Although decades of research suggest a link between vitamin D deficiency and neurologic disorders including multiple sclerosis (MS), Alzheimer dementia (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS), the role of vitamin D supplementation in the prevention and management of these conditions is unclear.
A brief overview of potential mechanisms underlying the link between vitamin D levels and neurologic disorders is shown in Figure 1.1 Each of these disorders has a unique connection with vitamin D receptors as well as reactions or processes that are enhanced or mitigated by serum vitamin D levels.1
Vitamin D Deficiency
Vitamin D was discovered to be a steroid-like hormone in 1968 and later was isolated as the active hormonal form of vitamin D3, chemically known as 1,25(OH)2D3.1,2 Vitamin D receptors are found on virtually every tissue in the human body including the brain and entire nervous system.2
Laboratory evaluation of serum vitamin D level assesses for 25-hydroxy vitamin D [25(OH)D], which is measured in ng/mL and is the sum of both D2 (ergocalciferol) and D3 (cholecalciferol) reflecting the total blood content of vitamin D.3
Several medical societies have issued recommended minimum serum concentrations of 25(OH)D including the National Academy of Medicine (formerly the Institute of Medicine), Endocrine Society, International Osteoporosis Foundation, and American Geriatric Society.1 The National Academy of Medicine not only set a recommended range of 20 to 50 ng/mL but also a maximum of 50 ng/mL, based on an increase in fractures as well as increases in pancreatic and prostate cancers at higher doses.4 A vitamin D level of 30 ng/mL is the average that most societies recommend.1 However, guidance on vitamin D supplementation in patients with neurologic conditions is lacking.
Vitamin D deficiency is more prevalent among people living in areas above the 40th parallel North and below the 40th parallel South or in areas of reduced sunlight, with higher levels of melanin, and who are 65 years and older.3 Sunlight provides approximately 80% to 90% of recommended vitamin D dose per day, far surpassing the amount derived from a well-balanced diet.3
Multiple sclerosis is a disease of the central nervous system that encompasses demyelination, neurodegeneration, and chronic inflammation.5 Environmental risk factors have been elucidated in connection with MS, including infections (eg, Epstein-Barr virus), smoking, inflammation, locality (with regards to latitude), climate, and vitamin D deficiency.1,3 Latitude, in particular, is highly correlated with the geographic distribution of MS, with increased frequency in areas above the 40th parallel North and below the 40th Parallel South.1,3 These areas also have higher rates of vitamin D deficiency, which further supports the correlation between MS and hypovitaminosis D.1,3
Vitamin D supplementation may not only prevent the development of MS but also appears to help treat this disease by decreasing the relapse rate.3,5 Several studies have shown possible benefits of supplementation in MS, with dosing varying from 10,000 to 40,000 IU/day, but other trials have not shown favorable outcomes.5 Use of super-high dosing (eg, 50,000 to 2.604,000 IU/day) that result in vitamin D levels of 150 ng/mL and greater can lead to vitamin D toxicity with side effects that mimic MS relapse/progression, including muscle weakness and neuropsychiatric disturbances/psychosis.5 In some cases, irreversible kidney damage, cardiac dysrhythmia secondary to hypercalcemia have been reported.5
Alzheimer dementia presents as a progressive cognitive decline with behavioral changes and neurodegeneration secondary to the formation of neurofibrillary tangles and senile plaques.1,6 Landel et al6 noted that studies on vitamin D and AD date back to 1992 with reporting of “…decreased vitamin D receptor (VDR) mRNA levels in the hippocampus of AD patients.” Landel et al performed an extensive review of 38 human and animal studies regarding vitamin D and cognitive outcomes and concluded that vitamin D “may be important in aging and age-related cognitive decline” and “…may be associated with increased risk of developing AD and dementia, without being a causative agent.”6
In the large cross-sectional Rotterdam study, magnetic resonance imaging (MRI) in 2716 participants free of dementia showed that those with vitamin D deficiency had smaller hippocampus volume, brain volume, gray matter, and white matter compared with participants with normal vitamin D levels.7 Findings from a large-scale observational study involving prospective data from the UK Biobank on more than 294,500 people (primarily women older than 60 years) suggest that participants with low vitamin D levels had a 54% greater chance of developing dementia than those with normal levels.8
In a 6-month pilot study involving 43 people newly diagnosed with Alzheimer disease, use of vitamin D supplementation in combination with memantine was superior at halting cognitive decline compared with use of either intervention alone.9 Findings from other studies suggest that vitamin D helps to clear amyloid-b plaques in vitro.10,11 A randomized, placebo-controlled trial involving 210 patients with Alzheimer disease showed that 12 months of supplementation with vitamin D 800 IU per day was significantly associated with improvements in amyloid-β-related biomarkers (P <.001) and information, arithmetic, digit span, vocabulary, block design, and picture arrange scores (P <.05).12 A significant increase in full-scale IQ score was also found (P <.001).12
Researchers have also investigated the potential effects of vitamin D on orientation, memory, cognitive decline, and executive functions (measured by Mini-Mental Status Examination [MMSE]) in older adults without Alzheimer disease.13,14 In a longitudinal study of 1058 older adults who underwent serum vitamin D tests between 1997 and 1999 and follow-up cognitive testing 3 times over the next 12 years, vitamin D deficiency was associated with poorer performance on the MMSE.13