**5. Dietary Intake of Ascorbic Acid, Cognition and Alzheimer's Disease**

Associations between risk for AD and AA intake have been investigated in several large population studies, both in the US and also in one large European sample. One early study appeared very promising when data was reported from the Chicago Healthy Aging Project (CHAP) showing that none of the 633 > 65 years old, dementia-free participants that supplemented with AA, developed AD over the follow up period (mean 4 years) [109]. Study of dietary intakes in the same cohort did not support the same protective effect of AA [110]. It may be that even the dietary levels ingested were insufficient for the protective effect and that supplements are necessary to maintain optimal levels. In the earlier study only supplementation was considered, as single nutrient, multi-vitamin or no supplement, without comment as to dose. In the latter study, while the median all-source intake was 124.7 mg/day, with 16.1% of population taking supplements of some kind, the intake ranges were very large. In the lowest quintile intake from food and supplements was estimated at below 93 mg/day and the highest quintile was between 310 and 2530 mg/day. In neither case are blood AA levels reported and thus it is difficult to accurately determine AA status in the different populations. The differences between dietary and synthetic AA intake, and their comparable bioavailability in humans, are discussed in this issue [111]. Self-reported AA intakes (alone or in combination with vitamin E) were not predictive of AD diagnosis in a cohort of nearly 5,000 participants aged 65 and older over the course of 5 years [112]. Nor were beneficial effects of AA intake observed in a study of 980 dementia-free men and women of the Washington Heights-Inwood Columbia Aging Project [113].

A more complex pattern of effects was reported in the Honolulu Asia Aging Study which comprised men aged 71 to 93 years [114]. In cognitively intact individuals, AA intake was associated with a higher likelihood for enhanced cognitive function. High AA and vitamin E intake were associated with lower likelihood for vascular dementia. In contrast, there was no relationship between AD diagnoses and AA intake. Findings from the Cache County Study [115] suggest that AA and vitamin E supplementation may have some synergistic effects in reducing risk for AD, but AA alone did not decrease risk for AD. Self reported intake questionnaires and telephone assessments of cognitive ability were used in the very large cohort of nearly 15,000 women in the Nurses health study. No consistent associations were found between AA and cognitive ability in this group [116,117].

Perhaps one of the most interesting results came from the Rotterdam Scan Study [118]. This large study of over 5000 participants reported an 18% reduced relative risk for AD with higher AA intake. Most revealing was that the most dramatic protective effects were seen in smokers. Smoking leads to rapid depletion of AA in plasma in addition to additional ROS generated following inhalation of smoke. It therefore seems likely that rescuing AA deficiency in this group may have been more useful than supplementing AA on top of dietary in healthier individuals.

If AA deficiency really is a key factor in the development of AD, then it might be expected that populations with poorer intake would be more prone to developing dementia, or follow a faster path of deterioration once diagnosed. For the most part these studies draw strength from the large sample sizes used, numbering in the thousands. On the other hand, reliance on dietary intake questionnaires may be problematic, particularly in a study of cognitive ability where reliability may be acutely affected by even mild changes in recall ability [119]. Current intake may not reflect lifetime dietary habits and given data that suggest that amyloid plaque burden begins to form well before middle age [120], intakes during younger adulthood may be equally as important as supplements taken by older adults, perhaps contributing to a biological buffer against disease pathogenesis. Overall, the two promising positive results are outweighed by the seven studies that did not confirm a link between AA and AD. Ideally, reliable biomarkers of diet should be employed instead, or preferably in addition to study of dietary intake [121]. Measurement of AA levels, preferably over several time points, permits determination of whether participants have deficient or depleted AA levels, and more importantly allow grouping according to AA level. In this way dietary *versus* supplemental intake is not as important as the resulting AA levels, and high level supplements, which, due to the limitations of the SVCT1 transporter in the intestines, may not functionally provide more AA than lower supplements or good diet, are not weighted more heavily and biasing results.
