02. Can Vitamin D Deficiency Increase the Risk of Alzheimer’s Disease?

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Vitamins, Supplements, and Alzheimer’s Prevention

There is increased interest in the role that vitamins and other supplements may play in the prevention of neurodegenerative diseases, including Alzheimer’s. In a recent small study in which drastic lifestyle changes were shown to slow the rate of progression of Alzheimer’s disease, researchers included a variety of supplements in the regimen for patients in the intervention group – omega-3 fatty acids, vitamin B12, coenzyme Q, vitamin C, a probiotic, even lion’s mane.

All of these have either previously shown benefit at slowing cognitive decline or have theoretical reasons why they might be thought to do so. A new prospective cohort study using data from the UK Biobank adds to the growing evidence that vitamin D may also impact the development of major neurocognitive disorders, including Alzheimer’s and vascular dementia.

Study Finds Vitamin D Deficiency Linked to Dementia Risk

The new study cohort consisted of nearly 270,000 individuals with a mean age of 62 years. Nearly a fifth of participants showed signs of vitamin D deficiency defined as less than 30 nmol/L while over a third showed vitamin D insufficiency defined as levels between 30 and 50.

5% of the cohort reported regularly taking vitamin D supplements specifically while 20% noted taking a multivitamin, most of which would contain vitamin D. Unsurprisingly, deficiency was much lower among users of vitamin supplementation.

Overall, 2.6% of participants or about 7000 people were given a new dementia diagnosis during the follow-up period of 13.5 years. About half of these were given a diagnosis of Alzheimer’s specifically.

Dose-Dependent Relationship and Genetic Factors

Vitamin D deficiency and insufficiency exhibited an association with dementia and with Alzheimer’s and vascular dementia specifically, including when adjusting for covariates. In the most adjusted analysis, vitamin D deficiency was associated with a 25% increased risk for dementia and insufficiency with an 11% increased risk.

For individuals with levels less than 50, there appeared to be a dose-dependent relationship. When analyzing by APOE gene type, no statistically significant differences emerged.

One intriguing finding was that individuals with darker skin seemed to show no association between vitamin D levels and dementia risk, though it is important to note that this sub-analysis may have been underpowered. Finally, in terms of vitamin D supplements, the authors also found that use of vitamin D supplements was associated with a lower risk of Alzheimer’s and this correlation was especially strong for younger individuals aged 55 to 64 years.

Limitations and Implications of the Study

So what do we make of this? Well, these UK Biobank studies are notable because they use a prospective database, and they tend to be highly powered. The data source is rich and detailed.

The authors of this study also do a very good job of controlling for multiple potential confounders, acknowledging that this is an observational study at the end of the day, so no conclusions can be drawn about causality. It’s possible, for example, that individuals who are conscientious enough to take vitamin D supplements may also be more likely to take a variety of other supplements and that it is actually these other supplements that impact the risk for the development of dementia.

Also worth noting is that patients in the study were on the younger side in terms of when we might expect dementia to present, so we don’t know as much about the risk of dementia in the ninth decade, for example. Overall, though, the results add to the growing body of literature suggesting that lifestyle modifications may significantly impact the risk of developing dementia, including Alzheimer’s and vascular types.

Vitamin D and Neurodegeneration: Possible Mechanisms

In terms of vitamin D specifically, the findings are also consistent with some other studies. The authors note that a 2019 meta-analysis also found an increased risk of Alzheimer’s in low vitamin D states, with even larger effect estimates.

The mechanism through which vitamin D may prevent neurodegeneration remains unclear. Previous research has suggested that it may help to break down beta-amyloid plaques or prevent amyloid-induced neuronal apoptosis. Some suspect vitamin D may also protect against tau hypophosphorylation.

Vitamin D deficiency is extremely common, occurring in up to a quarter of individuals in the US and up to 40% of Europeans. This makes sense because vitamin D is most commonly obtained through exposure to sunlight, so those living at higher latitudes are at higher risk for deficiency.

Vitamin D can also be obtained through diet, particularly by eating foods like trout or salmon, white mushrooms, milk and soy. Notably, obesity is a significant risk factor for vitamin D deficiency due to sequestration of vitamin D metabolites in adipose tissue.

Implications for Clinical Practice

Given that low vitamin D levels had been linked to other neuropsychiatric issues including depression, anxiety and even schizophrenia, this study serves as a good reminder that it may be worth checking levels in our patients, particularly in middle-aged and older patients. It’s something we’ve started doing pretty routinely on the inpatient consultation service.

Patients found to be insufficient or deficient should be offered supplementation and counseled about the potential impact of low vitamin D levels on mental and physical health, including the possible increased risk for neurodegenerative illness.

Abstract

The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer’s disease, and vascular dementia: a UK Biobank based prospective cohort study

Li-Ju Chen, M.D. Sha Sha, M.D. Hannah Stocker, M.D. Hermann Brenner, M.D. & Ben Schöttker, M.D.

Background

Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations.

Objectives

We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VD) incidence.

Methods

With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank.

Results

Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07–1.31) for AD; 1.24 (1.08–1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02–1.19) for AD; 1.15 (1.03–1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively.

Conclusions

Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.

Reference

Chen, L. M.D. Sha, S. M.D. Stocker, H. M.D. Brenner, H. M.D. & Schöttker, B. M.D. (2024). The associations of serum vitamin D status and vitamin D supplements use with all-cause dementia, Alzheimer’s disease, and vascular dementia: a UK Biobank based prospective cohort study. The American Journal of Clinical Nutrition, Volume 119, Issue 4, 2024, Pages 1052-1064, ISSN 0002-9165.