**6. Blood Ascorbic Acid, Cognition and Alzheimer's Disease**

For studies that have made measurements of biological AA levels in blood and/or CSF, the sample sizes are typically much lower than the population based studies described above (see Table 1). The logistics and cost of so many measurements may be prohibitive, and even in studies that have a prospective aspect, true control groups are not possible. It would be unethical to maintain one group of participants at low AA levels, and it is also not possible to control for lifetime dietary habits in these studies. Nevertheless, these cross sectional studies can certainly provide an accurate and useful picture of typical nutrition profiles in various populations, alongside cognitive analyses.


An early study by Goodwin *et al.* [123] used the revealing method of dividing participants into percentiles according to AA status. Using these methods verbal memory recall and calculations were indeed associated with higher plasma AA. In contrast, and in support of the idea that deficiency can impact development of AD and other dementias Gale *et al.* [124] report a significantly increased risk for cognitive impairment in those with depleted (<12 μM) plasma AA or very low intake (<28 mg/day). Higher plasma AA was associated with better free recall, recognition and vocabulary, but not working memory in a prospective sample of older men (>65 years) [129]. In general, plasma levels of AA in the above studies have been consistently observed to be around 20 μM in patients with AD, *i.e.*, about the half of those measured in controls [7,125,127]. In agreement with studies showing that plasma AA levels are depleted in AD independent of dietary intake, peripheral AA depletion in AD patients with respect to controls has been repeatedly confirmed after correction for age, gender, fruit and vegetable intake, and comorbidities [7,125,127]. Another element strongly suggestive of low AA levels as a co-causal factor for neurodegeneration and AD rather than epiphenomenon of AD is the observation of similarly depleted plasma AA levels in both MCI patients and AD patients compared to controls [7]. Comparison of all these studies where effects are on particular subtypes of memory of cognition, *versus* disease risk, may indicate that avoiding deficiency, and optimally supplementing with AA may benefit different facets of cognitive health. Nevertheless, the directions of effect seem to be in the same direction.
