Vitamin D role in Alzheimer’s, Parkinson’s, and Huntington’s - March 2025

---

Unlocking the Potential of Vitamin D: A Comprehensive Exploration of Its Role in Neurological Health and Diseases

Biology 2025, 14(3), 280; https://doi.org/10.3390/biology14030280
by Rehana Khatoon
Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India

Table of Contents

Simple Summary
This review investigates the extended role of vitamin D beyond its traditional association with bone health, focusing on its influence on brain-related disorders. It highlights vitamin D’s involvement in regulating oxidative stress, inflammation, and anti-apoptotic pathways within the brain, with lower levels being linked to several neurological diseases. Vitamin D shows promise in reducing the risk or progression of neurodegenerative conditions through various protective mechanisms. This review added evidence from in vitro, in vivo, and clinical studies that demonstrate the positive effects of vitamin D across a range of different neurological disorders. In conclusion, vitamin D emerges as a potential neuroprotective agent with considerable relevance to human health.

Abstract
Vitamin D (VD), an indispensable micronutrient renowned for its pivotal role in bone health, is increasingly recognized as a frontline therapy for bone-related disorders owing to its involvement in maintaining calcium/phosphorus levels. Beyond these benefits, VD exhibits a modulatory impact on redox imbalance, inflammation, and anti-apoptotic pathways implicated in brain-related disorders. Recent findings reveal a notable decrease in VD and its receptor expression in the cerebrospinal fluid of individuals with brain diseases, indicating a positive association between VD levels and normal brain function. Moreover, emerging reports underscore VD’s potential in mitigating the pathophysiology of neurodegenerative diseases, including memory and motor impairments, mitochondrial dysfunction, and neuronal loss. Extensive in vitro and in vivo studies elucidate VD’s multifaceted neuroprotective mechanisms, effectively mitigating neuronal damage and ATP deprivation, thus reducing mortality and morbidity. This review comprehensively examines VD’s diverse attributes, encompassing antioxidative, anti-inflammatory, anti-apoptotic, and neurogenic effects. It provides contemporary insights into VD’s efficacious actions at appropriate doses and exposures across diverse neurological experimental models. Furthermore, the clinical relevance of VD in treating patients with neurological diseases is explored. Overall, this review contributes to the exploration of potential neuroprotective agents and holds promise for improving human health outcomes in the future.
 Download the PDF from VitaminDWiki

---

VitaminDWiki – Overview Alzheimer's-Cognition and Vitamin D contains:

• FACT: Cognitive decline is 19X more likely if low vitamin D
• FACT: Dementia is associated with low vitamin D levels.
• FACT: Alzheimer’s Dementia 2.3X more likely in elderly if low vitamin D – Dec 2022
• FACT: Dementia is associated with low vitamin D - many studies
• FACT: Alzheimer's Disease is 4X less likely if high vitamin D
• FACT: Every single risk factor listed for Alzheimer's Disease is also a risk factor for low vitamin D levels
• FACT: Elderly cognition gets worse as the elderly vitamin D levels get even lower (while in senior homes)
• OBSERVATION: Reports of increased vitamin D levels result in improved cognition
• OBSERVATION: Alzheimer’s patients 3X more likely to have a malfunctioning vitamin D receptor gene – 2012
• OBSERVATION: Alzheimer's Disease has been seen to halt when vitamin D was added.
• OBSERVATION: Alzheimer’s is associated with all 7 of the genes which restrict vitamin D
• OBSERVATION: 39 vitamin D and Alz. or Cognition intervention trials as of Sept 2018
• OBSERVATION: 2 Meta-analysis in 2012 agreed that Alzheimer's Disease. associated with low vitamin D
• OBSERVATION: 50X increase in Alzheimer's while decrease in vitamin D
• OBSERVATION: Vitamin D reduces Alzheimer’s disease in 11 ways
• OBSERVATION: Alzheimer’s cognition improved by 4,000 IU of vitamin D
• OBSERVATION: Plaque removed in mice by equiv. of 14,000 IU daily
• OBSERVATION: DDT (which decreases Vit D) increases risk of Alzheimer's by up to 3.8X
• OBSERVATION: 2% of people have 2 copies of the poor gene reference: Alz Org
• OBSERVATION: Genes do not change rapidly enough to account for the huge increase in incidence
• OBSERVATION: End of Alzheimer's videos, transcripts and many studies protocol has been very successful
  • It adjusts Vitamin D, B-12, Iron, Omega-3, food, etc, and can now be done at home. $75/month.
• FACT: Vitamin D is extremely low cost and has very very few side effects
• CONCLUSION: Everyone concerned about cognitive decline or Alzheimer's Disease should take vitamin D
• PREDICTION MET: By 2024 Omega-3 and high dose Vitamin D will be found to reverse Alzheimer's in humans
  There are 13+ Alzheimer’s meta-analyses in VitaminDWiki
  There are 97+ Alzheimer’s studies in VitaminDWiki
  Dementia is associated with low vitamin D - many studies 50+ studies
  16+ studies in both categories Cognitive and Omega-3

---

VitaminDWiki - Overview Parkinson's and Vitamin D contains:

• Vitamin D associated with Parkinson’s Disease in 55 studies, more studies needed- March 2022
• Parkinson's category has 119 studies
• Parkinson’s Disease and Vitamin D – review of 52 studies – May 2022
• Parkinson patients: 60 % taking Vitamin D – Dec 2019
• Low Vitamin D increases Parkinson's by 3X– July 2010 "only" a 30 year test, need more study
• Parkinson's disease prevented by Vitamin D, but small doses do not treat it - Aug 2023
• 10 clinical trials for PD with vitamin D intervention as of June 2023
• Parkinson’s Disease Summer School – alternative therapies included 60-80 ng of Vitamin D – Sept 2019
• Associated with PD are: Meta-analyses (12 ), Cognition (25 studies), Multiple Sclerosis (18 studies), VIRUS (4 studies), Omega-3 (3 studies), Vitamin D Receptor (11 studies)
• Note by the Founder of VitaminDWiki: I have twice recommended lots of Vitamin D to treat PD. Both got much better, but one had his doctor him cut back to just 2,000 IU. All of his recovery got reversed. With lots of vitamin D he could sing and bike, but now he can barely talk or walk

---

VitaminDWiki - Overview Schizophrenia and Vitamin D contains

14 reasons to think that schizophrenia is associated with low vitamin D
1) 97% of patients with schizophrenia are vitamin D deficient
2) Schizophrenia varies with latitude (UVB) by 10X (controversy)
3) Schizophrenia is more common in those with dark skin (when away from the equator)
4) Schizophrenia is associated with low natal vitamin D
5) Schizophrenia has been increasing around the world when vitamin D has been decreasing (controversy)
6) Schizophrenia is associated with low birth rate, which is associated with low vitamin D
7) Schizophrenia is associated with Autism which is associated with low vitamin D
8) Schizophrenia Bulletin Editorial (Jan 2014) speculated that Vitamin D could be a major player
9) Schizophrenia 2X more likely if low vitamin D - meta-analysis
10) Schizophrenia increased 40 % for Spring births after Danes stopped vitamin D fortification
11) Schizophrenia is associated with season of birth
12) Schizophrenia is associated with poor Vitamin D Receptor genes
13) Schizophrenia risk is decreased if give Vitamin D after birth
14) Schizophrenia symptoms reduced when Vitamin D levels are restored

---

VitaminDWiki - Ankylosing spondylitis and low vitamin D – many studies

---

7+ VitaminDWiki pages have HUNTINGTON in the title

The list is automatically updated

---

The Role of Vitamin D in Huntington's Disease: From Deficiency to Therapeutic Potential Perplexity AI March 2025

The complex relationship between Vitamin D and Huntington's disease (HD) has emerged as an important area of research in recent years. While Huntington's disease is primarily understood as a genetic disorder caused by an expanded HTT CAG repeat sequence, growing evidence suggests that Vitamin D deficiency may influence disease progression and that supplementation might offer therapeutic benefits. This report examines the prevalence of Vitamin D deficiency in HD patients, explores potential mechanisms through which Vitamin D affects neurological function in HD, reviews experimental evidence from animal studies, and discusses the potential for Vitamin D supplementation as a complementary therapeutic approach.

Prevalence and Significance of Vitamin D Deficiency in Huntington's Disease
Vitamin D deficiency appears to be remarkably common among individuals with Huntington's disease. A pioneering study by Chel et al. revealed that 89% of institutionalized patients with manifest HD had Vitamin D insufficiency, defined as serum 25(OH)D levels below 50 nmol/L 2 [5]. The mean serum 25(OH)D level in these HD patients was strikingly low at just 33 nmol/L (SD 15) 2. This prevalence of deficiency matches or even exceeds that observed in other neurodegenerative conditions such as Parkinson's disease [5] 7.

The significance of this deficiency extends beyond mere nutritional status. A positive association has been documented between serum 25(OH)D levels and functional capabilities in HD patients, specifically measured using the Functional Ambulation Classification (FAC) scores 2. This suggests that Vitamin D status may be linked to functional performance in individuals with HD, though the causal relationship remains to be fully established.

Furthermore, individuals with Huntington's disease demonstrate alterations in bone metabolism that may be connected to Vitamin D insufficiency. Costa de Miranda et al. discovered that bone mineral density and T-scores were significantly lower in Huntington's patients compared to healthy controls [5]. Perhaps more tellingly, Goodman et al. detected significantly lower bone mineral density in high-risk individuals prior to the clinical manifestation of HD, suggesting that bone metabolism alterations may begin early in the disease process 5.

Mechanisms of Vitamin D Action in Huntington's Disease
Research, particularly in animal models, has identified several mechanisms through which Vitamin D might influence Huntington's disease pathophysiology. These mechanisms provide a scientific foundation for understanding how Vitamin D deficiency might contribute to disease progression and how supplementation might offer beneficial effects.

Neuroprotective Effects Through Anti-inflammatory Action
Vitamin D3 demonstrates substantial neuroprotective capacity in combating neuroinflammation, which is a key pathological feature of HD 3. In experimental studies, Vitamin D administration has been shown to downregulate the gene expression of key proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in HD mice 3. Additionally, Vitamin D intake exhibited a detrimental effect on nuclear factor kappa B (NF-κB) gene expression in the striatum, an area particularly affected in HD 3. This anti-inflammatory benefit is particularly relevant as elevated levels of pro-inflammatory cytokines like TNF-α and increased NF-κB activity are known to precede striatal neurodegeneration in HD 3.

Modulation of Oxidative Stress
Oxidative stress represents another fundamental pathological mechanism in Huntington's disease. Vitamin D3 supplementation has demonstrated antioxidant effects in HD mice, decreasing the gene expression of oxidative stress markers such as catalases (Cat) and glutathione peroxidase (GpX4) 3 4. This suggests that Vitamin D may help reduce the burden of oxidative damage that contributes to neuronal loss in HD. The reduction in oxidative stress markers following Vitamin D supplementation correlates with improved outcomes in experimental models, suggesting this may be an important pathway through which Vitamin D exerts beneficial effects 3.

Enhancement of Cholinergic Neurotransmission
A particularly interesting mechanism involves Vitamin D's effects on cholinergic neurotransmission, which is often compromised in neurodegenerative conditions. Vitamin D3 administration has been shown to attenuate acetylcholinesterase (AChE) activity in both the cortex and striatum of HD mice 3. Since AChE breaks down acetylcholine, its inhibition by Vitamin D potentially restores acetylcholine levels, enhancing cholinergic signaling. Cholinergic deficiency and increased AChE levels have been previously linked to memory impairment in experimental models of HD, making this mechanism particularly relevant to cognitive symptoms 3.

Upregulation of Neurotrophic Factors
Perhaps one of the most promising mechanisms involves Vitamin D's ability to enhance the expression of crucial neurotrophic factors. In experimental HD models, Vitamin D supplementation led to significant enhancement in the expression of key neurotrophic factors including brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF) 3 4. These factors are essential for neuronal survival and function, and their depletion is implicated in HD pathogenesis. The Vitamin D receptor (VDR) appears to mediate this upregulation, activating neuronal survival pathways that may help preserve neurons in HD 3.

Modulation of Immune System Markers
Emerging evidence suggests Vitamin D also influences neuroinflammation through effects on immune receptors. Prolonged administration of Vitamin D3 has shown neuroprotective effects by decreasing the gene expression of the immune receptor T-cell receptor beta (TCR-β) subunit in both the cortex and striatum of HD mice 3. This is significant because enhanced expression of immune receptors is increasingly recognized as playing a role in neurodegenerative disorders.

Evidence from Animal Studies on Vitamin D Supplementation
Experimental studies in animal models of Huntington's disease have provided compelling evidence for the potential benefits of Vitamin D supplementation. These studies have examined various outcomes including survival, motor function, and neurobiological markers.

Impact on Survival
Perhaps the most striking finding comes from a study demonstrating that high-dose Vitamin D3 supplementation significantly increased the lifespan of transgenic HD animals. While vehicle-supplemented HD mice survived for a median of 73 days (range 67-94 days), those receiving Vitamin D3 supplementation lived substantially longer with a median survival of 101 days (range 74-109 days), representing a statistically significant improvement (p=0.048) 1. This prolongation of survival, even without measurable improvements in motor performance in that particular study, suggests that Vitamin D may exert fundamental neuroprotective effects that enhance overall resilience in HD 1.

Effects on Motor Function and Movement
The impact of Vitamin D on motor function in HD appears nuanced across different studies. Manjari et al. demonstrated that Vitamin D supplementation at a dose of 500 IU/kg/day rescued locomotor dysfunction and neuromuscular impairment in a 3-nitropropionic acid (3-NP) induced HD mouse model 4. The same research showed that Vitamin D supplementation induced survival signals, diminished oxidative stress, and reduced movement and motor dysfunction in these HD mice 4. However, another study by Klivényi et al. indicated that while Vitamin D3 significantly increased lifespan, it had no measurable effect on the motor performance of transgenic mice 1. These seemingly contradictory findings may relate to differences in animal models, dosing regimens, or assessment methods, highlighting the need for additional research.

Neurobiological Effects
At the neurobiological level, Vitamin D supplementation shows promising effects on brain function in HD models. Studies indicate that Vitamin D administration provides protective effects in maintaining both cortical and striatal functions in HD mice 3. As mentioned previously, Vitamin D significantly attenuated acetylcholinesterase activity in both the cortex and striatum, suggesting improved cholinergic neurotransmission which is essential for cognitive function 3. The observed enhancements in neurotrophic factor expression and reductions in oxidative stress markers after Vitamin D supplementation further support its beneficial neurobiological effects 3 4.

Therapeutic Potential and Clinical Implications
Despite the promising experimental evidence, the translation of these findings into clinical applications for Huntington's disease patients remains in early stages.

Current State of Clinical Research
Notably, despite the evidence of widespread Vitamin D deficiency in HD patients and promising results from animal studies, there are currently no completed supplementation studies in patients with Huntington's disease reported in the available search results 7. Experts in the field have emphasized that "investigations of disease-specific or general effects of Vitamin D administration, be it substitutional or prophylactic, should be of great interest" 7. This highlights a significant gap in the research that needs to be addressed through well-designed clinical trials.

Potential as a Complementary Therapy
The collective findings suggest that Vitamin D may serve as a valuable supplementary treatment in Huntington's disease management. Multiple researchers have proposed that "Vitamin D may be an effective supplementary treatment to beneficially influence clinical features of Huntington's disease" 1. However, it remains unclear whether Vitamin D exerts its effects through a specific neuroprotective mechanism or through a more general corroborative effect 1. Either way, given the established safety profile of Vitamin D supplementation when appropriately dosed, and the high prevalence of deficiency in HD patients, addressing Vitamin D status appears to be a reasonable clinical consideration.

Dosage and Administration Considerations
While optimal dosing regimens for Vitamin D in HD have not been established in human studies, the animal research provides some guidance. In mouse models, doses of 500 IU/kg/day have shown beneficial effects 3 4. However, direct extrapolation to human dosing requires caution. In general, Vitamin D sufficiency is considered when serum levels are above 50 nmol/L, with levels below 30 nmol/L indicating deficiency 9. Supplementation approaches would likely need to be tailored based on individual baseline levels, with the goal of achieving normal physiological ranges rather than supraphysiological concentrations.

Comparison with Other Nutritional Approaches in HD
Vitamin D is not the only nutritional intervention that has been investigated for potential benefits in Huntington's disease. Understanding how it compares with other approaches provides additional context for its potential role.

Vitamin E (Alpha-tocopherol)
Alpha-tocopherol (vitamin E) has been studied for HD based on the hypothesis that it reduces oxyradical damage to cell membranes 10. A prospective, double-blind, placebo-controlled study found that while treatment with d-alpha-tocopherol had no overall effect on neurologic and neuropsychiatric symptoms, post hoc analysis revealed a significant therapeutic effect on neurologic symptoms for patients early in the disease course 10. This parallels some findings with Vitamin D, suggesting that antioxidant therapies may be more effective in early stages of HD.

Thiamine (Vitamin B1) and Biotin
Recent research suggests another potential nutritional deficiency in HD: thiamine (vitamin B1). Studies indicate a thiamine deficiency in the HD brain, with the possibility that HD patients might benefit from thiamine and/or biotin supplementation therapy 11. This highlights that multiple nutritional factors may contribute to HD pathophysiology, potentially offering complementary therapeutic approaches.

Conclusion
The evidence indicates that Vitamin D plays a potentially significant role in Huntington's disease through multiple mechanisms including anti-inflammatory effects, antioxidant properties, enhancement of cholinergic neurotransmission, upregulation of neurotrophic factors, and modulation of immune system markers. The remarkably high prevalence of Vitamin D deficiency in HD patients (89%) suggests this may be more than coincidental and could contribute to disease progression.

Animal studies provide compelling evidence that Vitamin D supplementation can extend survival, improve motor function, and favorably modify neurobiological markers in HD models. However, the translation of these findings into clinical practice requires further investigation through well-designed human trials. Until such studies are completed, addressing Vitamin D deficiency in HD patients represents a reasonable clinical consideration given its established safety profile and the high prevalence of insufficiency in this population.

Future research should focus on determining optimal supplementation regimens, identifying which patients might benefit most from Vitamin D therapy, and exploring potential synergies with other treatments. Combination approaches that address multiple nutritional deficiencies including Vitamin D, vitamin E, thiamine, and biotin might offer more comprehensive benefits than single-nutrient interventions. As our understanding of the complex interplay between nutrition and neurodegeneration continues to evolve, Vitamin D appears to be an increasingly important piece of the therapeutic puzzle for Huntington's disease.

Citations:

1. https://pubmed.ncbi.nlm.nih.gov/27685770/
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC3908964/
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC10776327/
4. https://pubmed.ncbi.nlm.nih.gov/35413386/
5. https://tremorjournal.org/articles/74/files/submission/proof/74-1-3326-2-10-20200825.pdf
6. https://onlinelibrary.wiley.com/doi/10.1155/2015/192747
7. https://pmc.ncbi.nlm.nih.gov/articles/PMC7453965/
8. https://jamanetwork.com/journals/jama/fullarticle/2532012
9. https://hospiceofhuntington.org/get-help/tips-from-the-dietitian/vitamin-d-deficiency/
10. https://pubmed.ncbi.nlm.nih.gov/8526244/
11. https://dnascience.plos.org/2021/09/30/does-a-vitamin-deficiency-in-the-brain-lie-behind-huntingtons-disease/
12. https://pmc.ncbi.nlm.nih.gov/articles/PMC6121649/
13. https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1333217/full
14. https://tremorjournal.org/articles/10.5334/tohm.74
15. https://pmc.ncbi.nlm.nih.gov/articles/PMC8533313/
16. https://pubmed.ncbi.nlm.nih.gov/24516688/
17. https://www.mdpi.com/2227-9059/9/10/1284
18. https://www.imrpress.com/journal/JIN/21/6/10.31083/j.jin2106155/htm
19. https://pmc.ncbi.nlm.nih.gov/articles/PMC10674993/
20. https://en.hdbuzz.net/324
21. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796088