Introduction

Alzheimer’s disease (AD) is a genetic and sporadic neurodegenerative disorder that typically manifests as amnestic cognitive impairment, irreversible progressive function, cognition, and behavior loss with symptoms such as amnesia, prosopagnosia, and aphasia, and is the most common type of dementia [58, 89]. Over 57.4 million people worldwide suffer from AD or other dementias, and this number is predicted to rise to 153 million by 2050 [76]. The etiology of AD is complex and difficult to determine. In addition to endogenous factors such as age, genetics, and disease history, there is growing evidence that environmental pollutants are linked to the development of AD [63, 73, 135]. Identifying and intervening early on controllable environmental risk factors is important for preventing and delaying the development of AD [106].

Trace elements, such as lead (Pb), mercury (Hg), cadmium (Cd), arsenic (As), etc., are known neurotoxicants that can cross the blood–brain barrier and accumulate in the central nervous system, causing endoplasmic reticulum stress, mitochondrial damage, neuroinflammation, and neuronal apoptosis, etc. [9, 38, 65], belonging to the environment of the toxins with significant potential hazards [6]. While some other trace elements (copper (Cu), iron (Fe), zinc (Zn), magnesium (Mg), etc.) often act as catalysts in enzyme systems and play important roles in maintaining normal neurophysiology, including the synthesis of neurotransmitters, participation in catalytic reactions, maintenance of mitochondrial function and stabilization of protein structures [64]. Overexposure and homeostatic perturbations of trace elements lead to over-deposition of amyloid β (Aβ), hyperphosphorylation of tau, neural signaling, and the generation of free radicals, which are closely linked to the development of neurodegenerative pathologies and AD [8, 74, 144]. However, there is heterogeneity in the results of population-based studies on trace elements and AD due to differences in study design, population characteristics, sample sizes, biomaterials, testing methods, and evaluation criteria [82, 90, 107, 146]. There is no conclusive evidence regarding the changes that occur to trace elements in the circulation of AD patients.

This study reviewed and evaluated circulatory (serum, plasma, and blood) trace element levels in AD patients, aiming to comprehensively and systematically assess the association between trace elements and AD in case–control studies through meta-analysis, and to provide a theoretical framework for the identification of environmental risk and protective factors for AD, as well as the formulation of preventive strategies to proactively address healthy aging.

Methods

Literature search and selection

A search of the PubMed, Web of Science, and MEDLINE databases was conducted to identify case–control studies on trace element levels of AD patients published between January 2000 and April 2023. The search formula was detailed in the Supplementary material 1. Two investigators (JHZ and MQ) conducted a preliminary independent screening of titles and abstracts in the search catalog based on the following exclusion criteria: 1. irrelevant studies; 2. animal or in vitro cellular experiments; 3. systematic reviews, books and documents; 4. mechanistic studies. Articles that passed the initial screening were read in full, and studies meeting the following criteria were considered for inclusion: 1. A case–control study involving AD patients and healthy controls; 2. Patients met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA), the National Institute on Aging—Alzheimer’s Association (NIA-AA), the International Classification of Diseases-10 (ICD-10), the Diagnostic and Statistical Manual Fourth Edition criteria (DSM-4), or the Mini-mental state examination (MMSE) criteria for AD, or confirmed AD patients explicitly stated in the study. 3. Detects trace element concentrations in whole blood, plasma, or serum; 4. Contains complete extractable data. Consensus between two authors, with a third author (YQ) negotiating in case of disagreement. Where multiple publications on the same population existed, only the report with the most comprehensive data was included. Figure 1 illustrates the screening process.

Fig. 1
figure 1

Flowchart of systematic literature selection on trace elements and Alzheimer’s disease

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Data extraction and quality assessment

Two authors (XFL and XYX) independently evaluated each eligible study and extracted the following data: 1. first author’s name; 2. publication year; 3. study country; 4. element type; 5. type of biological samples; 6. sample size of AD and healthy groups; 7. percentage of females in groups; 8. mean age; 9. the mean and standard deviation of the trace element concentrations; 10. diagnostic criteria for AD; 11. detection method. All units were converted to μg/L due to differences in the underlying units of measurement among the studies.

Newcastle–Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the included studies. Based on the “star system”, included studies are evaluated from three broad aspects: selection of study participants, comparability between case and control groups, exposure factors [145]. Studies scored (0–3) as low, (4–6) as moderate, and (7–9) as high quality.

Data analysis

Meta-analyses were performed using the STATA (version 17.0) software. The heterogeneity between studies was assessed using Chi-square and I-square tests. Statistical heterogeneity was defined as a p-value less than 0.10 or an I2 statistic greater than 50%, and a random effects model was used to combine the results of multiple studies. Conversely, a fixed effects model was employed. The pooled standardized mean difference (SMD) represents the difference in means across individual studies and serves as the summary statistic. A subgroup analysis based on sample type was conducted to evaluate the impact of study characteristics as a potential source of heterogeneity. Sensitivity analyses were carried out to assess the impact of individual studies on the pooled SMD. Egger’s test and funnel plots were utilized to evaluate publication bias. The forest plots were drawn to visualize SMDs and 95% confidence intervals (CIs), and results were considered statistically significant when the p-value was less than 0.05.

Results and discussion

Basic characteristics of included studies

There were 52 case–control studies of circulating trace elements in relation to AD that were included in this study. Eleven elements were analyzed in the included studies: copper (Cu, 30 studies), iron (Fe, 19 studies), zinc (Zn, 17 studies), selenium (Se, 16 studies), lead (Pb, 11 studies), cadmium (Cd, 10 studies), mercury (Hg, 8 studies), manganese (Mn, 7 studies), aluminum (Al, 6 studies), arsenic (As, 4 studies), and magnesium (Mg, 4 studies). Table 1 summarizes the main characteristics of the publications included. Two investigators (YQ and YYL) assessed the quality of all included studies in the meta-analysis using the NOS. The overall quality of the studies was favorable (Table 1). The study population came from countries such as Italy (30.8%), the United States (9.6%), India (9.6%), South Korea (7.7%), Australia (7.7%), China (5.8%), and others (Fig. 2A). Of the included studies, 80.8% used the NINCDS-ADRDA as the diagnostic criterion for AD, and the remainder used NIA-AA (3.8%), DSM-4 (3.8%), MMSE (1.9%), and ICD-10 (1.9%) (Fig. 2B). Five detection techniques were used: Inductively coupled plasma-Mass Spectrometry (ICP-MS, 40.4%), atomic absorption spectrometry (AAS, 38.5%), colorimetric assay (CA, 15.4%), total Reflection X-Ray Fluorescence (TXRF, 1.9%), and inductively coupled plasma optical emission spectroscopy (ICP-OES, 1.9%) (Fig. 2C).

Table 1 Studies included in the meta-analyses
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Fig. 2
figure 2

A Proportion of participants' countries in the included studies; B Proportion of Alzheimer's disease diagnostic criteria used in the included studies; (C) Proportion of elemental detection methods used in the included studies

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Meta-analysis results

Cd levels in AD patients and controls

Ten studies compared Cd levels in the circulation of AD patients and controls. The combined sample size was 7522, consisting of 710 AD patients and 6812 healthy controls. Random effects model analysis showed that Cd levels were significantly higher in AD patients, with an SMD of 0.79 (95% CI 0.35, 1.24, p < 0.01). Subgroup analysis indicated that serum Cd levels were elevated in AD patients (SMD = 1.50, 95% CI 0.51, 2.48, p < 0.01). Figure 3A shows the forest plot of the SMD of Cd levels in AD patients and controls.

Fig. 3
figure 3

Forest plot of standardized mean difference (SMD) of (A) cadmium (Cd), (B) mercury (Hg), and (C) copper (Cu) levels in Alzheimer's disease patients and healthy controls

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Cd is a toxic, non-essential transitional heavy metal that is widespread in the environment and enters the body mainly through diet and smoking, with a half-life of about 25–30 years in the human body [42]. Several adverse effects associated with Cd exposure have been demonstrated, including renal tubular damage, impaired glomerular reabsorption, long bone fractures, and decreased bone density [91, 92]. A growing body of research has also identified the neurotoxicity of Cd exposure to the brain as a potential contributing factor to cognitive decline [70]. Bypassing the blood–brain barrier, Cd can enter the central nervous system via epithelial transport in the olfactory nervous system, inducing oxidative stress and leading to neuroinflammation and neuronal death [19]. Additionally, Cd may exacerbate neurodegeneration by altering the permeability of the choroid plexus, causing Aβ aggregation and tau neurofibrillary tangles [79]. Studies in animal models have shown that brain structures of rats exposed to Cd salts have increased acetylcholinesterase activity and exhibit cognitive impairment and anxious behavior [46]. Furthermore, learning and memory deficits caused by Cd exposure may be due to the inhibition of α-secretase, which facilitates the production of Aβ protein precursors, leading to the accumulation of Aβ and senile plaques [112]. Cd also interferes with the metabolism of other essential metals in the cell. Cd exposure disrupts intracellular calcium (Ca) homeostasis and increases extracellular Ca influx, which triggers neuronal apoptosis by activating mitogen-activated protein kinase and mammalian target of rapamycin pathways [30]. Several population studies have also confirmed the association between Cd exposure and low cognitive function [32, 66]. A cross-sectional study of 2,068 adults over the age of 60 based on the National Health and Nutrition Examination Survey in the United States found that elevated blood levels of Cd were associated with cognitive impairment [66]. A prospective cohort study in China, which followed 1554 participants for three years, found similar results and found that the higher the level of Cd in the blood, the more pronounced the cognitive decline [70]. In our study, serum Cd levels changed significantly in AD patients, while blood Cd levels remained stable. This cannot be ruled out because of the small sample size, which included only five studies on blood Cd. In addition, blood Cd represents a recent exposure level that fluctuates widely depending on the environment, diet, and smoking, and further prospective cohort studies and clinical trials are needed to confirm this.

Hg levels in AD patients and controls

Eight studies comparing serum and blood Hg levels in AD patients and healthy controls were included, comprising a total of 669 AD patients and 839 controls. The results of the random effects model showed that AD patients had higher Hg levels than healthy controls, with a pooled SMD (95% CI) of 0.59 (0.03, 1.16) (p < 0.01). In the biomaterial subgroup, serum Hg levels were significantly elevated in the AD groups (SMD = 1.49, 95% CI 0.30, 2.68, p < 0.01). Figure 3B shows a forest plot of the SMD of Hg levels in AD patients and controls stratified by biomaterial.

Hg exists in three forms: monomeric, inorganic, and organic (methylmercury and ethylmercury). Volcanic eruptions and anthropogenic activities (ore mining, coal burning, metal smelting, waste incineration, etc.) are the main sources of Hg in the environment [27]. The mechanism of Hg neurotoxicity is complex because Hg vapor can cross the blood–brain barrier and lipid cell membranes and accumulate in inorganic forms in cells, triggering oxidative stress and leading to cytotoxicity and apoptosis [4]. Inorganic Hg has a long half-life in the brain, especially in the thalamus and pituitary [28], and inhibits β-microtubulin, which in turn disrupts the dynamic balance and biochemical homeostasis within neurons [29]. Methylmercury can cross the blood–brain and placental barriers and accumulate for long periods in the thalamus and pituitary, reducing choline uptake in the cerebral cortex, cerebellum, hippocampus, and brainstem. This leads to a decrease in the raw material for the synthesis of acetylcholine and affects the metabolism of neurotransmitters, causing clinical symptoms such as psychiatric and behavioral disorders, sensory abnormalities, ataxia, mental retardation, and speech and hearing disorders [27]. Studies in cell cultures, animal models, and AD patients have found a relationship between Hg exposure and features of AD, such as elevated levels of Aβ40, Aβ42 and phosphorylation of tau protein in cerebrospinal fluid [27]. After 45 days of sustained exposure to mercuric chloride in rats, Hg was deposited in the brain parenchyma, triggering glutamatergic neurochemical dysfunction in the motor cortex and hippocampus, resulting in reduced spontaneous movement, learning and memory abilities [131]. Prolonged low-dose exposure to Hg produces neurotoxic symptoms such as tremors, unsteady gait, moodiness, distractibility, temporary memory impairment, slurred speech, decreased motor skills, sensory abnormalities, and reduced neural conduction [88]. In population studies, higher blood Hg levels have been associated with poorer cognitive scores and delayed recall [109, 143], and serum and cerebrospinal fluid Hg concentrations were significantly higher in AD patients [43, 146]. However, there have also been case–control studies of AD that found no significant differences in circulating Hg levels between the two groups [44, 86]. From a comprehensive analysis of the included studies, we conclude that the evidence for significantly elevated serum Hg levels in AD patients is reliable. Although blood Hg levels in AD patients were lower than in controls (SMD (95% CI) = − 0.19 (− 0.37, − 0.02)), there was no significant difference (p = 0.264), which cannot exclude an opposite trend due to differences in metabolism of the element in different biosample environments. Further validation is expected from additional biological samples and cohort studies.

Cu levels in AD patients and controls

Thirty studies have reported circulating levels of Cu in AD patients and controls. The combined sample size was 4303, with 2010 AD patients and 2293 controls. The results showed that circulating Cu levels were significantly higher in AD patients than in controls, and the pooled SMD (95% CI) was 0.70 (0.37, 1.04) (p < 0.01). Subgroup analyses showed that AD patients had significantly higher serum Cu levels than controls (SMD = 0.82, 95% CI 0.47, 1.16, p < 0.01), whereas blood and plasma Cu levels were not significantly different between the two groups. Figure 3C shows a forest plot of the SMD of Cu levels in AD patients and controls stratified by biomaterial.

Cu is an essential trace mineral that enters the body in inorganic form through drinking water and food, and is absorbed in the stomach and upper part of the small intestine, with the highest levels in the liver and brain [20, 50]. As an important transition metal, Cu is involved in a wide variety of redox reactions and is an essential cofactor for many catalytic enzymes [53]. Cu overload leads to the Fenton reaction and impairs mitochondrial function, generating reactive oxygen species (ROS) that disrupt macromolecular function and structure, leading to oxidative cell damage and death [54]. The majority of circulating Cu is synthesized in the liver as ceruloplasmin or bound to albumin or micronutrients (such as histidine and peptides), with the remaining small fraction (0.5–5.0%) of low molecular weight serum Cu defined as ultrafilterable Cu or free Cu [115, 120]. Free Cu readily crosses the blood–brain barrier and constitutes a “labile” Cu pool that may participate in the pathogenesis of AD by regulating the production, aggregation, and stabilization of amyloid in the form of protofibrils, and by promoting the aggregation and phosphorylation of tau induced by ROS or neuroinflammatory processes [104, 125]. Several clinical studies have demonstrated that elevated free Cu levels correlate with electroencephalographic-recorded brain activity, signs of cerebral atrophy, and Aβ and tau protein levels in pathologic cerebrospinal fluid [119, 148]. Studies in animal models have shown that amyloid plaques in AD have a high affinity for Cu, and that Cu dyshomeostasis leads to Aβ deposition in senile plaques and neuroprogenitor fiber tangles [140, 150]. In the brains of AD patients, Cu reduction produces H2O2 and toxic lipid oxidation products, leading to Aβ peptide oligomerization and accelerating plaque deposition and lipid peroxidation [80, 115]. Population-based studies have shown that AD patients exhibit significantly elevated serum Cu levels compared to controls [90, 100, 108, 146]. Furthermore, free Cu levels have been shown to reflect the duration and progression of brain disease, i.e., increased free Cu is often accompanied by deterioration in cognitive function, which is more pronounced in patients with dementia compared to those with mild cognitive impairment (MCI) [101, 116]. In addition, elevated serum free Cu levels increase the predisposition to AD by approximately threefold. Additionally, MCI patients with elevated free Cu levels have a threefold increased likelihood of converting to AD compared to MCI patients with normal free Cu levels [117]. This study shows that Cu levels in AD patients are markedly elevated in serum and remain stable in plasma and blood. Given the specific role of free Cu, it is crucial to conduct clinical studies on liver function in AD patients or utilize transgenic animal models to decipher the neurotoxic effects of Cu. Furthermore, longitudinal studies that encompass ceruloplasmin and free Cu interrelationships and imaging markers are essential to comprehend the role of Cu in AD progression.

Fe levels in AD patients and controls

A total of 19 studies compared serum and blood Fe levels in AD patients and controls, including 1,063 AD patients and 936 healthy controls. The results of the random effects model showed that circulating Fe levels were significantly lower in AD patients than in controls, with a pooled SMD (95% CI) of -0.58 (-1.03, -0.13) (p < 0.01). In the biomaterials subgroup, serum Fe levels were significantly reduced in AD patients (SMD = − 0.60, 95% CI − 1.09, − 0.10, p < 0.01), while blood Fe levels were unchanged. Figure 4A shows a forest plot of the SMD of Fe levels in AD patients and controls stratified by biomaterial.

Fig. 4
figure 4

Forest plot of standardized mean difference (SMD) of A iron (Fe), B selenium (Se) and C zinc (Zn) levels in Alzheimer's disease patients and healthy controls

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Fe is one of the most abundant essential trace minerals in the human body and an important transition metal. Several studies have shown that disorders of Fe homeostasis are involved in the etiopathogenesis of several neurodegenerative diseases, including AD [24, 34]. In these patients, Fe accumulation in certain regions of the brain (i.e., basal ganglia, hippocampus, neocortex, as well as the senile plaques and neurofibrillary tangles) is greater than that found in healthy aging and is often associated with oxidative stress [34, 36, 142]. And Fe overload and reduced bioavailability in the brain have been shown to decrease catalase activity, impair neurotransmitter production, and lead to memory, cognitive, and motor dysfunction [139]. On the other hand, the major Fe transport system also transports heavy metals, and inadequate Fe stores in the body increase the expression of divalent metal transporter-1 in cerebral neurons and vascular endothelial cells, which affects the uptake of heavy metals by the epithelial cells and increases the burden of heavy metals in the body [84]. Additionally, alterations in Fe levels impact Cu transport across the brain barrier. For instance, a significant increase (+ 55%) in Cu levels was observed in the cerebrospinal fluid, brain parenchyma, and choroid plexus of an Fe-deficient rat model [7]. Furthermore, research has indicated that anemia and reduced hemoglobin levels are associated with an elevated risk of developing AD [40, 105]. In MCI and early stages of AD, relatively low peripheral Fe levels and underlying neuroinflammation lead to elevated serum ferritin, whereas in advanced stages of the disease, elevated serum ferritin and impaired blood–brain barrier integrity led to elevated serum Fe [56]. This suggests that changes in serum Fe levels in AD patients are not consistent across the different stages of the disease, which may also explain the heterogeneous results of some studies of circulating Fe levels in AD patients [56, 90]. According to our results, AD patients had lower serum Fe levels than controls, which is consistent with the results of two previous meta-analyses [47, 130]. However, future studies should focus on the changes and associations of elemental levels at different stages of AD.

Se levels in AD patients and controls

Sixteen studies have reported circulating Se levels in AD patients and controls, including 683 AD patients and 745 controls, for a total of 1,428 individuals. Random effects modeling results showed that circulating Se levels were significantly lower in AD patients than in controls, with a composite SMD of -0.53 (95% CI − 0.85, − 0.21, p < 0.01). Subgroup analyses revealed that plasma Se levels were significantly reduced in AD patients (SMD = -0.83, 95% CI − 1.05, − 0.62, p < 0.01), whereas serum and blood Se levels did not change significantly. Figure 4B shows a forest plot of the SMD of Se levels in AD patients and controls stratified by biomaterial.

It is well known that oxidative stress plays an important role in the development and progression of AD, as the brain has a high rate of oxygen consumption and a high content of polyunsaturated lipids, making it susceptible to lipid peroxidation and oxidative damage [52]. Se is an important micronutrient also an antioxidant that affects the activity and synthesis of antioxidant enzymes such as glutathione peroxidase, selenoprotein P, thioredoxin reductase, and methionine sulfoxide reductase B [16]. In a memory-impaired rat model, Se is a neuroprotective agent that delays neuronal degeneration by reducing lipid peroxidation and limiting the production of Aβ proteins [10]. Se is a component of glutathione peroxidase, an enzyme that catalyzes the redox reaction of reduced glutathione with peroxides to resist lipid peroxidation and hydrogen peroxide and protect the brain from oxidative damage [72]. Selenoprotein P, the major Se transporter protein in brain tissue, exerts antioxidant effects by reducing phospholipid hydroperoxidase and inhibiting low-density lipoprotein oxidation [103]. Selenoprotein P has also been found in senile plaques and neurogenic fiber tangles in the brains of AD patients, suggesting that it plays a crucial role in safeguarding neurons from oxidative stress [113]. Population studies have found significant differences in peripheral circulating Se concentrations in AD and MCI patients compared to controls [31, 75, 147]. A nine-year cohort study found that low Se levels were positively associated with cognitive decline in the elderly [2]. A possible explanation is that the brain has the highest Se metabolic priority, and plasma Se is readily depleted in the presence of MCI and AD, prioritizing the synthesis of selenoproteins and other antioxidants in the brain to protect polyunsaturated fatty acids in neuronal cell membranes [26]. Thus, the significantly lower plasma Se concentrations in AD and MCI patients may result from increased depletion of glutathione peroxidase and other Se-dependent antioxidants during the development of AD [31]. Considering that Se may act directly as an antioxidant or indirectly on AD progression by improving brain metabolism, monitoring Se levels in the peripheral circulation as well as dietary Se supplementation may be beneficial interventions to increase brain free radical defense to delay AD progression.

Zn levels in AD patients and controls

Seventeen studies compared circulating Zn levels in AD patients and controls, comprising 869 AD patients and 1309 healthy controls, for a total of 2178 individuals. Random-effects model analysis showed that circulating Zn levels were significantly lower in AD patients than in controls, with a pooled SMD (95% CI) of − 0.99 (− 1.52, − 0.46) (p < 0.01). Subgroup analyses revealed that serum Zn levels were significantly lower in AD patients (SMD = − 1.21, 95% CI − 1.83, − 0.60, p < 0.01), whereas plasma and blood Zn levels did not change significantly. Figure 4C shows a forest plot of the SMD of Zn levels in AD patients and controls stratified by biomaterial.

Zn is a redox inactive essential trace element involved in stabilizing protein structures and catalyzing reactions in living organisms and is critical for brain function [15]. Several aging studies have found that lower serum Zn levels in the elderly are associated with inflammatory processes, increased amyloid levels, and decreased memory and cognitive function [128]. The Zn enters the brain across the blood–brain and blood-cerebrospinal fluid barriers, and cerebral capillary endothelial cells respond to changes in systemic Zn status by increasing or decreasing Zn uptake [37]. It has been suggested that Zn deficiency may contribute to the development of AD. Zn levels in the brain of AD patients are positively associated with Aβ peptide levels, plaque count, and dementia severity [94]. Reduced peripheral circulating Zn levels in AD patients will result in increased Zn uptake by brain capillary epithelial cells to maintain Zn stores, and large brain Zn stores may increase Aβ adhesion and promote Aβ aggregation and plaque formation [33]. A clinical intervention study in AD patients confirmed elevated serum Zn levels in AD patients following treatment with the Zn-binding compound clioquinol, which inhibits the binding of Zn ions to Aβ, thereby facilitating Aβ solubilization and reducing its toxicity [98]. Zn also has antioxidant and anti-inflammatory properties, reducing free radical formation by antagonizing redox-active transition metals and protecting the sulfhydryl groups of proteins from free radical attack [55]. On the other hand, there is evidence that there is an antagonism between Zn and Cu absorption, with both competing for the same carrier proteins in intestinal mucosal cells [129]. In a double-blind study of elderly AD patients over the age of 70, supplementation with Zn was found to reduce blood levels of free Cu and prevent cognitive decline [23]. Most studies generally agree with the findings of this study that AD is associated with low serum Zn levels [18, 111, 139]. Certainly, this causal relationship needs to be further substantiated by prospective cohort studies. Given the clinical significance of Zn deficiency in the progression of AD, Zn intervention may be a possible therapeutic target [37].

Residual trace element levels in AD patients and controls

Forest plots of SMD in AD patients and controls stratified by biomaterial for Al, As, Mg, Mn and Pb are shown in Figures S1-S5. The results of the random effects model showed that circulating levels of these trace elements did not change significantly in AD patients compared to healthy controls. The pooled SMD (95% CI) were: Al: 0.67 (− 0.05, 1.38); As: 0.87 (− 0.14, 1.88); Mg: − 1.86 (− 3.82, 0.09); Mn: − 0.19 (− 0.61, 0.24); Pb: 0.03 (− 0.19, 0.25), respectively.

Al, the most abundant neurotoxic metal in the Earth's crust [126], accumulates semi-permanent manner in AD-susceptible neuronal foci via the blood–brain barrier and the intracellular transport pathway of transferrin, and is involved in the induction of oxidative stress, APP gene up-regulation, and amyloid-β conformational changes [35, 134]. Some studies have reported higher AD morbidity or mortality in areas with high Al exposure, suggesting that chronic Al exposure contributes to AD [99, 141]. However, some dissenting voices have argued that bioavailable Al cannot enter the brain in sufficient quantities to cause damage [132], and also that there is still a lack of clear explanations for lifelong exposure to Al as a significant risk factor for AD due to deficiencies in epidemiological study design [77].

As is neurotoxic and impairs cognitive and memory functions. Exposure to As and its metabolites leads to ROS formation, inflammation, mitochondrial dysfunction, and disruption of not only protein homeostasis but also Ca signaling [93]. In addition, As is a known cardiovascular toxicant [133]. The vascular hypothesis of AD suggests that AD is the result of vascular damage that reduces cerebral blood perfusion rates and thus indirectly damages neurons [137]. Studies have shown that environmental As levels are positively correlated with mortality from AD [69, 83]. However, our study did not find significant changes in circulating As levels in AD patients, which is consistent with the findings of others [67, 86]. This may be partly due to the small number of studies included, but also to the fact that As is absorbed by amyloid plaques, which consume As from other body compartments such as blood. Therefore, more severe AD with more plaques shows lower serum As levels [12].

Mg is the second most abundant intracellular divalent cation and a cofactor for more than 300 metabolic reactions in the body [138]. It is neuroprotective, interacting with the N-methyl-D-aspartate (NMDA) receptor and blocking Ca channel in the NMDA receptor, preventing oxidative stress and neuronal cell death due to excitotoxicity [57]. Mg is also involved in normal neuronal maturation, neuromuscular transmission and maintaining the integrity of the blood–brain barrier [11]. As the blood–brain barrier keeps the daily fluctuations of blood Mg in brain tissue at bay, cerebrospinal fluid seems to be a more representative biomaterial for the analysis of Mg homeostasis in AD patients [134]. A systematic review of Mg levels in AD patients found that Mg concentrations were significantly lower in cerebrospinal fluid and hair of AD patients, but no differences were observed in serum and plasma [136]. The study concluded that serum Mg is not a reliable marker of Mg status in the elderly.

Mn is an essential metal for maintaining homeostasis, a cofactor for important metalloenzymes that regulate oxidative stress and the glutamate/glutamine cycle [114], and supports neurotransmission, cellular metabolism, antioxidant defenses, and participates in inflammatory responses in the human body [68]. However, there are conflicting results regarding Mn levels in the plasma and cerebrospinal fluid of AD patients [13, 48, 61, 94]. Mn overexposure causes neurotoxicity, including disruption of mitochondrial function and neurotransmitter metabolism, altered Fe homeostasis, and oxidative stress [51]. Studies have shown that elevated Mn levels are associated with increased plasma levels of amyloid-like protein-1 and Aβ peptide, which are hallmarks of AD [134]. In addition, prolonged exposure to Mn can lead to the loss of neurons and glial cells in the brain. It may also cause the overproliferation of astrocytes, resulting in what is known as “AD astrocytosis” [78].

Pb has complex and numerous mechanisms of neurotoxicity and is a known neurotoxicant that causes non-specific brain damage. Approximately 95% of the human Pb burden is in bone, bone Pb has a half-life of 20–30 years, whereas the average turnover period for blood Pb is about 30 days, and circulating Pb levels are associated with acute exogenous exposures [49]. Pb binds to divalent metal transporter proteins, crosses the blood–brain barrier instead of Ca and accumulates in the brain [102]. Causes oxidative stress by depleting thiols and disrupting antioxidant defenses, leading to endoplasmic reticulum stress, mitochondrial damage, and neuronal apoptosis [102]. In animal models, Pb treatment induces pathological changes associated with AD, including Aβ accumulation, elevated levels of total and hyperphosphorylated tau, inflammation, and memory deficits [14, 41]. In older populations, Pb exposure is associated with lower cognitive status and longitudinal cognitive decline, but additional prospective evidence from human clinical samples is needed [9].

Publication bias

The funnel plot for elements was shown in Figure S6. Sensitivity analyses indicated that none of the studies significantly affected the aggregate results. Egger's test results were as follows: Cd (p = 0.009), publication bias existed; Cu (p = 0.165), no publication bias; Hg (p = 0.072), no publication bias; Fe (p = 0.709), no publication bias; Se (p = 0.500), no publication bias; Zn (p = 0.094), no publication bias; Al (p = 0.024), publication bias existed; As (p = 0.034), publication bias existed; Mg (p = 0.035), publication bias existed; Mn (p = 0.854), no publication bias; Pb (p = 0.654), no publication bias.

Uncertainties and limitations

The limitations and uncertainties of this study may arise from the following: First, results on Cd, Al, As, and Mg ought to be interpreted cautiously, as publication bias was found in the inclusion studies. This may be attributed to the small number of studies included or methodological differences. Further studies are expected to confirm our findings. Second, SMD cannot adjust for potential confounders, so we should be cautious about the combination of results. Third, different trace elements have different in vitro exposure pathways and in vivo metabolism [149]. Additional monitoring studies on other biological materials (e.g., urine, cerebrospinal fluid, nails, hair, etc.) are warranted. Fourth, the analytical results derived from cross-sectional and case–control studies in this study do not prove causality. Finally, due to limited published studies on other elements, this study only analyzed the levels of eleven elements in AD patients, and other elements should receive more attention in the future.

Conclusions

In conclusion, we performed a systematic meta-analysis of case–control studies of trace elements in the circulation of AD patients, and found that serum levels of Cd, Hg, and Cu were significantly elevated in AD patients, whereas serum Fe, Zn, and plasma Se were significantly lower than in controls. Due to limitations in the number of studies and biological materials, other trace elements that showed publication bias or results that were not significantly different or were not included in this study deserve more attention in the future. In addition, the vast majority of included studies used a cross-sectional design, and more in-depth prospective cohort studies of the longitudinal course of elemental exposure, as well as patients with pre-AD, are needed to identify and assess the causality between trace element levels and AD, and to weigh the potential influence of trace elements throughout the disease process.