Vitamin D supplementation worsens Alzheimer's progression: Animal model and human cohort studies

• Published in: Aging cell Vol. 21; no. 8; pp. e13670 - n/a
• Main Authors: Lai, Rai‐Hua, Hsu, Chih‐Cheng, Yu, Ben‐Hui, Lo, Yu‐Ru, Hsu, Yueh‐Ying, Chen, Mei‐Hsin, Juang, Jyh‐Lyh
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2022; John Wiley and Sons Inc
• Subjects: Aged; Alzheimer Disease - metabolism; Alzheimer's disease; Animal models; Animals; Antibodies; Biotechnology; Cohort analysis; Cohort Studies; Dementia; Dementia disorders; Dietary Supplements; Disease Models, Animal; Disease prevention; Epidemiology; Genomics; Health insurance; Humans; Illnesses; Longitudinal Studies; longitudinal study; Mice; Neurodegenerative diseases; non‐genomic vitamin D signaling; Nutrient deficiency; Older people; p53; Population; Population studies; Presenilin 1; Retinoid X receptors; Signal transduction; Tumor Suppressor Protein p53; Vitamin D; Vitamin D - pharmacology; vitamin D receptor; Vitamin D receptors; Vitamin D3; Vitamin deficiency; Taiwan; longitudinal study; vitamin D receptor; non-genomic vitamin D signaling; Alzheimer's disease; vitamin D; p53
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.13670

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 Aβ 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 D3 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 D3 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. We studied whether it is beneficial to supplement vitamin D to APP/PS1 mice and humans. The animal studies show vitamin D deficiency is an early disease outcome and supplementation of vitamin D worsens AD brain pathology via enhancing VDR/p53 complex to impair autophagosome. Nationwide longitudinal cohort studies also suggest long‐term vitamin D supplementation is associated with higher risk of dementia in dementia‐free older adults and higher mortality in dementia individuals. Our results caution against prolonged use of vitamin D by AD patients and older adults.