Discussion
late-life cognitive diseases, neuronal cell death, hippocampal-dependent memory, lower habitual flavanol, pernicious
NEURODEGENERATIVE DISORDERS, DYSFUNCTION, PATHOPHYSIOLOGY
In the context of a clinical trial notable for its large scale and long duration, we find that although the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, a flavanol intervention-based restoration of memory was observed in the lower tertile of habitual diet quality and in the subset of participants with lower habitual flavanol consumption. The improvement in memory was apparent after 12 mo of intervention and appeared to be sustained over the 3 y of follow-up. Replicating and extending our previous finding in a much larger number of older people and for up to 3 y of follow up, we also found that diet quality is a key lifestyle factor linked to the hippocampal and not to the prefrontal component of cognitive aging, as indexed by performance on neuropsychological instruments that assess these respective systems. We demonstrate that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. Improvements in the flavanol biomarker over the course of the trial were associated with improving memory.The experimental findings implicate dietary flavanols as a specific constituent of a healthy diet that when habitual consumption is lower can underlie the hippocampal-dependent memory component of cognitive aging. This interpretation was confirmed in a subset of participants by measuring their urinary gVLM concentrations, a validated biomarker of flavanol consumption. Like diet quality, baseline gVLM levels selectively correlated with hippocampal-dependent memory, and the group with relatively lower gVLM levels exhibited worse baseline memory. In this subset of participants, the observed memory restorative pattern was even more pronounced, and based on a population distribution, their below-average gVLM concentrations effectively normalized after 1 y of the flavanol-based intervention. Furthermore, when investigating the whole sample, an increase in gVLM concentrations over the course of the trial was associated with improving hippocampal-dependent memory. Taken together, the findings allow the causal logic of “depletion–repletion” to be invoked in support of an etiological conclusion: that relatively lower flavanol consumption can act as a dietary driver of the hippocampal-dependent component of cognitive aging.While we have systematically repleted dietary flavanols in those with habitually lower flavanol consumption at baseline, we did not do the opposite. Therefore, we cannot definitively conclude whether lower dietary intake alone can induce the relatively poorer memory performance observed at baseline. However, given the association between flavanol consumption and memory observed at baseline in this and previous studies, a flavanol depletion experiment in humans, while potentially informative, might be deemed unethical. An alternative approach is for a future trial to enroll participants on the lowest end of the gVLM distribution and to test the prediction that a more dramatic improvement in memory will be observed upon flavanol repletion.Another reason supporting an etiological conclusion is related to anatomical biology. Showing that a healthy diet in general and flavanols in particular are most reliably linked to the hippocampal and not to the prefrontal component of cognitive aging implies mechanistic specificity. Previous studies in mice demonstrated that dietary flavanols can enhance hippocampal-dependent memory by increasing synaptic and blood vessel density, particularly in the dentate gyrus, a subregion of the hippocampus (One limitation of the study is that while there is general concordance between analyses stratified by habitual diet quality (While the effect size of the flavanol-associated increase in memory might be considered small, sustained and small effect sizes are often characteristic of randomized clinical trials that are based on diet and lifestyle modifications in generally healthy people and at a population level are often meaningful to health maintenance, dietary guidance, and public health (Compared to common late-life cognitive diseases such as neurodegenerative disorders, the pathophysiology of cognitive aging is distinct and less pernicious, characterized by synaptic dysfunction, not by neuronal cell death (We are not only living longer, but we are living cognitively more demanding lives. Our findings suggest that flavanol consumption might be considered in future dietary recommendations, perhaps together with the flavanol biomarker, specifically geared toward preventing or improving brain health in later life.