Vitamin D deficiency has been epidemiologically linked to Alzheimer's disease (AD) and other dementias, but no interventional studies have proved causality. Our previous work revealed that the genomic vitamin D receptor (VDR) is already converted into a non-genomic signaling pathway by forming a complex with p53 in the AD brain. Here, we extend our previous work to assess whether it is beneficial to supplement AD mice and humans with vitamin D. Intriguingly, we first observed that APP/PS1 mice fed a vitamin D-sufficient diet showed significantly lower levels of serum vitamin D, suggesting its deficiency may be a consequence not a cause of AD. Moreover, supplementation of vitamin D led to increased A beta deposition and exacerbated AD. Mechanistically, vitamin D supplementation did not rescue the genomic VDR/RXR complex but instead enhanced the non-genomic VDR/p53 complex in AD brains. Consistently, our population-based longitudinal study also showed that dementia-free older adults (n = 14,648) taking vitamin D-3 supplements for over 146 days/year were 1.8 times more likely to develop dementia than those not taking the supplements. Among those with pre-existing dementia (n = 980), those taking vitamin D-3 supplements for over 146 days/year had 2.17 times the risk of mortality than those not taking the supplements. Collectively, these animal model and human cohort studies caution against prolonged use of vitamin D by AD patients.
