Vitamin D Supplements May Make Alzheimer’s Worse

Researchers publishing in Aging Cell have found that administering Vitamin D to Alzheimer’s patients may actually make the problem worse.

A matter of cause and effect

Vitamin D deficiency is strongly linked to Alzheimer’s disease [1], and previous research has suggested that addressing this deficiency might be useful in treating the disease [2]. These researchers, however, believe that this conclusion represents a misunderstanding of cause and effect. Their previous work has shown that Alzheimer’s disease causes Vitamin D to be badly processed [3] and that supplementing Vitamin D at the earliest stages of progression in mice does not match human treatment plans.

This study, therefore, involves treating a mouse model of Alzheimer’s in its middle stages with Vitamin D and then comparing these murine results to human longitudinal studies.

A mouse model of Alzheimer’s uses Vitamin D badly

The researchers compared mice bred to have Alzheimer’s-like symptoms to wild-type mice, feeding both groups very specific amounts of Vitamin D. Within the first four months of life, the Alzheimer’s-prone group had significantly less Vitamin D in their plasma and cerebrospinal fluid than the wild-type mice did.

This was followed up with an analysis of Vitamin D in cells. Neurons exposed to amyloid beta, and then dosed with Vitamin D, showed much stronger cellular death (apoptosis) and self-consuming (autophagy) markers than amyloid beta-exposed neurons that were not given Vitamin D.

Encouraged, the researchers then went on to examine the effects of Vitamin D in their Alzheimer’s mouse model. Their findings were as they suspected: Alzheimer’s-prone mice given Vitamin D performed much worse on the cognitive Morris water maze test over time and had larger amyloid beta plaques along with more effects on the microglia.

Further research showed that, instead of the normal VDR/RXR interaction that characterizes normal Vitamin D processing, the presence of amyloid beta caused VDR to interact with p53 instead, which was in line with this team’s previous work [3]. Inhibition of p53 ameliorated many of these symptoms.

A broad source of human data

Taiwan’s national health database is extremely robust. With it, the researchers were able to obtain very specific data for a great many individuals to form longitudinal cohorts, excluding people with many comorbidities while matching Vitamin D takers to non-takers on a 1:1 basis for their study of incident dementia, which involved data from nearly 15,000 people. Additionally, data from nearly 1,000 people was used to study dementia-related mortality.

The data from these cohorts was clear. While low Vitamin D doses were not linked to a significant increase in dementia, adults taking medium or high doses of Vitamin D were much more likely to suffer from dementia over time. In the examination of people with pre-existing dementia, low and medium doses of vitamin D did not have a statistically significant effect, but a high dose was significantly associated with increased mortality.

Conclusion

This study is a sharp reminder as to why correlation and causation are different. Rather than low Vitamin D being a cause of Alzheimer’s disease, this research suggests that Alzheimer’s causes Vitamin D depletion in a way that promotes the accumulation of more amyloid beta. This thesis has not been conclusively proved in human beings, and it is clear that more direct human studies need to be done to determine the true relationship between Vitamin D and Alzheimer’s disease.

Literature

[1] Sommer, I., Griebler, U., Kien, C., Auer, S., Klerings, I., Hammer, R., … & Gartlehner, G. (2017). Vitamin D deficiency as a risk factor for dementia: a systematic review and meta-analysis. BMC geriatrics, 17(1), 1-13.

[2] Banerjee, A., Khemka, V. K., Ganguly, A., Roy, D., Ganguly, U., & Chakrabarti, S. (2015). Vitamin D and Alzheimer’s disease: neurocognition to therapeutics. International Journal of Alzheimer’s Disease, 2015.

[3] Lai, R. H., Hsu, Y. Y., Shie, F. S., Huang, C. C., Chen, M. H., & Juang, J. L. (2021). Non‐genomic rewiring of vitamin D receptor to p53 as a key to Alzheimer’s disease. Aging cell, 20(12), e13509.