We found that higher dietary intake of vitamin E, but not vitamin C, beta carotene, or flavonoids, was associated with a decreased long-term risk of dementia over an average of ten years in the Rotterdam Study. These findings extend an earlier analysis in this cohort, which indicated that higher consumption of vitamins E and C might be related to lower AD risk. Despite their differences, these studies provide consistent evidence for a modest benefit of dietary vitamin E on dementia risk over the shorter and longer term.
The brain is a site of high metabolic activity, which makes it vulnerable to oxidative damage, and slow accumulation of such damage over a lifetime may contribute to the development of dementia. In particular, when beta-amyloid (a hallmark AD pathology) accumulates in the brain, an inflammatory response is likely evoked that produces nitric oxide radicals and downstream neurodegenerative effects1
. Vitamin E is a powerful, fat-soluble antioxidant that may help to inhibit dementia pathogenesis. In experimental studies, vitamin E has been shown to attenuate toxic effects of beta-amyloid and improve cognitive performance in rodents3–8
. Although optimal timing for antioxidant benefits is unclear, existing evidence indicates that antioxidants affect early stages of dementia16–18
. Still, the on-going accumulation of beta-amyloid in AD may imply a sustained contribution of oxidative damage, and thus continued benefits of vitamin E intake throughout pathogenesis.
In contrast to our previous study, the current findings do not include an inverse association between vitamin C and dementia risk. However, this result was modest in our shorter-term analysis (HR, 0.66; 95% CI, 0.44–1.00)14
, and therefore chance is the most likely explanation. Alternatively, vitamin C intake could be important exclusively at later stages of dementia development, but this is less likely because previous studies suggest that antioxidants influence early stages of dementia pathogenesis16–18
. Another possibility is that reverse causation biased our initial finding (i.e. the presence of sub-clinical dementia in cases diagnosed shortly after baseline could have resulted in decreasing intake of vitamin C); yet, if this type of bias occurred, we would expect to observe similar effects for beta carotene, as both antioxidants are derived from “healthy” fruits and vegetables. Furthermore, we did not replicate our previous findings of interactions between vitamins E and C, or between any of the antioxidants and smoking; these too were likely due to chance. On balance, an important perspective may be the contrast between these differences and consistent vitamin E findings over time – evidence that supports a causal link between vitamin E intake and dementia risk.
Previous observational studies of dietary antioxidants and dementia risk have yielded inconsistent results based on relatively short or very long follow-up periods. In the Chicago Health and Aging Project (CHAP), greater intake of vitamin E, but not vitamin C or beta carotene, was associated with substantial reductions in AD risk over a mean follow-up of two years (OR, 0.30; 95% CI, 0.10–0.92, adjusted for potential confounders)11
. The PAQUID cohort found that higher intake of flavonoids (and not vitamin C) was related to decreased risk of dementia over a five-year span. In contrast, the Washington Heights-Inwood Columbia Aging Project (WHICAP) found no relations for vitamin E, vitamin C, or carotenes with AD over an average follow-up of four years, although confidence intervals were wide and vitamin E intake appeared to be very low13
. In a much longer study, the Honolulu Asia Aging Study (HAAS) found no associations for vitamin E, vitamin C, beta carotene, or flavonoids with dementia risk over a 30-year period (e.g. for vitamin E: HR, 1.33; 95% CI, 0.90–1.96, in multivariate-adjusted models comparing extreme quartiles)31
; however, 30% of participants were lost to follow-up, which could have contributed to these null findings. Furthermore, the ascertainment of dietary antioxidants thirty years prior to diagnosis of incident dementia may be too remote to detect associations. Overall, more research is clearly needed to assess points at which antioxidant intake might be most relevant to dementia risk.
In our study, dietary intakes of antioxidants were comparable to, if not greater than, those of existing studies. For vitamin E, our participants had similar intake (mean=13.9 mg/day) compared to those in HAAS (mean=13.8 mg/day), but considerably higher intake than CHAP (median=5.7 mg/day) or WHICAP (mean=4.0 mg/day). Vitamin C and beta carotene levels were relatively consistent across cohorts (the exception was low beta carotene levels in HAAS), and flavonoid intake was considerably higher in our cohort (mean=28.5 mg/day) compared to PAQUID (mean=14.1 mg/day) and HAAS (mean=4.1 mg/day). Thus, dietary antioxidant levels appear to be sufficient compared to previously-studied populations, such that low dietary exposure is unlikely to explain our null findings for three out of four antioxidants.
Several meaningful differences distinguish the implications of our study from those of previous clinical trials involving vitamin E and dementia. First, we provide population-based estimates of incident dementia risk over a decade, as opposed to trials that examined short-term risk of dementia progression in clinic-based populations. Second, our study focused on food-based antioxidants in the context of a Western-type diet, with intakes several-fold lower than supplementation levels in trials. Finally, we studied a variety of antioxidants and total vitamin E (including all 8 forms), whereas trials have evaluated single-form, alpha-tocopherol supplements. Thus, our study provides additional information, beyond that of clinical trials, on diet-based antioxidants and long-term risk of incident dementia at levels consistent with a Western-type diet.
Several limitations of this study should be considered. First, this is an observational study and therefore residual confounding could explain the associations we observed. Although we cannot dismiss this possibility, we adjusted our statistical models for various health and lifestyle factors, which made little difference in our results compared to adjustment for age alone. We were particularly concerned about possible confounding by polyunsaturated fat intake; however, this is unlikely to have occurred because we previously showed that polyunsaturated fat was not associated with dementia risk in the Rotterdam Study32
. In addition, any participants who changed dietary or supplement habits with respect to antioxidants over the long follow-up period would tend to bias our results toward the null. However, since we would expect such attenuation to affect observed relations for all four antioxidants, our consistent findings for vitamin E over shorter- and longer-term follow-up suggest that these changes did not influence our results substantially.
In summary, we found that higher consumption of vitamin E from foods was modestly associated with long-term risk of dementia in this cohort of older adults in the Netherlands. Future studies should continue to evaluate dietary intake of antioxidants in relation to dementia risk, including different points at which antioxidant intake might modulate risk.