Vitamin D‐mentia: Is Vitamin D Optional or Essential for Preventing Late‐Life Cognitive Decline?

Data accumulated since the original publication by Goodwin and colleagues in 1983 on the association between circulating levels of micronutrients and cognitive performance, confirm the adverse effect of subclinical micronutrient deficiency on cognitive function and onset of Alzheimer’s disease (AD) in otherwise healthy older adults. Of these micronutrients, vitamin D is of particular interest because it is not only a micronutrient provided by the diet (especially fatty fish and dairy products), but is also a secosteroid hormone synthesized in the skin under the action of solar ultraviolet B rays; circulating vitamin D levels are commonly low, especially in older adults, with a prevalence of hypovitaminosis D ranging from 60% to 100% according to the definition used; vitamin D acts as a steroid hormone in an endocrine manner by binding to specific receptors located in almost all tissues of the body, which suggests pleiotropic effects under physiological conditions. As a consequence, vitamin D, which has long been recognized for its involvement in skeletal and calcium metabolism, is now suspected to influence nonskeletal targets, including brain health and function. The biological mechanisms linking vitamin D to the brain have been extensively studied although not yet fully elucidated. The hippocampus, hypothalamus, cortex, and subcortex have vitamin D receptors (VDRs), which allow vitamin D to exert various neurophysiological and neuroprotective effects in brain areas essential to cognition. Vitamin D appears to be involved in neurophysiology in regulating, at the level of gene transcription, the synthesis of multiple neurotransmitters, including acetylcholine and dopamine. Clinically, a reduction of nerve conduction velocity has been reported in the case of severe hypovitaminosis D. Vitamin D also regulates the genetic expression of various neurotrophic agents and protects neural networks by controlling mitosis rate and neuronal growth. Vitamin D concentrations are directly associated with brain volumetry; individuals with lower circulating concentrations have smaller brain volume and larger ventricles. Vitamin D may also be involved in neuroprotection by suppressing the expression of inflammatory cytokines, thus promoting neuron viability and function. Vitamin D exerts antioxidant effects by interacting with reactive oxygen and nitrogen species and regulating the activity of the gamma-glutamyl-transpeptidase, a key enzyme in glutathione metabolism. Vitamin D could also prevent the onset or severity of cerebral ischemia. Vitamin D also attenuates amyloid-b42 accumulation by stimulating its phagocytosis and the brain-to-blood efflux transport, decreasing the burden of amyloid plaques. Finally, vitamin D prevents glutamate toxicity through the upregulation of VDR expression, together with antioxidant and antiischemic effects. All together, these properties could promote brain health and function and may explain why VDR-knockout transgenic mice models exhibit severe attentional and behavioral disorders. In humans, the influence of vitamin D on brain metabolism and activity was confirmed using magnetic resonance spectroscopy, with poorer neuronal function reported in older adults with hypovitaminosis D than in those with adequate status. Neuroepidemiology has consistently revealed a higher prevalence of AD, dementia, and cognitive disorders in older U.S., European, and Asian community-dwelling individuals with lower circulating vitamin D concentrations. In the same countries, individuals with hypovitaminosis D are at greater risk of dementia than those with normal levels. This issue of the Journal of the American Geriatrics Society contains an elegant systematic review and metaanalysis by Goodwill and Szoeke aimed at quantitatively assessing the effect of low vitamin D or vitamin D supplementation on cognition in midlife and older adults without a diagnosis of dementia. Twenty-six observational (12 cross-sectional, 14 longitudinal) and three interventional studies were included in the metaanalysis (n = 19–9,556). Hypovitaminosis D was associated with worse cognitive performance (summary odds ratio (OR) = 1.50, 95% confidence interval (CI)=1.23–1.83) and incident cognitive decline (summary OR = 1.14, 95% CI = 1.06–1.23). Regarding domain-specific cognitive abilities, mental speed and attention (summary OR = 1.23, P = .004) and visuospatial abilities (summary OR = 1.32, P = .03) had stronger associations with vitamin D than memory (P = .19). Finally, vitamin D supplementation had no significant effect on cognition (standard mean difference = 0.21, 95% CI = 0.05–0.46). The meta-analysis by Goodwill and Szoeke was slightly different from previous metaanalyses— although it found similar results—in focusing on cognitively intact adults before manifestation of clinical symptoms. Given the long prodromal stage of cognitive decline and dementia, vitamin D repletion may be of particular interest in midlife, a critical period for preventive See article by Goodwill and Szoeke