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Controversial Study Claims That Diets Lacking in Key Nutrients Could Contribute to Later-Life Memory Loss

A person holding kale.
Kale is a source of flavanols. Credit: Adolfo Félix/Unsplash
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A new study has claimed that a diet lacking nutrients normally found in certain vegetables and fruits, called flavanols, may influence our risk of developing age-related memory loss. However, the findings suggest that dietary supplements may provide only modest benefits, if any.

The study presented data suggesting that higher flavanol consumption among older adults is associated with superior scoring on memory tests and that boosting the level of flavanols in the diets of those who consume little of the compounds can enhance their performance on these memory tests. Nevertheless, the study, which aimed to assess whether flavanol pills could enhance memory, failed on its primary endpoint, suggesting no such benefit is apparent for the majority of people.

The study was organized by researchers at Columbia and Brigham and Women’s Hospital alongside researchers from Mars Edge, a division of food conglomerate Mars Inc.

Flavanols’ impact

Flavanols have been widely studied for their potential benefits in human health. The main dietary flavanols are quercetin, myricetin, kaempferol and fisetin. The compounds, which are enriched in tomatoes, kale, apples, grapes, red wine, cocoa and olives, have been proposed to have effects that may help ward off cancer and diabetes. They’re even thought to provide resistance against viral and bacterial agents.

Adam M. Brickman, professor of neuropsychology at Columbia University Vagelos College of Physicians and Surgeons and co-leader of the study, says, “The improvement among study participants with low-flavanol diets was substantial and raises the possibility of using flavanol-rich diets or supplements to improve cognitive function in older adults.”

The authors suggest that their findings point to the need for certain nutrients to be considered part of a healthy aging diet, in the same way that we consider other compounds essential for healthy brain development in infants. “In this century, as we are living longer research is starting to reveal that different nutrients are needed to fortify our aging minds. Our study, which relies on biomarkers of flavanol consumption, can be used as a template by other researchers to identify additional, necessary nutrients,” says the study's senior author, Scott A. Small, the Boris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons.

This optimism was not shared with academics outside the flavonoid field, however. “It is great to see a randomized trial in this space with decent numbers. The key result is in fact the trial result, which was clearly negative at all three years. In other words, there is no evidence that a diet rich in flavanols protects from memory loss,” said Naveed Sattar, a professor of metabolic medicine at the University of Glasgow who was not involved with the research.

Potential memory boost

Research in Small’s lab has focused for over a decade on the link between changes to memory during aging and a region of the brain called the dentate gyrus. Found within the hippocampus – a region critical to wider memory-related tasks – Small and colleagues previously showed that this region’s function could be enhanced by flavanols.

Other research has shown in pre-clinical model mice that a flavanol-derived compound, epicatechin, could encourage cell and blood vessel growth in the dentate gyrus. Small has since trialed flavanols in different human cohorts, which hinted that similar effects to those seen in mice could be realized in humans.

The latest study was part of the COSMOS (COcoa Supplements and Multivitamin Outcomes Study), program, which gave Small the chance to test out flavanols’ effects in a much larger group. In total, 3,500 people were recruited for the research. All were healthy older adults who were randomly asked to take either a placebo pill or an identical 500 mg flavanol capsule. This included 80 mg of epicatechins – which is the recommended daily intake for adults.

The study lasted three years. At the onset of the work and annually thereafter, the cohort was asked to take memory tests that aimed to assess short-term memory centered in the hippocampus. The team also assessed their baseline level of flavanol intake via surveys and, in a third of the cohort who agreed, urine samples. Additional sampling conducted throughout the trial showed that compliance with the regimen was high. Interestingly, no participants in the study were found to be severely flavanol-deficient at the study’s onset.

Digging down into deficit data

Most of the cohort were regularly eating flavanols in their diet, which potentially contributed to the headline finding that flavanols had little effect on memory scores for the group as a whole. To find an effect, the researchers had to dig down into their data, looking at the subset of the cohort who consumed the lowest amount of flavanols in their unsupplemented diet. In this group, memory scores improved by 16% after a year of taking flavanol pills. In comparison to a placebo group, there was a 10.5% memory boost. This improvement was sustained for the additional two years of the study.

While this benefit was said to be significant, the analysis conducted in the paper came in for heavy criticism. “The authors do claim that a couple of results are statistically significant but in my view this is because the analyses have been performed incorrectly,” said David Curtis, an honorary professor at University College London in a statement to the UK Science Media Centre.

The research shows that “flavanols have no effect on people who don’t have a flavanol deficiency,” says Small. Previous research that found no effect of flavanols on memory did not look at how subgroups were affected, Small explains. He also says that these previous studies may have failed to assess hippocampal memory – a point that will continue to be debated among behavioral neuroscientists. Dr. Carl Hodgetts, a senior lecturer at Royal Holloway, University of London, who was not involved in the research, suggests that the word choice tests used by Small might also fail to capture this dimension of recall, saying that “the relevance of these findings to the hippocampus and aging-related diseases like dementia are somewhat overstated in the paper.”

The next step, Small suggests, would be to look at adults with severe flavanol deficiency, who may experience a greater cognitive benefit from supplementation.

“Age-related memory decline is thought to occur sooner or later in nearly everyone, though there is a great amount of variability,” says Small. “If some of this variance is partly due to differences in dietary consumption of flavanols, then we would see an even more dramatic improvement in memory in people who replenish dietary flavanols when they’re in their 40s and 50s.”

Reference: Brickman AM, Yeung L, Alschuler DM et al. Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption. PNAS. 2023. doi: 10.1073/pnas.2216932120

This article is a rework of a press release issued by Columbia University Irving Medical Center. Material has been edited for length and content.