Background: The optimal intake levels of fruit and vegetables for maintaining long-term health are uncertain. Methods: We followed 66 719 women from the Nurses’ Health Study (1984–2014) and 42 016 men from the Health Professionals Follow-up Study (1986–2014) who were free from cardiovascular disease (CVD), cancer, and diabetes at baseline. Diet was assessed using a validated semiquantitative food frequency questionnaire at baseline and updated every 2 to 4 years. We also conducted a dose-response meta-analysis, including results from our 2 cohorts and 24 other prospective cohort studies. Results: We documented 33 898 deaths during the follow-up. After adjustment for known and suspected confounding variables and risk factors, we observed nonlinear inverse associations of fruit and vegetable intake with total mortality and cause-specific mortality attributable to cancer, CVD, and respiratory disease (all P _nonlinear <0.001). Intake of ≈5 servings per day of fruit and vegetables, or 2 servings of fruit and 3 servings of vegetables, was associated with the lowest mortality, and above that level, higher intake was not associated with additional risk reduction. In comparison with the reference level (2 servings/d), daily intake of 5 servings of fruit and vegetables was associated with hazard ratios (95% CI) of 0.87 (0.85–0.90) for total mortality, 0.88 (0.83–0.94) for CVD mortality, 0.90 (0.86–0.95) for cancer mortality, and 0.65 (0.59–0.72) for respiratory disease mortality. The dose-response meta-analysis that included 145 015 deaths accrued in 1 892 885 participants yielded similar results (summary risk ratio of mortality for 5 servings/d=0.87 [95% CI, 0.85–0.88]; P _nonlinear <0.001). Higher intakes of most subgroups of fruits and vegetables were associated with lower mortality, with the exception of starchy vegetables such as peas and corn. Intakes of fruit juices and potatoes were not associated with total and cause-specific mortality. Conclusions: Higher intakes of fruit and vegetables were associated with lower mortality; the risk reduction plateaued at ≈5 servings of fruit and vegetables per day. These findings support current dietary recommendations to increase intake of fruits and vegetables, but not fruit juices and potatoes.

Objectives: Gut-produced trimethylamine N-oxide (TMAO) is postulated as a possible link between red meat intake and poor cardiometabolic health. We investigated whether gut microbiome could modify associations of dietary precursors with TMAO concentrations and cardiometabolic risk markers among free-living individuals. Design: We collected up to two pairs of faecal samples (n=925) and two blood samples (n=473), 6 months apart, from 307 healthy men in the Men’s Lifestyle Validation Study. Diet was assessed repeatedly using food-frequency questionnaires and diet records. We profiled faecal metagenome and metatranscriptome using shotgun sequencing and identified microbial taxonomic and functional features. Results: TMAO concentrations were associated with the overall microbial compositions (permutational analysis of variance (PERMANOVA) test p=0.001). Multivariable taxa-wide association analysis identified 10 bacterial species whose abundance was significantly associated with plasma TMAO concentrations (false discovery rate <0.05). Higher habitual intake of red meat and choline was significantly associated with higher TMAO concentrations among participants who were microbial TMAO-producers (p<0.05), as characterised based on four abundant TMAO-predicting species, but not among other participants (for red meat, P-interaction=0.003; for choline, P-interaction=0.03). Among abundant TMAO-predicting species, Alistipes shahii significantly strengthened the positive association between red meat intake and HbA1c levels (P-interaction=0.01). Secondary analyses revealed that some functional features, including choline trimethylamine-lyase activating enzymes, were associated with TMAO concentrations. Conclusion: We identified microbial taxa that were associated with TMAO concentrations and modified the associations of red meat intake with TMAO concentrations and cardiometabolic risk markers. Our data underscore the interplay between diet and gut microbiome in producing potentially bioactive metabolites that may modulate cardiometabolic health.

Evaluation of time trends in dietary quality and their relation to disease burden provides essential feedback for policy making. We used an index titled the Alternate Healthy Eating Index 2010 to e...

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 N ⁶ -carbamoylthreonyladenosine. These findings reveal genotype-dependent metabolic profiles of cognitive health and support precision nutrition approaches for ADRD prevention.

Previous studies have shown inconsistent associations between red meat intake and cognitive health. Our objective was to examine the association between red meat intake and multiple cognitive outcomes. In this prospective cohort study, we included participants free of dementia at baseline from 2 nationwide cohort studies in the United States: the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Diets were assessed using a validated semiquantitative food frequency questionnaire. We ascertained incident dementia cases from both NHS participants (1980-2023) and HPFS participants (1986-2023). Objective cognitive function was assessed using the Telephone Interview for Cognitive Status (1995-2008) among a subset of NHS participants. Subjective cognitive decline (SCD) was self-reported by NHS participants (2012, 2014) and HPFS participants (2012, 2016). Cox proportional hazards models, general linear regression, and Poisson regression models were applied to assess the associations between red meat intake and different cognitive outcomes. The dementia analysis included 133,771 participants (65.4% female) with a mean baseline age of 48.9 years, the objective cognitive function analysis included 17,458 female participants with a mean baseline age of 74.3 years, and SCD analysis included 43,966 participants (77.1% female) with a mean baseline age of 77.9 years. Participants with processed red meat intake ≥0.25 serving per day, compared with <0.10 serving per day, had a 13% higher risk of dementia (hazard ratio [HR] 1.13; 95% CI 1.08-1.19; p_linearity < 0.001) and a 14% higher risk of SCD (relative risk [RR] 1.14; 95% CI 1.04-1.25; p_linearity = 0.004). Higher processed red meat intake was associated with accelerated aging in global cognition (1.61 years per 1 serving per day increment [95% CI 0.20-3.03]) and in verbal memory (1.69 years per 1 serving per day increment [95% CI 0.13-3.25], both p_linearity = 0.03). Unprocessed red meat intake of ≥1.00 serving per day, compared with <0.50 serving per day, was associated with a 16% higher risk of SCD (RR 1.16; 95% CI 1.03-1.30; p_linearity = 0.04). Replacing 1 serving per day of nuts and legumes for processed red meat was associated with a 19% lower risk of dementia (HR 0.81, 95% CI 0.75-0.86), 1.37 fewer years of cognitive aging (95% CI -2.49 to -0.25), and a 21% lower risk of SCD (RR 0.79, 95% CI 0.68-0.92). Higher intake of red meat, particularly processed red meat, was associated with a higher risk of developing dementia and worse cognition. Reducing red meat consumption could be included in dietary guidelines to promote cognitive health. Further research is needed to assess the generalizability of these findings to populations with diverse ethnic backgrounds.