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AlzRisk Risk Factor Discussion

Risk Factor:
  (vitamin C, vitamin E)
Risk Factor Type: Nutrition and supplements
Current Understanding:
The tables in the Risk Factor Overview present a modest number of reports with generally null results on nutritional antioxidants (vitamins C and E)—based on dietary intake, dietary supplement use, or plasma levels— and risk of Alzheimer disease (AD) and total dementia. Apart from a possible suggestion of benefits of dietary vitamin E on AD risk, these data provide little support for a role of nutritional antioxidants in the prevention of Alzheimer disease. There are several limitations in these studies that could lead to either spurious negative or positive associations, and thus explain the mixed results. It also remains possible that specific types of exposures defined by timing (e.g., in midlife rather than late life), duration (e.g., over many years), or dietary context (e.g., with phytochemicals) might have beneficial effects that could not be detected in the studies reported to date. The collective findings from current studies do not suggest a protective effect of vitamin C on the risk of developing AD and therefore do not warrant a recommendation of increasing intake of vitamin C in the diet or through supplements to prevent AD. However, individuals might choose to increase intake of vitamin C for other reasons. For vitamin E supplementation, the body of the evidence argues against its use to prevent dementia due to lack of efficacy and potential toxicity. However, dietary vitamin E may be beneficial, and appears to carry little risk of toxicity. For a review of the putative mechanisms by which these nutritional antioxidants may influence AD risk and detailed commentary on interpreting the findings below in a broader context, please view the Discussion.
Literature Extraction: Search strategy  * New *
Last Search Completed: 27 October 2016 - Last content update released on 22 Nov 2016.

Risk Factor Overview

Cite as:

Koyama A*, Weuve J*, Jackson JW, Ray M, Blacker D. "Nutritional antioxidants." The AlzRisk Database. Alzheimer Research Forum. Available at: Accessed [date of access]*.

*contributed equally

* * *


The tables in the Risk Factor Overview present a modest number of reports with generally null results on nutritional antioxidants (vitamins C and E)—based on dietary intake, dietary supplement use, or plasma levels— and risk of Alzheimer disease (AD). Results for plasma vitamin E and, to a lesser degree, dietary vitamin E, suggest potential benefit, while those for vitamin C suggest no benefit. There are several limitations in these studies of nutritional antioxidants, which may partially explain these mixed findings.

Potential Mechanism of Action

Extensive evidence has implicated oxidative stress in the pathogenesis and progression of AD (Christen 2000). It is known that neurons are sensitive to damage from oxidative stress, and brains of individuals with AD often have lesions with features characteristic of oxidative damage. Much experimental research has indicated that antioxidants are neuroprotective. In vitro and animal studies have shown that vitamin C is able to inhibit hydrogen peroxide-generated oxidation (Grant, Barber et al. 2005; Waugh 2008) as well as to induce expression of brain-derived neurotrophic factor (Grant, Barber et al. 2005). A neuroprotective effect of vitamin E has also been shown in some animal studies, altering gene expression in the hippocampus (Rota, Rimbach et al. 2005). In humans, a randomized controlled trial (RCT) found that supplementation with vitamin E and C together, but not vitamin E alone, returned both plasma and cerebrospinal fluid (CSF) vitamin C levels to normal, consequently reducing the susceptibility of CSF and plasma lipoproteins to in vitro oxidation (Kontush, Mann et al. 2001).

In addition to these fairly general effects on neurodegeneration, there may be more specific effects on amyloid beta protein, a key component of the senile plaques characteristic of AD brains. Amyloid beta protein (A-beta) is associated with pro-oxidant activity, so it is thought that antioxidants may help prevent AD by reducing the deposition or toxicity of A-beta (Frei 1994; Christen 2000). In support of this notion, there is some evidence from animal studies that antioxidants may help prevent amyloid beta-induced cognitive deficits (Yamada, Tanaka et al. 1999). For all these reasons, there has been considerable interest in evaluating the potential of antioxidants for the prevention and treatment of AD.

Methodological Issues


The tables report on use versus non-use of supplemental antioxidants (vitamin C, vitamin E, and their combination), levels of antioxidant consumption in food (vitamin C, vitamin E), levels of total antioxidant intake (vitamin C, vitamin E), and plasma concentrations of vitamin E. Each of these measures has inherent advantages and disadvantages in terms of the relevance of the exposure they capture in relation to AD risk.

Supplement vs. dietary intake: Some studies report on supplements and others report on dietary intake. Supplement use typically involves much larger doses, particularly for vitamin E, which is not present in large amounts in the diet, but studies of supplement use typically do not report specific dosing or frequency of use. Several studies have reported on the combined use of vitamin C and E supplementation, corresponding to recent biologic data on their interaction. However, there are no studies of combined dietary intake (although we do show findings from studies that have examined combined dietary and supplemental intakes of each vitamin separately). In addition, no studies of supplement use controlled for food intake, even though fat and certain specific solid foods are known to increase the absorption of vitamin E (Jeanes, Hall et al. 2004; Leonard, Good et al. 2004). Last, no studies addressed other potential benefits of some dietary forms of vitamin E. Vitamin E in foods is a mixture of multiple tocopherols and tocotrienols, whereas supplements are primarily composed of alpha-tocopherol. Other forms of vitamin E, such as gamma-tocopherol, which has anti-inflammatory properties, or a combination of several forms of the vitamin, might confer additional benefits (Mangialasche, Kivipelto et al. 2010).

Plasma measures: A small number of studies reported here evaluated plasma concentrations of vitamin E, which may be more indicative of bioavailability, thus circumventing problems with recall and the correspondence between intake and absorption. Given the approximately 2-day residence time of vitamin E in the plasma (Ong, Niki et al. 1995), however, plasma concentrations will not reflect long-term exposure if intakes have varied substantially over time. There are no reported studies of plasma vitamin C.

Dose and timing: The effect of dose may be complex: very low and very high doses may well be hazardous, while doses within a nutritionally appropriate range could be beneficial with a potentially linear dose response curve. The health effects of antioxidants are likely also to depend on timing and duration of intake. In particular, the hypothesized relation of antioxidant exposures to AD risk implicitly assumes that benefits accrue with extended exposure over a long period, although the critical timing and duration of exposure remains unclear. Repeated measures—whether by questionnaire or in plasma—across the lifespan would be ideal for obtaining more precise estimates of long-term antioxidant intake and would help to distinguish the effects of long-term intake from recent intake, or midlife vs. late-life intake. Yet even those studies that collected two or more waves of dietary data often used just one wave of data in their analyses. Most studies enrolled participants well past middle age, and they did not elicit retrospective information on midlife diet (although these data would likely be subject to substantial recall error). One study assessed midlife dietary intake, but did not conduct repeated intake assessments through the 30 year follow-up period (Laurin, Masaki et al. 2004); it detected no association between antioxidant intake and AD.

Absorption: The bioavailability of consumed nutritional antioxidants (i.e., the degree to which they become available for physiologic use) depends on how efficiently they are absorbed in the gut and transported throughout the body. Age at measurement adds additional challenges. In older adults, absorption is typically less efficient, so blood levels are typically lower for a given intake of vitamin C (Garry, Vanderjagt et al. 1987; Brubacher, Moser et al. 2000). Not surprisingly, because nutritional antioxidant intake typically occurs in the context of food, the presence of other nutrients may be important. For instance, vitamin C may be more important in the presence of particular metals—with megadoses causing iron overload (and neurologic consequences)(Fleming, Tucker et al. 2002)—or in the presence of vitamin E, which vitamin C can restore from its oxidized form back to its original form (Bruno, Leonard et al. 2006). For vitamin E, as noted above, specific nutrients and food types may contribute to absorption.

Self report data: In epidemiologic studies, exposure to nutritional antioxidants is typically assessed by dietary questionnaires that elicit self reports of recalled food and supplement intake over time spans ranging from the past 24 hours to the past year. Extensive research has evaluated the reliability and validity of self-reported intakes. In general, while intakes estimated from questionnaires may not be accurate, they do preserve the ranks of actual intakes within a study population (i.e., persons with higher actual intakes are classified as having high questionnaire-based estimated intakes) (Ortiz-Andrellucchi, Sanchez-Villegas et al. 2009) and are correlated with bioavailability. Thus, barring other complications, questionnaire-based estimates of nutritional antioxidant intake can be adequate for use in large-scale studies where the “dilution effects” of measurement noise can be outweighed by the statistical power of large sample sizes.

However, questionnaire-based assessment close to the time of onset may be problematic because people with declining memory may not accurately report their diet or supplement use (Foley and White 2002). Although most studies used a screening process to eliminate individuals with poor cognitive function (because it could represent prodromal illness), it is still likely that some individuals in the preclinical phase of their disease were accepted into the studies. If these persons failed to report their exposure accurately, this could introduce additional error in the estimation of antioxidant intake and absorption; if such individuals systematically report high or low intakes there could be a bias (e.g., underreporting due to failure to recall supplement use could lead to a spurious finding of benefit) .


Confounding: A major concern in the analysis of vitamin intake, particularly for supplements, is that people who use supplements and those with healthier diets tend to have higher levels of education, to engage in more health-promoting behaviors, and to be cognitively healthier (Lyle, Mares-Perlman et al. 1998; Kirk, Cade et al. 1999; Foley and White 2002; Luchsinger, Tang et al. 2003; Zandi, Anthony et al. 2004; Boothby and Doering 2005; Gray, Anderson et al. 2008). Most studies adjusted for education, and many for health status, but it is likely that these proxies do not sufficiently represent health-seeking behavior, so residual confounding may be a concern in some analyses, potentially resulting in overestimates of the protective effect of antioxidant intake.

Other sources of potential bias: In some populations, supplement users and those with a healthier diet may also have more health problems (Engelhart, Geerlings et al. 2002; Foley and White 2002), suggesting that those recently diagnosed with a chronic illness may have initiated supplement use or altered their diet to protect their health. If that illness is also related to AD risk, then higher level of antioxidant intake would be correlated with greater AD risk, but as a consequence of disease rather than as a predictor. On the other hand, supplement use may wane in a period of subtle early cognitive decline (prior to dementia or MCI diagnosis), making nonuse of supplements spuriously appear to be related to AD risk.

Modeling issues: The studies varied in how they modeled levels of exposure. This was particularly true for supplement use, which was typically coded as yes or no, but studies used a wide variety of thresholds to define yes (e.g., taking supplements at least one day per week over the past year, taking supplements during at least one week of the month prior to baseline, or taking vitamin C or E-containing multivitamins).

All studies of dietary vitamin C and E as well as total vitamin C and E (diet + supplements) standardized intakes to total calories consumed, and analyzed intake in quantiles. The use of ordinal variables may reduce the influence of “extreme” exposures that can arise with many self-report instruments (e.g., very high levels of vitamin C intake among individuals who report frequent consumption of foods and supplements with high vitamin C content), but also may reduce a study’s ability to identify a significant association, particularly if the typical dose in the highest quantile falls below that needed to confer protection or if the typical dose in the lowest quantile exceeds the level at which adverse effects occur.

Studies of Other Outcomes and Randomized Controlled Trials

Longitudinal studies of cognitive function in older adults have shown mixed results for both vitamins E and C. One cohort study reported a significant protective effect of dietary and supplementary vitamin C on cognitive decline (Wengreen, Munger et al. 2007). Two cohort studies found that decreased cognitive decline was significantly associated with combined vitamin C and E supplement use, but not with vitamin C supplement use alone (Grodstein, Chen et al. 2003; Maxwell, Hicks et al. 2005). Other studies have shown no relationship between vitamin C supplementation (Kang, Cook et al. 2009) or total dietary antioxidant capacity (Devore, Kang et al. 2010) and cognitive change over time.

Three randomized controlled trials (RCTs) have evaluated the effects of antioxidants on cognition or cognitive decline in cognitively intact older persons. These studies ranged in duration from 5-10 years of treatment and evaluated vitamin E doses ranging from 600 IU every other day to 900 IU per day and 250 to 500 mg daily for vitamin C. Vitamin C or E supplement use was not related to performance on cognitive tests at the end of the study after 5-7 years (2002; Yaffe, Clemons et al. 2004). In another RCT, vitamin E supplement use was not significantly associated with differences in cognitive decline (Kang, Cook et al. 2006).

In addition, two major clinical trials have examined the role of vitamin E in the treatment of mild cognitive impairment (MCI) or AD. In a trial of progression from MCI to AD, assignment to 2,000 IU of vitamin E per day had no effect on incident AD or preservation of cognitive functioning over the three years of follow-up (Petersen et al., 2005). In the single large-scale trial of vitamin E (2,000 IU/day) among persons with moderate AD, vitamin E appeared to slow the progression of disease over two years of follow-up, although there was no impact on cognitive decline during the study period (Sano et al., 1997).

Finally, it has long been known that high-dose vitamin E supplementation should be avoided among those with vitamin K deficiency, clotting disorders, or warfarin (Coumadin) use because it can increase the risk of bleeding, but vitamin E was otherwise thought to be entirely safe. Recently, however, data have emerged that suggest that vitamin E supplementation may be less benign than previously believed. A large clinical trial of 400 IU daily for the prevention of heart disease and cancer showed not only no benefits for heart disease or cancer, but also an increased risk for heart failure in the vitamin E group compared to placebo (Lonn et al., 2005). One study also reported a modest increased risk of lung cancer, primarily in current smokers (Slatore, Littman et al. 2008). A meta-analysis of 11 vitamin E trials (Schurks, Glynn et al. 2010) also found a small dose-dependent increased risk of overall mortality with vitamin E treatment, although it should be noted that the overall effect was very small, and some of the included trials were secondary prevention trials for heart disease that included participants with considerable baseline cardiac risk (Miller et al., 2005).

Discussion and Recommendations

Apart from a possible suggestion of benefits of dietary vitamin E on AD risk (which must be interpreted carefully in light of the potential for residual confounding), these data provide little support for a role of nutritional antioxidants in the prevention of Alzheimer disease. It remains possible that specific types of exposures defined by timing (e.g., in midlife rather than late life), duration (e.g., over many years), or dietary context (e.g., with phytochemicals) might have beneficial effects that could not be detected in the studies reported to date.

The collective findings from current studies do not suggest a protective effect of vitamin C on the risk of developing AD and therefore do not warrant a recommendation of increasing vitamin C intake through diet or supplements for the prevention of AD. These findings have no bearing, however, on decisions regarding increasing vitamin C intake for beneficial effects on other health outcomes, due to more convincing findings in other fields and the rarity of vitamin C toxicity.

The lack of observed effectiveness, coupled with data on small but detectable risks of vitamin E supplementation, argue against using this agent for prevention of dementia (Brown and Crowley, 2005), and the most recent American Psychiatric Association Practice Guidelines for Dementia do not recommend vitamin E for the treatment of MCI or AD (Rabins, Blacker et al. 2007). However, findings on dietary and plasma vitamin E provide suggestive evidence of a protective effect, and the lower levels of vitamin E available in dietary sources lead to less concern about toxicity.


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