**8. Ascorbic Acid and Vascular Cognitive Aging**

The primary focus of this review is on AD, both with and without a vascular component. The main pathological hallmarks of AD (amyloid and tau deposits, neuronal death, neurotransmitter signaling, synaptic density) are shared across cases because the nature of AD is multifactorial. However, in the same way that many of these symptoms are also found in other cases of dementia,

e.g., pure vascular dementia, frontotemporal dementia, dementia with lewy bodies, it can easily be argued that many of the findings described are related to neurodegeneration in general and are thus applicable to many dementias and even normal aging. Previous schools of thought have considered vascular- *versus* AD-type dementia cases as separate entities, however accumulating evidence suggests that vascular pathology plays a central role in AD onset and development [138–140]. In a community sample of older adults (75+ years) almost 50% of the clinically diagnosed AD cases showed a possible vascular component [141]. Similarly, the next most prevalent dementia form, vascular dementia, presents overlapping traditional hallmarks of AD including amyloid-β accumulation. As a direct consequence of this complexity, a cure is difficult to find, and prevention becomes even more critical. The role of AA has recently been reviewed in relation to endothelial cell function, which may explain importance in its role in vascular health. In addition to the more well-known functions of AA such as synthesis and deposition of collagen in the basement membrane and antioxidant defense against ROS, other roles include stimulating endothelial proliferation, inhibiting apoptosis, and sparing endothelial cell-derived nitric oxide to help modulate blood flow [15].

The ability of AA to prevent age-associated cognitive decline and dementia risk may require a population with high vascular risk. AA has demonstrated some ability to reduce vascular risk factors and more recently vascular comorbidities are being acknowledged as important factors to reduce for prevention of age related dementias [138,139,142–147]. Some of the "vascular" mechanisms include: (1) reducing carotid intima-media-thickness [2,148]; (2) reducing lipid peroxidation [3,4,149–151]; and (3) reducing endothelial dysfunction [15].

We recently observed healthy elderly in the lowest plasma AA tertile at higher risk of carotid intima-media thickness >1.2 mm; a threshold established as pathologic by the European Society of Hypertension and the European Society of Cardiology 2007. It should be noted that this relationship was not appreciated with other antioxidants that include: uric acid, vitamins A and E, and enzymatic enzymes superoxide dismutase and glutathione oxidase activity. Another study of 8453 participants in NHANES II concluded that individuals with plasma AA ≥ 45.4 μM had a 21%–25% reduced risk for CVD-related death and a 25%–29% reduced risk of all-cause mortality compared to the participants with plasma AA < 23 μM [152]. In the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study [153] a 33% lower risk of developing coronary heart disease was shown in subjects with the highest plasma AA compared to the lowest (mean, 27.6 μM) over six years of follow up. Long in advance to these results, the EPIC-Norfolk study had found that plasma AA concentrations in 8860 men and 10,636 women were inversely correlated to mortality from all causes and CVD. In this study, each 20 μmol/liter increase in plasma AA was associated with a 20%–30% reduction in risk for all-cause and CVD mortality [154]. When 563 elderly men were randomly allocated to one of four treatment groups in a clinical trial that included dietary intervention, omega-3 supplementation, both or neither, carotid intima-media thickness progression over a three-year term was reduced in those undergoing dietary intervention that included daily AA intake [155]. Vitamin E [156] or combined antioxidants [157] in the dietary intervention groups were not successful.

These data suggest that AA has a role in modifying vascular risk factors and vascular disease, which could represent mechanisms by which AA might reduce dementia risk in people carrying this vascular risk profile [158].

Recent research has demonstrated that it is now possible to non-invasively measure AA (and GSH) levels in the human brain using MEGA-PRESS MRI (a type of spectroscopic MRI imaging) [159]. These techniques were used to compare AA, GSH and lactate in brain in 22 young (20 years) *versus* 22 normally aging (76.6 years) subjects [160]. The study reported decreased GSH and increased lactate with age, indicating oxidative damage, but no change in AA between the groups. The authors recruited candidates that ate less than five fruits and vegetables per day and did not take supplements, then provided food calculated to contain 30 mg/1000 kcal in an attempt to provide all subjects with the recommended daily intake. Thus, potential group differences were already minimized, and at ~60 mg/day circulating and brain AA levels may still have been sub-optimal in all subjects, reflected by the estimated brain levels of 0.4–1.2 μmol/g (their Figure 3 [160]) tissue wet weight. It is reported that brain AA content was not associated with AA in blood, however these data are not recorded. So although this study does not provide a definitive statement of AA in brain in the elderly, development of this fascinating and ingenious technique to measure AA in brain may add a critical factor to future studies of the role of AA in the brain.
