Vitamin D, Cognition and Alzheimer's Disease: The Therapeutic Benefit is in the D-Tails

Abstract

Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer's disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider.

Keywords: Alzheimer’s disease; clinical trials; cognitive function; vitamin D.

Fig.1

Vitamin D acquisition, metabolism and modes of action. Cholecalciferol or vitamin D3 and ergocalciferol or vitamin D2 follow the same metabolic pathway. Blood metabolites include 25(OH)D produced by the liver, which is bound to vitamin D binding protein. Renal and extra-renal CYP27B1 (1α-hydroxylase) produces the active metabolite 1,25(OH)2D. 25(OH)D or 1,25(OH)2D enters the cell through passive diffusion or megalin-dependent transport. Once inside the cell, 1,25(OH)2D binds to its nuclear receptor VDR and after dimerization with RXR, forms a regulatory complex which can bind target genes that contain a vitamin D responsive element (VDRE). 1,25(OH)2D can also induce rapid non-genomic responses by binding to its membrane receptor MARRS or a membrane VDR and regulate the activity of adenylate cyclase, PLC and PKC proteins. 1,25(OH)2D also induces modulation of calcium release from intracellular stores and can interact with TGF and EGF receptors to modulate cell cycle processes. These different modes of action and the crosstalks operated by vitamin D signaling ultimately lead to transcription modulation of hundreds of genes, depending on the cell-type considered.

Fig.2

Proposed mechanisms of vitamin D-mediated multi-targeted effects in AD. Vitamin D imbalance is proposed to alter mechanisms implicated in aging and AD pathogenesis. Suggested protective effects of vitamin D supplementation concern regulation of vascular processes and oxidative stress, calcium homeostasis, neurotransmission, modulation of immune and inflammatory processes, and direct impact on amyloidogenesis, ultimately improving cognitive functions.