National Health Research Institutes

Prolonged use of vitamin D supplements might increase risk of dementia, NHRI study reveals

August 29, 2022

Many recent epidemiological studies have linked vitamin D deficiency to a higher risk of Alzheimer’s disease (AD) and other dementias. However, the causal relationship between vitamin D deficiency and dementia has remained elusive. As there is no effective treatment or preventive intervention for AD, and as supplementation of vitamin D is considered beneficial in maintaining brain health, some people have come to believe that vitamin D supplementation might confer some protection against dementia.

To clarify whether vitamin D deficiency is a risk factor or an outcome of AD, a research group under J.L. Juang of the Institute of Molecular and Genomic Medicine at Taiwan’s National Health Research Institutes (NHRI) fed AD mice with a vitamin D sufficient diet. The animals, however, exhibited markedly lower levels of serum vitamin D compared to wild-type controls. This suggests that vitamin D deficiency is actually an outcome of early AD.

They then investigated whether the vitamin D receptor level was also affected, because the binding of vitamin D to its receptor would typically increase the protein level of the receptor. Following this rationale, one would expect lower levels of vitamin D receptor in AD patients due to lower vitamin D levels in AD patients compared to individuals without AD. Unexpectedly, the study showed an inverse relationship between receptor and ligand levels, suggesting that vitamin D signaling might have been disturbed during AD pathogenesis.

Subsequent investigation discovered that beta amyloid, a compound that builds up in AD brains, is the causal factor responsible for the observed change. Mechanistically, beta amyloid triggers the interaction of vitamin D receptor with tumor suppressor p53 in promoting neuronal cell death. Notably, this interaction was strongly enhanced by vitamin D. The investigators concluded that, in contrast to previous thought, vitamin D could have a damaging effect in promoting AD.

This surprising result prompted the group to test whether their findings in animal models could be validated in human subjects. They collaborated with Dr. Chih-Cheng Hsu, a physician scientist at NHRI, to analyze relevant information from Taiwan’s National Health Insurance Research Database.

Their population-based cohort studies suggested that dementia-free older adults were 1.8 times more likely to develop dementia, and those with pre-existing dementia were at 2.0 times higher risk of mortality if taking vitamin D3 supplements continuously for over 146 days per year. Because both animal model and human retrospective studies have produced concordant results, the investigators have raised the concern that prolonged use of vitamin D by AD patients and older adults may be detrimental to brain health.

These results have been published in the journal Aging Cell in 2021 and 2022.