The physiologically active form of vitamin D, 1,25-dihydroxyvitamin D3, is a fat-soluble steroid hormone with a well established role in skeletal health. A growing body of evidence suggests that low vitamin D levels also play a role in the pathogenesis of a wide range of non-skeletal age-associated diseases such as cancer, heart disease, type 2 diabetes and stroke. Low serum 25-hydroxyvitamin D (25(OH)D) levels, a stable marker of vitamin D status, are also associated with increased odds of prevalent cognitive dysfunction, Alzheimer’s and all-cause dementia in a number of studies, raising the possibility that vitamin D plays a role in the aetiology of cognitive dysfunction and dementia. So far the majority of human studies reporting associations between vitamin D and cognition or dementia have been cross-sectional or case-control designs that are unable to exclude the possibility that such associations are a result of disease progression rather than being causal. Animal and in-vitro experiments have identified a number of neuroprotective mechanisms that might link vitamin D status to cognitive dysfunction and dementia including vasoprotection and amyloid phagocytosis and clearance, but the clinical relevance of these mechanisms in humans is not currently clear. Two recent large prospective studies go some way to establish the temporal relationship with cognitive decline. The relative risk of cognitive decline was 60% higher (relative risk 1.60, 95% CI 1.2-2.0) in elderly Italian adults who are severely deficient (<25 nmol/L) when compared them with those sufficient (>75 nmol/L). Similarly the odds of cognitive decline were 41% higher (odds ratio 1.41, 95% CI 0.9-2.2) when elderly US men in the lowest quartile (<50 nmol/L) were compared with those in the highest quartile (>74 nmol/L). To our knowledge no prospective studies have examined the association between 25(OH)D levels and incident dementia or neuroimaging abnormalities. The possible therapeutic benefits of vitamin D have attracted considerable interest as over 1 billion people worldwide are thought to have insufficient 25(OH)D levels, which can be increased using inexpensive well-tolerated dietary supplements. However, no large randomized controlled trials have yet examined the effect of vitamin D supplements upon cognitive decline or incident dementia. Further studies are urgently needed to establish which mechanisms may have clinical relevance in human populations and whether vitamin D supplements are effective at minimizing cognitive decline or preventing dementia.
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