Higher, long-term consumption of berries, anthocyanidins, and total dietary flavonoids were related to significantly slower rates of cognitive decline in this cohort of older women, even after careful consideration of confounding by socioeconomic status. We report the first epidemiologic evidence that greater intakes of blueberries and strawberries (top food contributors to anthocyanidin intake) were highly associated with slower rates of cognitive decline – consistent with a large body of experimental data supporting cognitive benefits of berries. The magnitude of associations that we identified for berries and flavonoids were equivalent to the cognitive differences that we observe in women up to 2.5 years apart in age – that is, women with higher intake of berries and total flavonoids appeared to have delayed cognitive aging by as much as 2.5 years.
Very small trials have indicated that berry supplementation can enhance cognitive function over twelve weeks in older adults with early cognitive impairments 8, 9
. In a study of older men (n=342), total flavonoid consumption was related to a lower risk of cognitive impairment, although findings were not statistically significant (comparing the top versus bottom tertiles: odds ratio=0.86, 95% confidence interval=0.39, 1.89) 24
. However, this study had limited power to detect associations between flavonoids and cognition due to its modest size. A larger study in France (n=1,640) identified a relation between greater flavonoid intake and slower cognitive decline over a ten-year period (p-trend=0.05 in models adjusted for age, sex, and education) 25
. These results were attenuated and became non-significant upon adjustment for smoking, body-mass index, and fruit and vegetable intake; however, the inclusion of fruit and vegetable intake probably represents over adjustment because these foods contain flavonoids, and therefore the adjusted results are difficult to interpret. In all of these studies, no specific information on long-term dietary habits was available; as previously noted, long-term diet is likely to be most relevant for cognitive decline. In our data, correlations were modest across repeated measures of berry intake (ρ=0.2–0.3), which probably reflects true within-person changes in berry consumption over time (e.g., due to changes in berry availability by year and region26, 27
) and also reflects some amount of random measurement error. By averaging reported intakes over multiple dietary assessments, we account for within-person changes in intake and also reduce random measurement error (as has been previously documented by our group28
). Thus, for biologic and statistical reasons, existing epidemiologic data probably underestimate any relation between flavonoids and cognition.
Substantial biologic evidence supports our finding that berry and flavonoid intake may be related to cognition. Berry-derived anthocyanidins are uniquely and specifically capable of both crossing the blood-brain barrier and localizing in brain regions involved in learning and memory (e.g., the hippocampus).10
In multiple studies of rats, blueberry or strawberry supplementation significantly reduced age-related declines in neuronal signaling and cognitive behavior, and supplementation at older ages reversed neuronal and cognitive decline 29
. More generally, several flavonoids have been shown to inhibit the c-jun N-terminal kinases, apoptosis signal-regulating kinase-1, and p38 pathways, which can lead to reductions in neuroinflammation and enhanced neuronal viability. In addition, flavonoid-rich foods can activate extracellular receptor kinase and protein kinase B/Akt pathways, which are thought to enhance memory and cognition. Overall, although flavonoids are traditionally regarded for their antioxidant properties, the discovery of these various molecular targets suggests that flavonoids may act through multiple mechanisms; this might explain why, other than a specific effect of anthocyanidins, we largely observed that greater overall flavonoid intake appeared more important than any single flavonoid subclass or flavonoid-rich food.
Our study has limitations. First, this is an observational study, and we cannot rule out the possibility that residual confounding explains observed associations. However, we adjusted for a large variety of health and lifestyle factors, as well as socioeconomic and dietary variables, and observed very little change in our effect estimates before and after adjustment, which suggests that residual confounding is unlikely to further influence our findings meaningfully. Second, the self-reported dietary information contains some random misclassification; however, this would tend to bias our results toward the null and therefore cause an underestimate of the relation between flavonoids and cognition. Finally, we identified associations between higher berry and flavonoid intake and slower cognitive decline in an all-female cohort, and therefore our results could be limited in their generalizability to men. Yet, few existing studies have reported substantial sex differences in dietary risk factors for cognitive decline and dementia, suggesting that limited generalizability is probably not a large concern in our study. Still, future studies should consider men in analyses of berries, flavonoids, and cognitive decline.
In conclusion, we found that higher consumption of berries and anthocyanidins, as well as total flavonoids, is associated with a slower progression of cognitive decline in older women. These findings potentially have substantial public health implications, as increasing berry intake represents a fairly simple dietary modification to test in older adults for maintaining cognition.