Objective To investigate the optimal combination of dietary polyphenols associated with the long-term risk of dementia in a large prospective French cohort of older persons, the Three-City (3C) Study. Methods We included 1,329 older adults without dementia from the 3C study with assessment of intake of 26 polyphenol subclasses who were followed up for 12 years for dementia. Using partial least squares for Cox models, we identified a pattern of polyphenol intake associated with dementia risk. Results The pattern combined several flavonoids (dihydroflavonols, anthocyanins, isoflavonoids, flavanones), stilbenes (including resveratrol), lignans, and other subclasses (hydroxybenzaldehydes, naphthoquinones, furanocoumarins). Compared with participants in the lower quintile of pattern score, those in the higher quintile had a 50% lower risk of dementia (95% confidence interval 20%–68%, p for trend <0.01) in multivariate models. Conclusions In this French cohort, a polyphenol pattern provided by a diet containing specific plant products (nuts, citrus, berries, leafy vegetables, soy, cereals, olive oil) accompanied by red wine and tea was associated with lower dementia risk.

Scope: Untargeted metabolomics may reveal preventive targets in cognitive aging, including within the food metabolome.Methods and results: A case‐control study nested in the prospective Three‐City study includes participants aged ≥65 years and initially free of dementia. A total of 209 cases of cognitive decline and 209 controls (matched for age, gender, education) with slower cognitive decline over up to 12 years are contrasted. Using untargeted metabolomics and bootstrap‐enhanced penalized regression, a baseline serum signature of 22 metabolites associated with subsequent cognitive decline is identified. The signature includes three coffee metabolites, a biomarker of citrus intake, a cocoa metabolite, two metabolites putatively derived from fish and wine, three medium‐chain acylcarnitines, glycodeoxycholic acid, lysoPC(18:3), trimethyllysine, glucose, cortisol, creatinine, and arginine. Adding the 22 metabolites to a reference predictive model for cognitive decline (conditioned on age, gender, education and including ApoE‐ε4, diabetes, BMI, and number of medications) substantially increases the predictive performance: cross‐validated Area Under the Receiver Operating Curve = 75% [95% CI 70–80%] compared to 62% [95% CI 56–67%].Conclusions: The untargeted metabolomics study supports a protective role of specific foods (e.g., coffee, cocoa, fish) and various alterations in the endogenous metabolism responsive to diet in cognitive aging.

B vitamins may lower the risk of dementia, yet epidemiological findings, mostly from countries with folic acid fortification, have remained inconsistent. We evaluated in a large French cohort of older persons the associations between dietary B vitamins and long-term incident dementia. We included 1321 participants from the Three-City Study who completed a 24 h dietary recall, were free of dementia at the time of diet assessment, and were followed for an average of 7.4 years. In Cox proportional hazards models adjusted for multiple potential confounders, including overall diet quality, higher intake of folate was inversely associated with the risk of dementia (p for trend = 0.02), with an approximately 50% lower risk for individuals in the highest compared to the lowest quintile of folate (HR = 0.47; 95% CI 0.28; 0.81). No association was found for vitamins B6 and B12. In conclusion, in a large French cohort with a relatively low baseline folate status (average intake = 278 µg/day), higher folate intakes were associated with a decreased risk of dementia.

The gut microbiome is involved in nutrient metabolism and produces metabolites that, via the gut–brain axis, signal to the brain and influence cognition. Human studies have so far had limited success in identifying early metabolic alterations linked to cognitive aging, likely due to limitations in metabolite coverage or follow-ups. Older persons from the Three-City population-based cohort who had not been diagnosed with dementia at the time of blood sampling were included, and repeated measures of cognition over 12 subsequent years were collected. Using a targeted metabolomics platform, we identified 72 circulating gut-derived metabolites in a case–control study on cognitive decline, nested within the cohort (discovery n = 418; validation n = 420). Higher serum levels of propionic acid, a short-chain fatty acid, were associated with increased odds of cognitive decline (OR for 1 SD = 1.40 (95% CI 1.11, 1.75) for discovery and 1.26 (1.02, 1.55) for validation). Additional analyses suggested mediation by hypercholesterolemia and diabetes. Propionic acid strongly correlated with blood glucose (r = 0.79) and with intakes of meat and cheese (r > 0.15), but not fiber (r = 0.04), suggesting a minor role of prebiotic foods per se, but a possible link to processed foods, in which propionic acid is a common preservative. The adverse impact of propionic acid on metabolism and cognition deserves further investigation.

Brain lipid metabolism appears critical for cognitive aging, but whether alterations in the lipidome relate to cognitive decline remains unclear at the system level. We studied participants from the Three-City study, a multicentric cohort of older persons, free of dementia at time of blood sampling, and who provided repeated measures of cognition over 12 subsequent years. We measured 189 serum lipids from 13 lipid classes using shotgun lipidomics in a case-control sample on cognitive decline (matched on age, sex and level of education) nested within the Bordeaux study center (discovery, n = 418). Associations with cognitive decline were investigated using bootstrapped penalized regression, and tested for validation in the Dijon study center (validation, n = 314). Among 17 lipids identified in the discovery stage, lower levels of the triglyceride TAG50:5, and of four membrane lipids (sphingomyelin SM40:2,2, phosphatidylethanolamine PE38:5(18:1/20:4), ether-phosphatidylethanolamine PEO34:3(16:1/18:2), and ether-phosphatidylcholine PCO34:1(16:1/18:0)), and higher levels of PCO32:0(16:0/16:0), were associated with greater odds of cognitive decline, and replicated in our validation sample. These findings indicate that in the blood lipidome of non-demented older persons, a specific profile of lipids involved in membrane fluidity, myelination, and lipid rafts, is associated with subsequent cognitive decline. The complete list of funders is available at the end of the manuscript, in the Acknowledgement section.