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.

Key Words: 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.

INTRODUCTION

Dementia is a clinical syndrome characterized by progressive and irreversible loss of brain cells, leading to a decline in cognitive function that is severe enough to impair independence and daily functioning[1]. Dementia is the seventh most common cause of death worldwide, and a major cause of dependency and disability in older people. According to the World Health Organization, dementia accounts for more years lived with disability than almost any other neurological disorder[2].

The most common underlying causes of dementia include Alzheimer’s disease, vascular dementia, Lewy body dementia, and frontotemporal dementia[1]. Age is the most significant risk factor for dementia, and its prevalence rises steeply with advancing age, affecting approximately 1% of those aged 65 years and more than half of those aged 90[3]. As global life expectancy increases, the number of people living with dementia is projected to rise sharply, placing a substantial economic and social burden on the healthcare system. Dementia is the leading cause of institutionalization in the elderly, often resulting in high levels of functional dependence and caregiver strain[4].

Young-onset dementia, which occurs before the age of 65 years, is less common but has a particularly profound impact on working life, family responsibilities, and social functioning. Misdiagnosis in this age group can delay appropriate care, further compounding caregiver burden[5]. While dementia is often perceived as inevitable with aging, several modifiable midlife risk factors have been identified, including obesity, hypertension, hearing loss, traumatic brain injury, and excessive alcohol intake[6]. Lifestyle interventions targeting these factors may help to delay the onset of cognitive decline and reduce the prevalence[7]. Alzheimer’s disease and vascular dementia, the two most common subtypes, are also linked to preventable conditions, such as atherosclerosis, cardiovascular disease, diabetes, and dyslipidemia, in addition to non-modifiable risk factors, such as advancing age and genetic predisposition[8].

Recent research has drawn attention to vitamin D as a potential modifiable risk factor for dementia. Hypovitaminosis D affects at least one billion people worldwide and has been associated with impaired cognitive performance and an increased risk of dementia in older adults[9]. Vitamin D functions not only as a regulator of calcium homeostasis and bone health, but also as a neuroactive steroid influencing brain development, neurochemistry, and adult brain function[10].

Vitamin D receptors (VDRs) are widely distributed in the brain regions involved in memory and cognition, such as the hippocampus and cortex[11]. The biologically active form of vitamin D, 1,25(OH)₂D₃, crosses the blood-brain barrier (BBB) and exerts neuroprotective effects, including the modulation of neurotrophic factors, neurotransmitter synthesis, and regulation of gene expression via vitamin D response elements (VDREs)[12]. Experimental studies have shown that vitamin D reduces amyloid-induced neurotoxicity, promotes amyloid clearance by activating macrophages, and supports neuronal proliferation, differentiation, neuroplasticity, and survival[13].

Nevertheless, despite compelling biological mechanisms, findings from observational and interventional studies remain inconsistent, particularly in randomized controlled trials (RCTs), warranting cautious interpretation. This integrated review aims to synthesize current knowledge on the epidemiology, potential mechanisms, and interventional evidence regarding vitamin D and dementia, while identifying key gaps for future research. This review was prepared following the TITAN Guidelines 2025[14] to ensure transparent reporting of narrative reviews and appropriate use of artificial intelligence.

METHODOLOGY

A comprehensive literature search was performed using electronic databases, including PubMed, Scopus, and Google Scholar, covering studies published in English up to August 2025. Search terms included combinations of “vitamin D”, “25-hydroxyvitamin D”, “dementia”, “Alzheimer’s disease”, “cognitive decline”, and “neurodegeneration”. Both observational and interventional studies as well as relevant mechanistic research, systematic reviews, and meta-analyses were considered. The reference lists of the included articles were screened to identify additional relevant publications. Studies were included if they reported original data or synthesized evidence linking vitamin D status or vitamin D supplementation with dementia risk, cognitive outcomes, or underlying biological mechanisms. The findings were thematically organized into sections addressing epidemiological associations, mechanistic insights, and interventional evidence. The quality of evidence was appraised with particular attention paid to study design, sample size, measurement methods, and potential sources of bias.

VITAMIN D PHYSIOLOGY AND BRAIN FUNCTION

Vitamin D can be obtained through two main pathways: Dietary intake and cutaneous synthesis via ultraviolet B (UVB) radiation. In the skin, a photolytic reaction converts 7-dehydrocholesterol to previtamin D₃, which is then isomerized to vitamin D₃ (cholecalciferol). Dietary sources include fatty fish, fortified dairy products, and supplements, although diet alone is often insufficient to maintain an optimal vitamin D status[15].

Once in circulation, vitamin D₃ undergoes a two-step hydroxylation process: First in the liver by 25-hydroxylase enzymes to produce 25-hydroxyvitamin D [25(OH)D], and then in the kidney by 1α-hydroxylase (CYP27B1) to yield the biologically active form, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃ or calcitriol]. The discovery that CYP27B1 is expressed in multiple tissues, including the brain and immune cells, has expanded our understanding of vitamin D beyond calcium and bone metabolism, suggesting its local intracrine or paracrine actions[15,16].

The biological effects of 1,25(OH)₂D₃ are mediated by VDR, a member of the nuclear steroid hormone receptor superfamily. Upon activation, VDR forms a heterodimer with the retinoid X receptor, which binds to VDREs in target gene promoters to regulate transcription[17]. This genomic mechanism modulates the genes involved in cell proliferation, differentiation, neuroprotection, and neurotransmission. Non-genomic pathways, although less clearly characterized, may also contribute to rapid cellular responses[18].

VDRs are widely expressed in the central nervous system, particularly in the hippocampus, cortex, and substantia nigra, which are critical for memory and executive functions. In neurons and glial cells, vitamin D influences multiple processes relevant to brain health, including calcium homeostasis, oxidative stress regulation, and the suppression of pro-inflammatory pathways[19]. Experimental studies have suggested that vitamin D modulates amyloid metabolism, enhances amyloid clearance by macrophages, and reduces amyloid-induced neurotoxicity.

Vitamin D also plays a key role in brain plasticity by regulating neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, and by influencing neurotransmitter synthesis[20]. For example, vitamin D upregulates glutamate decarboxylase (GAD65 and GAD67), enzymes required for the production of the inhibitory neurotransmitter gamma-aminobutyric acid. These effects contribute to synaptic stability and neuronal communication[21].

In addition to its neurological effects, vitamin D has important immunomodulatory functions. It enhances innate immunity by stimulating antimicrobial peptides such as cathelicidin, and modulates adaptive immunity by shifting T-cell differentiation toward regulatory and anti-inflammatory phenotypes[22]. These immune-regulatory actions may indirectly benefit the brain by reducing systemic inflammation, which is a known contributor to neurodegeneration.

Vitamin D status is influenced by several personal and environmental factors as shown in Figure 1. Synthesis declines with age due to reduced skin 7-dehydrocholesterol content and changes in the dermal structure. Skin pigmentation also affects melanin synthesis, with higher melanin content reducing UVB penetration and requiring longer sun exposure for adequate production[23]. Lifestyle factors, such as outdoor activity, clothing habits, and geographical latitude, further impact vitamin D levels, potentially influencing neurological health over the lifespan.

Figure 1 Overview of vitamin D metabolism.

EPIDEMIOLOGICAL EVIDENCE

Cross-sectional studies have consistently demonstrated that low vitamin D status is associated with poorer cognitive function. Individuals with lower serum 25(OH)D concentrations perform worse on tests of global cognition, executive function, and processing speed, even after adjusting for demographic and health-related confounders[24,25]. These findings suggest a possible role for vitamin D in cognitive health; however, because cross-sectional designs capture data at a single time point, they cannot establish temporal relationships, leaving the possibility of reverse causation open.

Prospective studies offer stronger evidence by tracking participants over time. Severe vitamin D deficiency has been linked to a two-fold or greater risk of developing dementia and Alzheimer’s disease[13]. Large-scale cohorts have shown that low baseline 25(OH)D levels predict incident Alzheimer’s disease and vascular dementia[26]. Other longitudinal studies reported that deficiency is associated with accelerated cognitive decline, particularly in the memory and executive domains[25]. These findings support a temporal relationship, suggesting that vitamin D deficiency precedes cognitive deterioration. Nonetheless, heterogeneity in baseline thresholds, follow-up durations, and cognitive assessment tools complicate direct comparisons across studies.

Systematic reviews and meta-analyses have reinforced the association between vitamin D status and cognitive outcome. Multiple pooled analyses have confirmed that low serum 25(OH)D levels are associated with a higher risk of all-cause dementia, Alzheimer’s disease, and cognitive impairment[27,28]. Dose-response analyses indicate that concentrations below 50 nmol/L are linked to significantly increased dementia risk[29], although some evidence suggests a threshold rather than linear relationship[30].

Vitamin D deficiency appears to disproportionately affect certain cognitive domains, with memory and executive functions most frequently implicated[31]. These domains are among the strongest predictors of the progression of dementia. Biological plausibility is supported by experimental data showing that vitamin D influences neurotrophic factor expression, reduces oxidative stress, regulates neuroinflammation, and promotes amyloid clearance, while modulating tau phosphorylation[32].

The strength of the association between vitamin D status and dementia risk may vary by disease subtype. For Alzheimer’s disease, multiple prospective cohorts have found that deficiency is linked to increased incidence[13,26]. In vascular dementia, prospective evidence indicates that low vitamin D levels are associated with small-vessel disease and white matter lesions, which are pathologies central to vascular cognitive impairment[26]. For less common dementias, evidence is sparse. Low vitamin D levels have been associated with an increased risk of Parkinson’s disease[33], suggesting a possible overlap with Lewy body dementia pathophysiology. However, studies examining Lewy body and frontotemporal dementia remain small and underpowered, limiting firm conclusions[34]. At present, the most consistent epidemiological evidence supports an association between Alzheimer’s disease and vascular dementia.

BIOLOGICAL MECHANISMS LINKING VITAMIN D TO DEMENTIA

Emerging evidence suggests that vitamin D exerts multifaceted neuroprotective effects relevant to the pathogenesis of dementia. Beyond its classical role in calcium homeostasis, vitamin D regulates amyloid metabolism, tau phosphorylation, neuroinflammation, oxidative stress, vascular function, and mitochondrial activity. These pathways converge to shape neuronal survival and cognitive integrity, offering mechanistic insights into why deficiency may accelerate neurodegenerative processes.

Amyloid and tau pathology

Accumulation of Aβ plaques and tau neurofibrillary tangles represents the pathological signature of Alzheimer’s disease. Recent evidence indicates that vitamin D enhances amyloid clearance by triggering receptors expressed on myeloid cell 2 (TREM2)-dependent mechanisms as shown in Figure 2. In human microglial HMO6 cell models, 1,25(OH)₂D₃ significantly increased Aβ uptake while concurrently promoting an anti-inflammatory M2 phenotype, suggesting that vitamin D augments microglial phagocytic function via TREM2 signaling[35]. Complementary findings show that 1,25(OH)₂D₃ modulates BBB transport by increasing low-density lipoprotein receptor-related protein 1 (LRP1) and suppressing the receptor for advanced glycation end products, favoring the efflux of Aβ from the brain to the periphery[36]. These observations are based on earlier macrophage studies, which demonstrated that vitamin D primes immune cells to phagocytose Aβ, laying a foundation for subsequent mechanistic research.

Figure 2 Vitamin D/vitamin D receptor signaling pathways in neuroprotection.

Vitamin D also influences tau biology. Neuronal models have shown that VDR activation suppresses glycogen synthase kinase 3β (GSK3β), a principal tau kinase, thereby attenuating iron-induced tau hyperphosphorylation[37]. This mechanistic axis linking vitamin D signaling to LRP1-mediated amyloid transport and GSK3β-driven tau phosphorylation suggests that deficiency could potentiate both arms of Alzheimer’s pathology.

Emerging evidence suggests that basal tau phosphorylation and physiological amyloid-β production may represent adaptive responses to oxidative and metabolic stress, with reported metal-chelating and antioxidant properties under tightly regulated conditions[37]. Vitamin D appears to modulate this homeostasis in a dose-dependent manner by attenuating oxidative stress through upregulation of antioxidant enzymes while simultaneously regulating kinases and phosphatases involved in tau phosphorylation[30,38]. At optimal levels, vitamin D enhances microglial phagocytosis and amyloid-β clearance via VDR-mediated immunomodulatory pathways, including suppression of pro-inflammatory cytokines and promotion of an anti-inflammatory phenotype[34,35]. Conversely, dysregulated or excessive vitamin D signaling may alter immune responses and amyloid processing, potentially influencing AD trajectory. These observations underscore a nuanced, hormetic role for vitamin D in balancing protective vs pathogenic protein signaling in Alzheimer’s disease.

Anti-inflammatory and antioxidant effects

Neuroinflammation is a pivotal driver of dementia progression and vitamin D exerts broad immunomodulatory effects that counteract this process. In vitro studies have demonstrated that vitamin D attenuates Aβ-induced microglial activation, significantly reducing the expression of interleukin-6, tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2 by inhibiting NF-κB signaling[38]. Reviews have further highlighted the central role of VDR-mediated signaling in regulating microglial inflammatory responses, reinforcing the relevance of this pathway in dementia as shown in Figure 3.

Figure 3 Anti-inflammatory and antioxidant effects of vitamin D.

Oxidative stress is a critical factor in neuronal injury. Vitamin D enhances the Nrf2/heme oxygenase-1 antioxidant pathway, thereby reducing reactive oxygen species and strengthening endogenous defense systems[39]. Taken together, these findings suggest that deficiency makes the brain susceptible to unchecked inflammatory and oxidative insults, exacerbating neuronal loss and cognitive decline.

Cerebrovascular health

Vascular contribution to dementia is increasingly being recognized, and vitamin D deficiency appears to impair cerebrovascular resilience. Mechanistic studies indicate that vitamin D regulates endothelial NOS, improves endothelial function, and lowers arterial stiffness, thereby sustaining cerebral perfusion[40]. At the BBB level, 1,25(OH)₂D₃ preserves tight-junction proteins (claudin-5, occludin, and ZO-1), suppresses NF-κB activation, and reduces oxidative stress in endothelial cells subjected to hypoxia-reoxygenation, suggesting a protective role in barrier integrity as shown in Figure 4[41].

Figure 4 Role of vitamin D in blood-brain barrier showing how it can impact proteins or molecules that regulates cerebral perfusion. VDR: Vitamin D receptor; BBB: Blood-brain barrier.

Population-level evidence supports an indirect vascular pathway. Mendelian randomization studies report that genetically higher 25(OH)D levels are associated with a lower risk of stroke-for instance, each genetically predicted standard deviation increase in 25(OH)D corresponds to an odds ratio (OR) of 0.92 for stroke [95% confidence interval (CI): 0.85-0.99] suggesting vitamin D may causally influence cerebrovascular risk[42]. However, another large MR study (280000+ individuals) found no causal association between genetically determined 25(OH)D levels and ischemic stroke or its subtypes (OR, 1.01; 95%CI: 0.94-1.08), indicating a complex relationship[43].

Mitochondrial function and neuronal energy metabolism

Mitochondrial dysfunction is a central feature of neurodegeneration and vitamin D has been implicated in sustaining neuronal bioenergetics. Preclinical studies have demonstrated that vitamin D supplementation preserves mitochondrial respiratory chain activity and ATP production in toxin-induced models, thereby protecting against neuronal loss. Importantly, VDR binds to mitochondrial DNA and regulates the transcription of oxidative phosphorylation subunits, directly linking vitamin D signaling to energy metabolism[44]. In disease models, 1,25(OH)₂D₃ restored mitochondrial membrane potential and normalized calcium-handling proteins, such as FDX1 and NCLX, highlighting its role in stabilizing mitochondrial function[45]. Recent comprehensive reviews reinforce these findings, underscoring that vitamin D aids ATP synthesis and safeguards neurons from energy failure, which is a critical driver of dementia progression[46].

INTERVENTIONAL EVIDENCE

The translation of epidemiological associations between vitamin D deficiency and dementia in terms of interventional efficacy has been challenging. RCTs provide the highest level of evidence, but have yielded mixed findings, raising questions about trial design, dosage, and population characteristics.

RCTs

Large-scale RCTs of generally healthy older adults have predominantly reported null effects on cognitive outcomes. The VITAL trial (daily 2000 IU vitamin D₃; median follow-up 2.8 years) found no significant effect on global cognition or decline, with changes in composite z-scores comparable between treatment and placebo (mean difference -0.01; 95%CI: -0.01 to 0.02)[47]. Similarly, the D-Health trial (n ≈ 21000; monthly 60000 IU: 5 years) reported no difference in Telephone Interview for Cognitive Status scores or in the incidence of cognitive impairment (mean difference 0.04; 95%CI: -0.14 to 0.23)[48]. The DO-HEALTH trial (n ≈ 2157; 2000 IU/day for 3 years), designed primarily for musculoskeletal outcomes, reported no significant improvement in cognitive performance[49]. Collectively, these high-power studies in community-dwelling older adults suggest limited benefits when supplementation is initiated late in life and in populations without severe baseline deficiency.

In contrast, smaller targeted RCTs in high-risk groups suggest potential cognitive advantages. A Chinese RCT in patients with mild cognitive impairment (n = 183; 800 IU/day for 12 months) demonstrated significant improvements across multiple cognitive domains, including full-scale IQ, information, digit span, vocabulary, block design, and picture arrangement (P < 0.001) compared to placebo[50]. In Alzheimer’s disease, a Chinese RCT (n = 210; 800 IU/day for 12 months) showed that vitamin D supplementation improved picture arrangement, digit span, vocabulary, and total IQ scores, along with favorable shifts in Aβ biomarkers[51]. However, these trials were short in duration, single-center, and limited in scope, restricting their generalizability.

Meta-analyses of intervention studies

A 2023 meta-analysis of 24 RCTs (n ≈ 7557) found no significant effect of vitamin D supplementation on global cognition overall (Hedges’ g = 0.128, P = 0.008), but noteworthy benefits appeared among vulnerable groups and those with baseline deficiency (Hedges’ g = 0.414 and 0.480, respectively)[52]. Meanwhile, a Cochrane review concluded that vitamin D plus calcium supplementation had no effect on cognitive function over approximately eight years (mean difference -0.1 Mini-Mental State Examination [MMSE] points; 95%CI: -0.81 to 0.61), assigning the evidence a low to moderate certainty due to small sample sizes and methodological variability[53]. Taken together, the current interventional evidence suggests that vitamin D supplementation alone is unlikely to serve as a universal preventive strategy against dementia as shown in Table 1.

Table 1 Studies showing the relationship between vitamin D and cognitive function.

Ref.	Population	Intervention (dose and duration)	Outcome (primary)	Key insight
Kang et al[47]	Generally healthy older adults (n = 3424)	2000 IU/day (2.8 years)	No benefit (no change in global cognition)	Intervention may be too late in “healthy” adults to prevent decline. Limited benefit when supplementation is initiated late in life in populations without severe baseline deficiency
Pham et al[48]	Community-dwelling older adults (n ≈ 21000)	60000 IU/month (5 years)	No benefit (no difference in cognitive impairment)	Monthly “bolus” dosing might differ biologically from daily intake
Bischoff-Ferrari et al[49]	Active older adults (n = 2157)	2000 IU/day (3 years)	No benefit (no change in cognitive performance)	Participants had high baseline vitamin D (replete), limiting potential gain. this high-power study suggests limited benefit when supplementation is initiated late in life
Yang et al[50]	Mild cognitive impairment patients (n = 183)	800 IU/day (12 months)	Improved [full-scale IQ, information and block design (P < 0.001)]	Targeted intervention in the early stage of pathology shows potential advantage
Jia et al[51]	Alzheimer’s disease patients (n = 210)	800 IU/day (12 months)	Improved (total IQ, Aβ biomarkers)	Benefit observed in established disease, possibly via amyloid clearance
Chen et al[52]	Mixed populations (24 RCTs)	Various	Mixed (benefit only in vulnerable groups)	Supports the “targeted” hypothesis: Only those with deficiency/impairment benefit

RCT: Randomized controlled trial.

Limitations of current evidence

A key limitation of the existing literature is its heavy reliance on observational designs that are inherently subject to residual confounding and reverse causation. For instance, individuals in the preclinical stages of dementia often exhibit reduced outdoor activity, which may diminish UV-mediated vitamin D synthesis, thus complicating interpretations of the temporal sequence in observational associations. Studies have specifically highlighted this challenge, noting that lower sun exposure due to early cognitive decline may lead to reduced vitamin D levels, rather than the other way around[13]. Moreover, meta-analytic reviews[54] have emphasized that such observational designs cannot definitively distinguish causality from correlation. These methodological issues underscore the importance of cautious interpretation and the need for better-designed research, including Mendelian randomization and long-term trials.

Another limitation is the heterogeneity of the vitamin D measurements. Circulating 25(OH)D is an accepted biomarker of vitamin D status, yet variability across immunoassays and liquid chromatography-mass spectrometry methods often yields inconsistent results, with bias exceeding the allowable error in up to 48% of samples[55]. The lack of assay standardization not only hampers cross-study comparability but also complicates the determination of clinically meaningful cut-offs[56]. Furthermore, vitamin D concentrations exhibit marked seasonal and geographic fluctuations owing to variations in sunlight exposure, which are frequently unaccounted for in analyses and potential hidden confounders[57].

Cognitive outcomes represent another domain of inconsistencies. Trials and cohort studies employ a wide range of screening tools, from global tests such as the MMSE to domain-specific neuropsychological batteries, making it difficult to compare outcomes across studies[58]. This lack of uniformity may obscure the domain-specific effects of vitamin D that remain undetected when using coarse global instruments. For example, a meta-review highlighted significant heterogeneity in study design and cognitive measures, limiting the ability to synthesize domain-specific findings. Additionally, cognitive tools such as the MMSE are prone to ceiling/floor effects and low sensitivity to change, which can mask subtle declines in targeted domains such as executive function and memory[59].

Finally, the field is challenged by publication bias; studies showing positive associations between vitamin D and cognition are far more likely to be published, while null or negative findings often go unreported. Systematic reviews of health outcomes have repeatedly noted this tendency, cautioning that the benefits of vitamin D may be overestimated[60]. More broadly, Ioannidis’ landmark analysis of scientific research posits that selective reporting and reproducibility issues, especially in highly popular fields, can lead to inflated perceptions of efficacy[61].

FUTURE DIRECTIONS AND RESEARCH GAPS

Although the evidence linking vitamin D to dementia risk is growing, critical research gaps must be addressed before firm clinical recommendations can be made. First, large, adequately powered RCTs with standardized cognitive outcomes are needed. Most existing trials are underpowered, short in duration, or treat cognition as a secondary endpoint, limiting their interpretability[62,63]. Large-scale initiatives, such as VITAL[47], illustrate the feasibility of multi-center, long-term approaches and should serve as a model for future efforts.

The adoption of a lifespan perspective is equally important. Observational evidence suggests that low vitamin D levels in midlife are associated with an elevated risk of developing dementia later in life, underscoring that effective prevention strategies should consider vitamin D exposure trajectories across decades, rather than focusing solely on late-life supplementation. For instance, in the Atherosclerosis Risk in Communities Study, midlife vitamin D deficiency was significantly linked to incident dementia over a 20-year follow-up, although it was not associated with late-life neuropsychological performance[64]. Similarly, cohort data[30] have shown that baseline vitamin D deficiency is associated with a higher incidence of dementia.

Another priority is to incorporate genetic insights as VDR gene polymorphisms can modify individual responsiveness to vitamin D exposure and supplementation. A systematic review[65] demonstrated that variants such as FokI and TaqI significantly alter outcomes after vitamin D supplementation, suggesting that genomic profiling could enable precision targeting and help explain heterogeneity in trial results. Therefore, researchers should consider stratifying or tailoring interventions based on the VDR genotypes.

Finally, multidomain intervention strategies, which combine vitamin D supplementation with diet, physical activity, cognitive training, and vascular risk management, hold promise for more robust and lasting cognitive benefits. The FINGER trial[66], a landmark 2-year randomized controlled study, showed that such a comprehensive approach successfully preserved cognitive function in older adults at a risk of decline. Emerging global efforts, including the World-Wide FINGERS network, have built on this model and aim to validate multimodal frameworks across diverse cohorts.

CONCLUSION

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. RCTs 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. Addressing this question through large, rigorously designed trials with standardized cognitive measures remains a critical research priority, with the potential to shape future clinical and population-level strategies.