Introduction

Dementia is a term to describe a clinical syndrome of acquired, progressive decline in cognitive functions in the loss of one or more cognitive abilities caused by brain disease or injury, severe enough to reduce a person's ability to perform daily activities [1]. Alzheimer's disease is a subtype of dementia, characterized by the formation of neuritic plaques and neurofibrillary tangles. The extracellular deposition of Aβ peptide, known as amyloid plaques. The neurofibrillary tangle consists of abnormal intracellular accumulations of phosphorylated tau protein within the perikaryal cytoplasm of certain neurons [2]. AD is the most common type of dementia, accounting for at least 75% of dementia cases in the elderly population. Approximately, there are around 50 million AD patients in the world and expected to increase by threefold in 2050 [2]. AD puts a heavy burden on healthcare systems around the world, costing more than $80 billion each year [3].

A past study by Perez-Lopez and colleagues reported the crucial role of vitamin D in maintaining cognitive function [4] another study also suggests the vitamin D receptors present in the brain regions responsible for cognitive functions and memory development [5]. The roles of Vitamin D in neurotrophy, neurotransmission, neuroprotection, and neuroplasticity may explain vitamin D deficiency involvement in the progression of AD [6]. Several past studies have reported the relationship between vitamin D deficiency and cognitive decline. An updated meta-analysis by Chai and colleagues reported significant associations between vitamin D deficiency and AD, with severe vitamin D deficiency having the strongest association [7] other meta-analyses also reported that Plasma or serum 25-hydroxyvitamin D concentration related to the risk of AD in inverse association [8]. The meta-analysis of the prospective cohort studies of Vitamin D concentration and the risk of AD reported that serum vitamin D deficiency or insufficiency was not statistically significant and associated with the risk of AD ([9]); this finding showed the inconsistent result between past meta-analysis. Thus, we are conducting an updated meta-analysis of vitamin D and AD association.

Methods

This study followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [10].

Literature searching and selection method

Initially, two authors independently filtered the databases of the selected studies on PubMed up to December 2022, using specific keywords: “vitamin D” AND “Alzheimer.” We used the following inclusion criteria to select eligible studies that assess the relationship between low vitamin D serum levels and Alzheimer’s disease: (1) Observational studies that evaluated the association between low vitamin D serum levels at baseline and subjects with AD; (2) studies that reported hazard ratio (HR) alongside 95% confidence intervals (CIs) as risk estimates. The literature search was particularly for English language studies only. We excluded the following studies: (i) non-original articles (narratives, systematic review, meta-analyses, abstracts, comments, or editorials); (ii) case report/ series; (iii) studies assessing other conditions not within our scope; (iv) incomplete data. The main outcome was the risk estimates of low vitamin D serum levels as risk factor of develo** AD.

Data extraction and quality assessment

two independent authors read and inspected the titles and abstract according to the inclusion criteria—next, these authors examined a full-text review. If there were a lack of agreement between the two authors, the primary author would settle the disagreement and make a final judgment. Articles that matched the inclusion criteria were selected, and additional studies were retrieved according to the references of the articles collected.

We collected and summarized the subsequent data: Main author(s), publication years, study design, nation of origin, serum 25(OH)D levels, follow-up duration, and statistical adjustment. The Oxford Center for Evidence-Based Medicine (OCEBM) scale assessed each study's ratings. The scale categorized each study with ratings ranging from 1 to 5, with 1 meaning high-quality studies such as clinical trials and 5 representing case series/reports [11].

Statistical analysis

We conducted the analyses using Review Manager (RevMan) statistic software (version 5.3). The hazard ratio (HR) and 95% confidence interval (CI) were analyzed as effect size. We also analyzed I2 statistics to assess heterogeneity between studies. I2 of more than 50% was considered high heterogeneity. A Fixed-effects model was performed when there was no heterogeneity between studies. On the contrary, A random effects model will be used when data are considered heterogeneous. P-values of less than 0.05 (P ≤ 0.05) were statistically significant [12, 13].

Results

Study characteristics

The initial search strategy identified 562 articles. After removing copies, followed by abstract screening, 24 full-text articles were evaluated for their eligibility. The final review included six articles [14,15,16,17,18,19] of five prospective studies and one cross-sectional. Figure 1. displays the PRISMA flow chart.

Fig. 1
figure 1

PRISMA flow chart of study selection

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This process resulted in the selection of 6 studies that evaluated the relationship between vitamin D deficiency and AD, involving 10,884 participants for the meta-analysis. Of the included studies, author(s), publication years, study design, nation of origin, serum 25(OH)D levels, follow-up duration, statistical adjustment, and study ratings. Overall, most of the studies had high-quality ratings (Table 1). All selected studies observed patients with low vitamin D serum levels (< 25 ng/ml) as a risk factor of AD.

Table 1 Baseline characteristics of patients in the included studies
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Low vitamin D serum levels and risk of AD

A meta-analysis with random effects model was conducted to summarize the estimated risk of AD in patients with low levels of serum vitamin D. The analysis showed that patients with low levels of vitamin D (< 25 ng/ml) had a greater risk of develo** AD compared with those who had normal serum vitamin D levels (HR: 1.59, 95% CI: 1.09, 2.33, I2 = 77%, Fig. 2). The I2 value was 77% indicating heterogeneity between studies.

Fig. 2
figure 2

Risk association between low vitamin D levels (25(OH)D < 25 ng/ml) and AD

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Discussion

This meta-analysis provided additional evidence of low vitamin D levels and the risk of Alzheimer's disease. A total of 6 studies were included in this study, involving 10,884 participants. The analysis showed that patients with vitamin D deficiency (< 25 ng/ml) had a higher risk of AD compared to patients with adequate vitamin D supply (≥ 25 ng/ml). A previous meta-analysis [8] in 2018 reported the inverse association between 25-hydroxyvitamin D concentration to the risk of dementia. This study included Ten cohort studies with more than 20.000 participants. A year later, a meta-analysis involving twelve prospective cohort studies and four cross-sectional studies reported the same results as the previous meta-analysis. This meta-analysis reported a significant association between Vitamin D deficiency and dementia, with severe deficiency (< 10 ng/ml) having the strongest association compared to moderate vitamin D deficiency (10–20 ng/ml). [7] within the same year, other meta-analyses reported different results. Meta-analyses by Yang K and colleagues reported that the relation between vitamin D deficiency and insufficiency with the risk of AD was not statistically significant. This study involved six prospective cohort studies with more than 1000 AD cases [9].

The pathomechanism of AD may cause by two types of neuropathology changes. The first neuropathology change is a positive lesion due to the accumulation of neurofibrillary tangles, amyloid plaques, and other deposits in the AD patient's brain. The second neuropathology change is due to the loss of neuropil, neural and synaptic. Besides, neurodegeneration can cause by factors such as oxidative stress and neuroinflammation [2].

Several studies have reported vitamin D's potential benefit and relationship with AD. Vitamin D may affect the first neuropathology change by promoting the clearing of amyloid plaques, as reported in animal and human studies [20, 21]. Vitamin D also prevents cognitive dysfunction via its roles in neuroprotection, neurotrophy, neurotransmission, and neuroplasticity, although its mechanism is still unclear [6]. Vitamin D also showed the potential to prevent neuroinflammation by inhibiting the production of TNF-a and IL 6 in in-vitro studies [22].

This study has limitations. Firstly, this study included one cross-sectional study, thus increasing the possibility of bias. Secondly, our study focused mainly on the relationship between Alzheimer's disease risk and low vitamin D levels. It was unclear whether the vitamin D level had changed in further follow-up. Lastly, the patients involved in this study are mainly from Europe and America. Thus this study may not be applied to the world population.

Conclusion

This meta-analysis provided evidence of the relationship between low vitamin D levels with the risk of AD. The random effects model analysis showed that low vitamin D levels (< 25 ng/ml) are a risk factor for develo** AD. Maintaining normal vitamin D levels may lower the risk of AD.