Significance
hippocampal-dependent memory, late-life cognitive diseases
SECONDARY, CORTEX
Edited by Fred Gage, Salk Institute for Biological Studies, La Jolla, CA; received October 5, 2022; accepted March 29, 2023Just like there are specific constituents of our diets that are vital for the developing brain, other dietary constituents might be important for the aging brain. This study, a culmination of 15 y of research from mice to humans, provides biomarker-based evidence that dietary consumption of flavanols, a food constituent found in certain fruits and vegetables, can be etiologically linked to age-related memory decline.Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion–repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.“Cognitive aging” is a term used to describe how some of our cognitive abilities decline during the aging process, independent of late-life cognitive diseases (Studies suggest that habitual dietary patterns, diet quality, and even specific dietary constituents might represent etiologic factors that affect cognitive aging (In a 3-mo, randomized, placebo-controlled trial (We set out to confirm these observations by integrating multiple longitudinal cognitive assessments into an ongoing large-scale, multiyear, randomized, double-blind placebo-controlled trial, the COcoa Supplement and Multivitamin Outcomes Study (COSMOS; NCT02422745) through an ancillary study COSMOS-Web (NCT04582617) that used web-based cognitive assessments. To address the motivating question, we focused on the one arm of COSMOS in which either a flavanol-containing cocoa extract [500 mg of cocoa flavanols, including 80 mg of (–)-epicatechin] or a placebo was given daily to more than 3,500 generally healthy older men and women. Besides testing whether the flavanol intervention might improve hippocampal-dependent memory, especially in those with relatively poorer habitual diets, the study also allowed us to test the effect over extended durations. Additionally, given its size and scope, COSMOS allowed us to test at scale whether dietary flavanols are indeed differentially linked to hippocampal and not to frontal cortex function. Finally, because many of the COSMOS participants provided urine samples, we were able to apply a validated urine-based biomarker of dietary flavanol consumption (In the context of COSMOS-Web, determining whether the flavanol intervention improved hippocampal-dependent memory across all participants at year 1 was the prespecified primary end point, and whether the intervention improved hippocampal-dependent memory primarily in participants with relatively lower habitual diet quality was the prespecified secondary end point.