**2. Alzheimer's disease**

Alzheimer's disease (AD) can be described as a multifactorial, metabolic disease as this disease is characterized by impairments in multiple cellular processes. For example, AD pathology includes alterations in the sequential proteolytic processing of the amyloid precursor protein (APP) which results in the formation of neurotoxic Aβ plaques, in the phosphorylation of the microtubule-associated protein Tau, in lipid and energy metabolism, and in inflammation. Among others, AD pathogenesis is influenced by lipophilic vitamins [38].

Epidemiological studies indicate a relationship between vitamin D deficiency and AD. A systematic review and meta-analysis concluded that patients affected by AD have lower levels of serum 25(OH)D3 than healthy controls [39]. Furthermore the level of vitamin D is shown to be significantly reduced in the cerebrospinal fluid of AD patients [40]. Another meta-analysis from Shen and colleagues shows that vitamin D hypovitaminosis (25(OH)D3 level < 50 nmol/L) is associated with a 21% increased risk of AD [41]. Different results were obtained by a study, measuring serum level of 25(OH)D3 via radioimmunoassay in patients with MCI or diagnosed dementia compared to healthy controls. Analysis of the cognitive performance showed significant differences between these groups. Vitamin D levels of 65.2 ± 17.9 nmol/L for controls, 61.4 ± 18.8 nmol/L for MCI, and 65.0 ± 20.3 nmol/L for AD were reported in this study; however the differences in vitamin D concentrations between these groups were not statistically significant. Interestingly, the authors show that approximately 12% of the MCI and AD patients used some kind of vitamin D supplementation, whereas only 5% of healthy controls did so. Furthermore, 80% of the MCI patients, 50% of the AD patients, and 62% of the control individuals regularly used nutritional supplements, which could have influenced the results as discussed by the authors. In conclusion, the authors comment that their "findings cannot exclude the possibility that targeted vitamin supplementation can act as a modifying measure, although it is less likely that vitamin intake can prevent dementia onset" [42].

Several longitudinal studies provide homogeneous results indicating that a deficiency in serum 25(OH)D3 is linked to a greater risk and incidence of dementia and AD [43–47]. A current prospective study analyzed 25(OH)D3 level, cognitive decline, and incidence of dementia in 916 patients for 12 years and reported a more pronounced cognitive decline and a threefold increased risk of AD in individuals with hypovitaminosis D [48].

In line, a study from 2018 analyzing the serum vitamin D level in AD patients described decreased levels in various stages of AD. Additionally, the authors indicate 25(OH)D3 as significant predictor for severe AD and argue for vitamin D

**129**

*The Effects of Vitamin D Deficiency on Neurodegenerative Diseases*

als who can have a benefit from supplementation [50].

supplementation in AD patients [49]. Moreover, Wang et al. recently reported a delayed onset of psychotic symptoms when vitamin D was used in AD patients and suggest variations in vitamin D-influenced genes as biomarkers for those individu-

These studies consistently indicate a link between insufficient dietary intake of vitamin D and cognitive diseases like AD. However, these studies did not address the question whether vitamin D deficiency is a cause and thus risk factor for AD or a consequence of this neurodegenerative disease mediated by accompanying dietary and behavioral changes. Some more evidence of a causal relationship between hypovitaminosis D and AD was achieved by Mendelian randomization (MR) studies that use genetic associations on inherited alleles unaffected by confounding factors or disease progression. It was reported that two polymorphisms in the *VDR* gene are associated with AD risk in patients younger than 76 years [51]. A subsequent meta-analysis including six AD studies also revealed this relationship [52], as well as an earlier study using genotyping of 213 participants [53]. Wang et al. also provide this genetic evidence and could further generate functional data indicating a link between the VDR and the genetic AD risk [54]. Furthermore, the study of Mokry and colleagues supports genetically decreased vitamin D levels as causal risk of AD, by analyzing the effect of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism on 25(OH)D3 levels and the risk of AD in more than 56,000 participants [55]. A recently published MR study from Larsson and colleagues including 17,008 AD cases and 37,154 controls reported an inverse association between 7 SNPs related to elevated vitamin D3 levels with AD, in which 2 of them were significant [56]. A study creating a vitamin D synthesis risk score analyzing more than 1000 Swedish men in a follow-up of 18 years is controversially discussed as this study revealed no link between baseline vitamin D status and the

Concerning clinical studies, randomized placebo-controlled trials analyzing the effect of vitamin D supplementation on AD risk and progression are still missing. However, recently nonrandomized studies showed positive findings about that relationship. A current study reported improvements in the cognitive status of MCI patients (n = 16) in an 18-month follow-up after 6 months of vitamin D supplementation. Additionally, vitamin D supplementation protected lymphocytes from

In contrast to the missing clinical trials, several animal and cell culture studies underline a causal relationship between vitamin D and AD. One study described an increased neurogenesis and enhanced cognition after feeding a transgenic mouse model of AD (5xFAD mouse model) with a daily dose of 500 IU/kg vitamin D for 5 months [59]. Additionally, animal and cell culture studies allow analyzing combination therapies, for example, a supplementation of both vitamin D and resveratrol. This resulted in an improvement of cognitive function and reduced levels of Aβ42 in the hippocampus along with decreased tau phosphorylation in the parietal cortex of a mouse model with AD-related memory impairment [60]. In line, a novel study from 2019 reported an improvement of the AD-related pathology in 5xFAD mice after intravenous injection of vitamin D-binding protein which was loaded on a biocompatible polymer (PLGA) [61]. Especially cell culture and animal-based studies are indispensable for clarifying the molecular mechanisms of vitamin D action in neurodegenerative diseases. They revealed that vitamin D exerts its protective effects via VDR-related, genomic, as well as non-genomic actions directed to processes like Aβ metabolism, neurogenesis, immune modulation, and neuronal calcium homeostasis. A study from Landel et al. examined the transcriptome of 5xFAD mice after 5 months of vitamin D3 supplementation and reported a large number of differentially expressed genes. The authors suggest an

*DOI: http://dx.doi.org/10.5772/intechopen.89160*

long-term risk of dementia [57].

oxidative stress [58].

#### *The Effects of Vitamin D Deficiency on Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.89160*

*Vitamin D Deficiency*

D among others [37].

**2. Alzheimer's disease**

genesis is influenced by lipophilic vitamins [38].

can prevent dementia onset" [42].

with hypovitaminosis D [48].

several cognitive tests. High doses of vitamin D enhanced visual memory, while low doses (400 IU/day) improved verbal memory. As summarized by the authors, there seems to be a small positive effect of vitamin D3 supplementation on executive functioning, despite the outlined limitations (modest sample size with wide range of ages, no true placebo group) [35]. Recently, Aspell et al. give a well elaborated overview over a possible supporting role of vitamin D in cognitive function in age [36]. In the following chapter, we will present the results of current available studies examining the impact of vitamin D supplementation on brain-related disorders for each neurodegenerative disease itself. Up to this date, also the nutrition research field examines the influence of dietary components on brain health. In a recent review from Moore et al., the authors describe a potential protective role for vitamin

Alzheimer's disease (AD) can be described as a multifactorial, metabolic disease as this disease is characterized by impairments in multiple cellular processes. For example, AD pathology includes alterations in the sequential proteolytic processing of the amyloid precursor protein (APP) which results in the formation of neurotoxic Aβ plaques, in the phosphorylation of the microtubule-associated protein Tau, in lipid and energy metabolism, and in inflammation. Among others, AD patho-

Epidemiological studies indicate a relationship between vitamin D deficiency and AD. A systematic review and meta-analysis concluded that patients affected by AD have lower levels of serum 25(OH)D3 than healthy controls [39]. Furthermore the level of vitamin D is shown to be significantly reduced in the cerebrospinal fluid of AD patients [40]. Another meta-analysis from Shen and colleagues shows that vitamin D hypovitaminosis (25(OH)D3 level < 50 nmol/L) is associated with a 21% increased risk of AD [41]. Different results were obtained by a study, measuring serum level of 25(OH)D3 via radioimmunoassay in patients with MCI or diagnosed dementia compared to healthy controls. Analysis of the cognitive performance showed significant differences between these groups. Vitamin D levels of 65.2 ± 17.9 nmol/L for controls, 61.4 ± 18.8 nmol/L for MCI, and 65.0 ± 20.3 nmol/L for AD were reported in this study; however the differences in vitamin D concentrations between these groups were not statistically significant. Interestingly, the authors show that approximately 12% of the MCI and AD patients used some kind of vitamin D supplementation, whereas only 5% of healthy controls did so. Furthermore, 80% of the MCI patients, 50% of the AD patients, and 62% of the control individuals regularly used nutritional supplements, which could have influenced the results as discussed by the authors. In conclusion, the authors comment that their "findings cannot exclude the possibility that targeted vitamin supplementation can act as a modifying measure, although it is less likely that vitamin intake

Several longitudinal studies provide homogeneous results indicating that a deficiency in serum 25(OH)D3 is linked to a greater risk and incidence of dementia and AD [43–47]. A current prospective study analyzed 25(OH)D3 level, cognitive decline, and incidence of dementia in 916 patients for 12 years and reported a more pronounced cognitive decline and a threefold increased risk of AD in individuals

In line, a study from 2018 analyzing the serum vitamin D level in AD patients

described decreased levels in various stages of AD. Additionally, the authors indicate 25(OH)D3 as significant predictor for severe AD and argue for vitamin D

**128**

supplementation in AD patients [49]. Moreover, Wang et al. recently reported a delayed onset of psychotic symptoms when vitamin D was used in AD patients and suggest variations in vitamin D-influenced genes as biomarkers for those individuals who can have a benefit from supplementation [50].

These studies consistently indicate a link between insufficient dietary intake of vitamin D and cognitive diseases like AD. However, these studies did not address the question whether vitamin D deficiency is a cause and thus risk factor for AD or a consequence of this neurodegenerative disease mediated by accompanying dietary and behavioral changes. Some more evidence of a causal relationship between hypovitaminosis D and AD was achieved by Mendelian randomization (MR) studies that use genetic associations on inherited alleles unaffected by confounding factors or disease progression. It was reported that two polymorphisms in the *VDR* gene are associated with AD risk in patients younger than 76 years [51]. A subsequent meta-analysis including six AD studies also revealed this relationship [52], as well as an earlier study using genotyping of 213 participants [53]. Wang et al. also provide this genetic evidence and could further generate functional data indicating a link between the VDR and the genetic AD risk [54]. Furthermore, the study of Mokry and colleagues supports genetically decreased vitamin D levels as causal risk of AD, by analyzing the effect of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism on 25(OH)D3 levels and the risk of AD in more than 56,000 participants [55]. A recently published MR study from Larsson and colleagues including 17,008 AD cases and 37,154 controls reported an inverse association between 7 SNPs related to elevated vitamin D3 levels with AD, in which 2 of them were significant [56]. A study creating a vitamin D synthesis risk score analyzing more than 1000 Swedish men in a follow-up of 18 years is controversially discussed as this study revealed no link between baseline vitamin D status and the long-term risk of dementia [57].

Concerning clinical studies, randomized placebo-controlled trials analyzing the effect of vitamin D supplementation on AD risk and progression are still missing. However, recently nonrandomized studies showed positive findings about that relationship. A current study reported improvements in the cognitive status of MCI patients (n = 16) in an 18-month follow-up after 6 months of vitamin D supplementation. Additionally, vitamin D supplementation protected lymphocytes from oxidative stress [58].

In contrast to the missing clinical trials, several animal and cell culture studies underline a causal relationship between vitamin D and AD. One study described an increased neurogenesis and enhanced cognition after feeding a transgenic mouse model of AD (5xFAD mouse model) with a daily dose of 500 IU/kg vitamin D for 5 months [59]. Additionally, animal and cell culture studies allow analyzing combination therapies, for example, a supplementation of both vitamin D and resveratrol. This resulted in an improvement of cognitive function and reduced levels of Aβ42 in the hippocampus along with decreased tau phosphorylation in the parietal cortex of a mouse model with AD-related memory impairment [60]. In line, a novel study from 2019 reported an improvement of the AD-related pathology in 5xFAD mice after intravenous injection of vitamin D-binding protein which was loaded on a biocompatible polymer (PLGA) [61]. Especially cell culture and animal-based studies are indispensable for clarifying the molecular mechanisms of vitamin D action in neurodegenerative diseases. They revealed that vitamin D exerts its protective effects via VDR-related, genomic, as well as non-genomic actions directed to processes like Aβ metabolism, neurogenesis, immune modulation, and neuronal calcium homeostasis. A study from Landel et al. examined the transcriptome of 5xFAD mice after 5 months of vitamin D3 supplementation and reported a large number of differentially expressed genes. The authors suggest an

interaction of vitamin D with estrogen and insulin signaling to regulate the identified pathways [62]. Consistently, we could show that a deficit of vitamin D causes a dysregulation of numerous genes that are involved in multiple cellular processes like neurogenesis, inflammation, mitochondrial function, oxidative stress, signal transduction, and APP homeostasis in brains of hypovitaminosis D mice [63]. In respect to the impaired APP homeostasis, several studies using primary cortical neurons or human neuroblastoma cell lines were able to show beneficial effects of vitamin D and its analogues on anabolism and catabolism of the neurotoxic Aβ peptide [64, 65]. In line with these findings, a vitamin D3-enriched diet leads to an increased Aβ clearance in mouse models of AD [66–68]. Consistent with the results of animal studies, Hooshmand et al. could demonstrate an association of increased plasma 25(OH)D3 levels with higher concentrations of CSF Aβ1-42 in 75 patients, reflecting a decreased Aβ1-42 aggregation in human brain parenchyma [69]. In contrast, a recent cross-sectional study failed to find significant associations between plasma vitamin D levels at baseline and Aβ load in different brain regions. But the authors themselves argue that those findings could be explained by an improper timing of measurements or rather no analysis over time or by a hypovitaminosis D-related cognitive decline independent of APP homeostasis [70]. The potential neuroprotective role of vitamin D3 is based on findings that it regulates the transcription of the neurotrophin nerve growth factor, glial-derived nerve factor, and neurotrophin 3 which are important for neuronal survival [71–73]. Furthermore, the expression of the neuroprotective cytokine IL-34 was shown to be increased in dose- and time-dependent manner by calcitriol in neuroblastoma cells [74]. In respect to a relationship between vitamin D and neuronal calcium levels, a review describes a reduced autophagy due to impairments in calcium signaling as a consequence of hypovitaminosis D [6].
