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Vitamin D & Dementia

iStock-1367780024_EditedResults of a large prospective cohort study were recently published in Alzheimer’s & Dementia, describing the association between vitamin D supplementation and dementia incidence within the National Alzheimer's Coordinating Center (NACC) cohort. As the authors point out, there is considerable interest in vitamin D as a potential modifier of risk, as dementia affects 50 million people around the world and prevalence is predicted to triple by 2050, with a lack of effective medications for either treatment or prevention.

A number of randomized trials have previously been conducted, examining the effects of supplementation on both cognitive function and amyloid beta (Aβ)-related biomarkers, and although some have indicated a positive effect, the most recent meta-analysis of 9 randomized trials did not report any benefit. However, the authors of this recent cohort study point out that multiple limitations of previously published trials may explain the lack of perceived benefits, including small sample sizes, short duration and/or follow-up, inconsistency in dosing/formulation of vitamin D, etc.

This recent study may address some of these limitations. For example, while the meta-analysis of 9 randomized trials included a total of 2,345 participants, this cohort study included 12,388 participants. At a median age of 71, nearly 40% took some form of supplemental vitamin D, and were followed for 10 years. This study also assessed possible associations with the form of vitamin D used (D2 vs. D3), calcium supplementation, APOE genotype, race, sex, etc.

Over the 10-year period, nearly 22% of participants progressed to dementia. After multi-variate adjustment, vitamin D supplementation was associated with a 40% lower risk of incident dementia. Vitamin D was also associated with higher 5-year dementia-free survival (83.6% among vitamin D users vs. 68.4% among non-users). Greater dementia-free survival was observed with vitamin D use in participants that had normal cognitive function at baseline (compared to no vitamin D), as well as those that started with mild cognitive impairment (MCI).

The benefits of vitamin D seemed to apply to every variable included in the analysis; risk reduction was observed for all forms of vitamin D supplementation (i.e., with or without calcium, and as either cholecalciferol or ergocalciferol), and across all strata of sex, cognitive diagnosis, and APOE ε4 carrier status. Although the benefits applied across the spectrum, greater benefits were observed in some populations; for example, a 49% reduction in dementia incidence was observed in women exposed to vitamin D compared to only a 26% reduction among men. Similarly, those with normal cognitive benefit at baseline experienced a greater reduction in risk of 56% compared to only a 33% reduction among those with MCI at baseline. Non-carriers of ε4 alleles also had a greater reduction in the risk of dementia with vitamin D exposure than carriers did, though both groups benefited. A number of limitations to the study were raised, including the lack of information on vitamin D dosage, baseline 25-OH vitamin D levels, or even length of supplementation, as well as limited adjustments for socioeconomic status, sunlight exposure, or the use of other potentially beneficial supplements.

This study is an encouraging one, which will hopefully lead to follow-up studies that more closely evaluate dosing and baseline vitamin D levels, among other variables not included in this analysis. For example, we recently learned that dosing by body weight may be especially important for the reduction of chronic disease risk, with higher doses needed among people with higher BMIs. A recent review published in Cells also describes other variables that may be important, including polymorphisms in the vitamin D receptor (VDR) gene. This review describes multiple mechanisms by which vitamin D would be expected to have positive neurological effects, all mediated primarily through VDR. For example, activation of VDR increases neurotrophin gene expression and promotes anti-inflammatory pathways within the central nervous system that may slow the aging process. Vitamin D also protects against a variety of toxins and reactive oxygen species, all of which would likely accelerate the aging process in its absence. Animal studies also suggest that supplementation of vitamin D helps prevent age-related decline in brain-derived neurotrophic factor (BDNF) levels and activities of antioxidant enzymes and acetylcholinesterase, all likely to mitigate aging within the brain.

Many experimental studies also indicate vitamin D may reduce Aβ toxicity or pathological Aβ aggregation, mechanisms that predict a possible benefit for Alzheimer’s related pathology. The mechanisms are too many to list here, but include enhanced expression of nuclear factor erythroid 2–related factor (Nrf2, which itself upregulates a cell’s antioxidant enzyme machinery, such as glutathione production), reduced neuroinflammation, decreased Aβ load and tau hyperphosphorylation, etc. (see the review in Cells for more details).

There are still many unanswered questions – is there a threshold of baseline 25-OH vitamin D levels under which supplementation improves risk, or an optimal dosage or blood value to aim for? Would supplementation work best when combined with other nutrients or medications which complementary effects, such as anti-inflammatories like curcumin? Which variables are the most important for deciding who benefits the most? Baseline 25-OH vitamin D, gender, APOE genotype, VDR polymorphisms, etc.? Hopefully this recent study is the springboard for other well-done longitudinal clinical trials with enough participants and duration to help answer some of these questions.

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