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 , and previous research has suggested that addressing this deficiency might be useful in treating the disease . 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  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 . 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.
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.
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 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.
 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.
 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.
William B. Grant
July 23, 2022
Very bad article by Lai et al.
First, calcitriol is not appropriate for supplementation since its concentration is highly regulated (Vieth, 2020).
Second, meta-analyses fine significant inverse correlations between serum 25(OH)D conentration and incidence of Alzheimer’s disease and dementia (Jayedi, 2019).
Third, Mendelian randomization studies find inverse correlations between genetically-determined 25(OH)D concentrations and risk of Alzheimer’s disease (Wang, 2020) and dementia (Navale, 2022).
Thus, this article’s recommendation for Alzheimer’s disease patients to avoid prolonged usd of vitamin D should be ignored.
Vitamin D supplementation: cholecalciferol, calcifediol, and calcitriol.
Vieth R.Eur J Clin Nutr. 2020 Nov;74(11):1493-1497. doi: 10.1038/s41430-020-0697-1.
Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response †.
Jayedi A, Rashidy-Pour A, Shab-Bidar S.Nutr Neurosci. 2019 Nov;22(11):750-759. doi: 10.1080/1028415X.2018.1436639.
Circulating Vitamin D Levels and Alzheimer’s Disease: A Mendelian Randomization Study in the IGAP and UK Biobank.
Wang L, Qiao Y, Zhang H, Zhang Y, Hua J, Jin S, Liu G.J Alzheimers Dis. 2020;73(2):609-618. doi: 10.3233/JAD-190713.
Vitamin D and brain health: an observational and Mendelian randomization study.
Navale SS, Mulugeta A, Zhou A, Llewellyn DJ, Hyppönen E.Am J Clin Nutr. 2022 Apr 22:nqac107. doi: 10.1093/ajcn/nqac107.
July 25, 2022
I also fully agree with William B. Grant’s comment questioning the validity of this research since it was done with Calcitriol, not vitamin D3 (Cholecalciferol) that most supplement users take. Calcitriol is metabolized very differently from vit D3 and blood levels cannot be regulated by the liver and kidneys, and is more readily toxic, especially a higher dose,. “The dementia patients prescribed a high cumulative dose of calcitriol (>146 capsules of 0.25 mcg per year) were found to have a 2.17-fold increase in risk of death, compared with those not prescribed the drug (Figure 4b and Table S6). We found no significant difference in mortality among those taking medium doses (43.8–146 capsules/year) or low cumulative doses (<43.8 capsules/year), compared with nonusers (Figure 4b and Table S6)." Lai RH, Hsu CC, Yu BH, Lo YR, Hsu YY, Chen MH, Juang JL. Vitamin D supplementation worsens Alzheimer's progression: Animal model and human cohort studies. Aging Cell. 2022 Jul 12:e13670. doi: 10.1111/acel.13670. Epub ahead of print. PMID: 35822270.
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