Neurobiological mechanisms linking vitamin d signaling to cognitive decline and neurodegeneration: Untangling epidemiology, pathophysiology, and evidence

Abstract

Dementia is a leading cause of disability and dependence among older adults, and its prevalence is projected to increase sharply with age. While age and genetics remain the dominant risk factors, modifiable contributors are gaining attention, including vitamin D deficiency, which is highly prevalent worldwide. This integrated review synthesizes current evidence on the association between vitamin D status and dementia, spanning the epidemiological, mechanistic, and interventional domains. Epidemiological studies have consistently linked low serum 25-hydroxyvitamin D levels with poorer cognition, faster decline, and higher risk of Alzheimer’s disease and vascular dementia, although causality cannot be inferred. Mechanistic data suggest that vitamin D regulates amyloid and tau pathology, reduces neuroinflammation and oxidative stress, supports cerebrovascular integrity, and preserves mitochondrial function. Translation into clinical benefit has proven difficult; large randomized trials in generally healthy older adults, including VITAL and D-Health, report null effects, whereas smaller studies in vitamin D-deficient or cognitively impaired populations suggest potential improvements. Meta-analyses confirm mixed findings, typically indicating small or non-significant effects, with possible benefit restricted to vulnerable groups. The limitations across the literature include residual confounding in observational studies, assay variability, seasonal influences, heterogeneous cognitive measures, and publication bias. Future priorities include adequately powered randomized trials with standardized vitamin D assessments and harmonized cognitive endpoints as well as investigations into genetic moderators and multi-domain interventions. In conclusion, although vitamin D deficiency is consistently associated with cognitive decline and dementia, definitive evidence of causality remains lacking. Clarifying whether supplementation can alter dementia trajectory is a pressing public health priority.

Keywords: Dementia; Vitamin D; Alzheimer’s disease; Cognitive decline; Neurodegeneration

Core Tip: Vitamin D deficiency has been consistently linked to an increased risk of cognitive decline and dementia, with mechanistic studies providing biologically plausible pathways through its effects on amyloid and tau regulation, neuroinflammation, cerebrovascular health, and mitochondrial function. These converging data make vitamin D an attractive target for dementia prevention. However, the causality remains unproven. Randomized controlled trials have produced largely inconclusive findings, often limited by small sample sizes, short follow-up periods, or cognitive outcomes assessed only as secondary endpoints. As a result, the current evidence does not justify routine vitamin D supplementation as a therapeutic strategy for dementia prevention or management. However, if a causal role is ultimately confirmed, the public health implications would be substantial, given both the global prevalence of vitamin D deficiency and the rising incidence of dementia.