenetic aging in women with PTSD alone, depression alone, and co-occurring depression and PTSD did not differ from the reference group of women without PTSD or depression in analyses adjusted for age, self-reported race, cell proportions, and ancestry principal components. In longitudinal analyses, we similarly did not find any difference in change in epigenetic age over time by PTSD and depression status at baseline. Among the health factors, in cross-sectional analyses, higher BMI was significantly and consistently associated with greater epigenetic aging measured by the PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE clocks, but not measured by the Hannum or Horvath clocks. Physical activity was not consistently associated with epigenetic aging measured by Hannum, Horvath, PhenoAge, or GrimAge. In analyses with the DunedinPoAm and DunedinPACE clocks, women who reported exercise equivalent to 1 or more hours/week walking had slower epigenetic aging than women with less exercise. Diet quality was not consistently associated with epigenetic aging measured by any of the clocks. Our data do not provide evidence that biological aging, as measured by any of the six epigenetic clocks, is a pathway linking PTSD with mortality and diseases of aging.

Alzheimer's disease (AD) and AD-related dementias (AD/ADRD) have a substantial genetic basis, with APOE4 homozygotes increasingly recognized as a distinct genetic subtype. To identify genotype-specific metabolic pathways and modifiable risk factors, we integrated genetic, plasma metabolomic and dietary data from 4,215 women and 1,490 men in prospective cohorts. Here we show that the associations of 57 metabolites with dementia risk varied by APOE4 genotype or other AD/ADRD risk variants. For example, cholesteryl esters and sphingomyelins were most strongly associated with increased dementia risk in APOE4 homozygotes, whereas inverse associations with glycerides were specific to this genotype. Dimethylguanidino-valeric acid was more strongly associated with dementia risk among carriers of the rs2154481-C allele (APP). Adherence to the Mediterranean diet more effectively modulated dementia-related metabolites in APOE4 homozygotes, suggesting targeted prevention strategies. Incorporating metabolomic data modestly improved dementia risk prediction, particularly during early follow-up. Mendelian randomization analysis identified 19 putative causal relationships between metabolites and cognitive outcomes, including protective effects of 4-guanidinobutanoate, carotenoids and N6-carbamoylthreonyladenosine. These findings reveal genotype-dependent metabolic profiles of cognitive health and support precision nutrition approaches for ADRD prevention.

Background: Exfoliation syndrome (XFS) is a form of deleterious ocular aging mediated by genetic and environmental factors that frequently produces glaucoma (XFG). We aimed to develop a genetic risk score (GRS), assess its clinical utility, and identify metabolites/metabolite classes associated with a high GRS. Methods: For 39,472 Nurses’ Health Studies (NHS, 1980–2018; NHS2, 1989–2019) and Health Professionals Follow-up Study (1986–2018) participants aged ≥ 40 years reporting eye exams and no baseline glaucoma, we formed an eight-single nucleotide polymorphism Genetic Risk Score (GRS8) using loci with genome-wide associations with XFS. We estimated relative risks (RR) for incident XFG suspect (XFGS)/XFG (n = 118 cases) and Harrell’s C statistics. Among 7547 participants with plasma metabolites measured via liquid chromatography-mass spectrometry, we evaluated the relation between GRS8 and 427 individual metabolites and 20 metabolite classes, adjusting for multiple comparisons. Results: Higher GRS8 was associated with XFGS/XFG (GRS8 RRQuintile(Q)5vs.Q1 = 3.82, 95% CI: 1.76, 8.29). GRS8 significantly (p = 0.04) improved model prediction from C-index of 88% (95% CI: 0.84, 0.92) to 93% (95% CI: 0.91, 0.95) when added to a basic risk model including age, sex, period at risk, intraocular pressure, and glaucoma family history. Metabolite class analyses revealed positive associations of bile acids and inverse associations of fatty acyls with GRS8 (adjusted p < 0.001). Conclusions: XFS GRS8 improved XFGS/XFG prediction, and a higher XFS GRS8 was associated with altered levels of fatty acyl and bile acid metabolite classes.