Table 2.

Overview of the reviewed studies and their main results related to investigated chemicals and AD.

Study:	Included Countries:	Study Design:	Sample:	Chemical:	Exposure Assessment:	Outcome(s):	Results and Main Conclusions:	Summary *:
Aloizou et al., 2020 [30]	US, UK, Ecuador, South Africa, Costa Rica, Brazil, Egypt, Spain, Iran, France, India, Sweden, China, Chile, Gulf, Netherlands, Greece, Canada, Australia, Taiwan	Review	N of studies: 30 human studies (and 15 animal studies) Setting: cross-sectional, longitudinal, case-control, cohort, case cohort, and ecological studies Target group: occupational	pesticides	questionnaire: occupational and non-occupational, environmental and self-reported-pesticides exposures, and place of residence serum: cholinesterase, acetylcholinesterase, and OC pesticides levels plasma: butyrylcholinesterase (BuChE) and red blood cell acetylcholinesterase (AChE) activity and concentrations of 3 OC pesticides urine: TCP levels, DEP, DETP, DAP metabolites, and TCPy	cognitive functions, dementia, and AD	An overall indication from epidemiologic evidence supported an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia, and AD.	⇧
Gunnarsson and Bodin, 2019 [31]	Not specified	Systematic literature review and meta-analyses	N of studies: 31 studies on pesticides (4 on AD) and 14 studies on metals (3 on AD) Setting: cohort or case-control studies Target group: occupational	pesticides	Job Exposure Matrix (JEM), self-reported exposure (questionnaire/interviews), DDE concentration in serum, AD diagnosis, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and interaction with apolipoprotein E (APOE4) status	AD	The relative risk (RR) for AD and pesticides was 1.50 (95% confidence interval (CI) 0.98–2.29). Exposure to pesticides increased the risk of AD by at least 50%.	⇧
Yan et al., 2016 [32]	Canada, France, US, Australia	Systematic review and meta-analysis	N of studies: 7 Setting: 3 cohort and 4 case-control studies Target group: occupational, AD patients, and healthy controls	pesticides	prospectively, self-report ever/never occupational exposure, retrospectively, proxy reports job history, risk factor information, and code into JEM	AD	A positive association between pesticide exposure and AD was detected: odds ratio (OR) = 1.34 (95% CI 1.08–1.67). The summary ORs from the crude and adjusted effect size studies were 1.14 (0.94–1.38, N = 7) and 1.37 (1.09–1.71, N = 5), respectively. All subgroup analyses showed that pesticide exposure was associated with an increased risk of AD but only half of them with statistical significance. A significantly increased risk detected in cohort studies: OR = 1.37 (1.08–1.75) but not in case-control studies: OR = 1.24 (0.78–1.97). The OR of the self-reported group was 1.37 (1.08–1.75), and the OR of the proxy-reported group was 1.24 (0.78–1.97) when stratified according to method used to access exposure.	⇧ ⇔
Killin et al., 2016 [33]	Canada, US, France, Netherlands, UK	Systematic review	N of studies: 60 (10 on pesticides, 2 on As, and 2 on Pb) Setting: 6 cohort, 2 cross-sectional, 2 review studies on pesticides, 2 cross-sectional studies on As, 1 cross-sectional, and 1 review study on Pb Target group: occupational, environmental, and regional	pesticides, Pb, and As	self-reported risk factor and exposure to pesticides by questionnaire, exposure to pesticides from residential history and census data, cumulative exposure to pesticides based on job history, comparison of annual aveage-adjusted mortality rates between two different locations (As), principal components analysis, and AD cases identified from a registry (Pb)	dementia, and AD	Quality of overall evidence regarding defoliants/fumigants was weak but regarding pesticides/fertilizers/herbicides/insecticides strong. Among the different chemicals investigated, the strongest evidence was found for pesticide exposure but findings were heterogenous. Evidence of associations between occupational exposure, Pb, As and dementia was rather weak.	⇔ for pesticides ⇩ for Pb and As
Olayinka et al., 2019 [34]	Sweden, UK, Canada, France, US, Australia, Turkey, Denmark, Taiwan, Finland, Japan	Systematic review	N of studies: 29 (6 on pesticides, 2 on Pb, and 1 on Hg) Setting: 11 cohort and 18 case-control studies Target group: occupational and environmental	pesticides and metals (Pb, Hg)	occupational and environmental exposure	AD	Significant evidence was detected of the association between pesticide exposure and AD, depending on the group of the pesticides; occupational exposure to OP pesticides, fumigants and defoliants was more significant than occupational exposure to pesticides such as herbicides and insecticides in relation to AD risk. Due to the low number of studies, the effect of Pb and Hg on AD risk was difficult to estimate.	⇧ ⇩ for pesticides ⇔ for Pb and Hg
Krewski et al., 2017 [35]	Not specified	Synthesis of systematic reviews	Studies on the risk factors associated with the onset and progression of 14 neurological conditions, including AD	pesticides	-	AD	Exposure to pesticides was associated with AD with sufficient evidence.	⇧
Mostafalou and Abdollahi, 2017 [36]	Not specified	Systematic review	N of studies: 448 (6 on AD) Setting: 2 case-control, 3 cohort, and 1 ecological studies Target group: occupational and environmental	pesticides	questionnaire, geographic information system (GIS), and level of pesticides in serum	AD	In cohort studies there were 1.4- and 2.4-times higher risk of AD in people occupationally exposed to any pesticides and 1.5 increased risk of AD with exposure to OP and OC compounds based on the longitudinal and prospective analysis of exposures.	⇧
Santibáῆez et al., 2007 [37]	Canada, France, US, England and Wales, Australia	Systematic review	N of studies: 24 (6 on pesticides and 6 on Pb) Setting: 21 case-control and 3 cohort studies Target group: occupational	pesticides and Pb	occupational exposure	AD	Increased and statistically significant associations between AD and pesticide exposure were observed in studies of greater quality and prospective design. No evidence was detected of association for Pb.	⇧ for pesticides ⇩ for Pb
Xu et al., 2018 [38]	Korea, Australia, Spain, Italy, China, Sweden	Quantitative meta-analysis and systematic review	N of studies: 42 (7 on Hg, 8 on Cd, and 10 on Pb) Setting: case-control studies Target group: AD patients and healthy controls	Cd, Hg, and Pb	levels of toxic metals assessed from the circulation (blood, serum/plasma)	AD	According to the meta-analysis significantly elevated circulatory levels of Hg: pooled standardized mean difference (SMD) = 0.55 (95% CI 0.15–0.95, p = 0.0073) and Cd (SMD = 0.62, 0.12–1.11, p = 0.0144) were detected in AD patients compared to controls. Regarding Pb, reduced circulatory levels detected in AD patients in comparison to controls (SMD = −0.23, −0.38 to −0.07, p = 0.0043). Elevated Cd- and Hg-levels in the circulation, especially in serum, may contribute to the progression of AD.	⇧ for Hg and Cd ⇩for Pb
Cicero et al., 2017 [39]	Not specified	Systematic review	N of studies: - Setting: case-control studies Target group: occupational, AD patients, and healthy controls	Pb, Hg, Cd, and As	blood/serum/plasma, cerebrospinal fluid (CSF), nail, and hair	AD, dementia, and cognitive functions	An inverse relation between Hg excretion and cognitive functions in exposed workers was detected. In four case-control studies higher blood Hg levels in AD patients compared to controls. However, in the other studies, lower concentrations of Hg (one study) or no difference (four studies). No differences in the CSF Hg concentration (two studies). Nail-Hg concentrations significantly lower in AD patients (two studies), and inconsistent findings in the hair-Hg examination (two studies). Data was inconclusive on Cd, As, and Pb.	⇧ ⇩ ⇔
Gong and O’Bryant, 2010 [40]	Not specified	Review	Both animal and epidemiological studies	As	Not specified	AD	As-exposure hypothesis was supported by a simple mechanism for AD development and progression in certain AD patients. As exposure is associated with amyloid, vascular, and inflammatory hypotheses of AD.	⇧
Mutter et al., 2010 [41]	Not specified	Systematic review	N of studies: 88 (incl. 8 animal studies) Setting: mainly case-control and comparative cohort studies, also cross-sectional studies Target group: occupational	Hg	brain tissue, blood, urine, hair, nails, and CSF	AD	Significant memory deficits in individuals exposed to inorganic Hg was found in 32 out of 40 studies. In some autopsy studies elevated Hg-levels detected in brain tissues of AD patients. Measurements of Hg-levels in blood, urine, hair, nails, and CSF were discrepant. Inorganic Hg may contribute to the development of AD, increase the pathological influence of other metals, and promote neurodegenerative disorders via disruption of redox regulation. The influence of inorganic Hg on the nervous system was weaker in epidemiological studies compared to animal and in vitro-studies.	⇧ ⇔
Sharma et al., 2020 [42]	Not specified	Review	The available data for human neurotoxicity due to toxic chemicals was collected	Pb, Hg, Cd, As, and pesticides	-	AD	Neurotoxic metals such as Pb, Hg, Cd, and As as well as some pesticides have been associated with AD because of their ability to produce senile/amyloid plaques and neurofibrillary tangles (NFTs)-the features behind the neuronal dysfunctions such as AD.	⇧
Wang et al., 2021 [43]	China	Cross-sectional study	N: 1556 adults (802 males and 754 females, an average age of 57.0 +/− 11.5 years). 321 (20.6%) participants in the cognitive-impaired (CI)-group and 1235 (79.4%) participants in the cognitive-normal (CN)-group.	As	cognitive function measured by Chinese version of MMSE, internal-As exposure measured by hair As-concentrations (HAs), and external-As exposure measured by the distance between the participant‘s location of residence and the Realgar Plant	cognitive impairment	The CI-group had a significantly lower MMSE score compared to the CN-group (16.6 +/− 5.47 vs. 26.3 +/− 2.81, p < 0.05). In the CI-group much higher HAs than in the CN-group with a statistically significant difference (0.27, 0.14–0.56 mg/kg vs. 0.20, 0.10–0.41 mg/kg, p < 0.05). The prevalence of arsenicosis (arsenic poisoning) was significantly higher in the CI-group compared to the CN-group (64.5% vs. 45.3%, p ˂ 0.05). A negative correlation between hair-As concentrations and MMSE scores was detected (correlation coefficient (r) = −0.151, p < 0.001). Arsenicosis was a risk factor for cognitive impairment (OR = 1.84, p ˂ 0.05).	⇧
Yang et al., 2018 [44]	Taiwan	Case-control study	N: 434 adults (170 AD patients and 264 controls, age ≥ 50 years, an average age of 73.65, standard deviation (SD) 8.46). A propensity-score-matched population of 82 AD patients and 82 controls.	Cd, Pb, Hg, and As	AD patients: clinical neuropsychological examination and cognitive-function assessments incl. MMSE and clinical dementia-rating scale. Blood levels of Cd, Pb, and Hg and urine levels of As levels.	AD risk	The AD risk of study participants with high urinary inorganic As (InAs%) or low dimethylarsinic acid (DMA%) was significantly increased (p ˂ 0.05), similar findings in the propensity-score-matched population. People with high median level of InAs% or/and a low median level of DMA% had approximately two- to threefold significant AD risk. Cd, Pb, and Hg were not associated with AD risk.	⇧ for As ⇩ for Cd, Pb, and Hg
Li et al., 2020 [45]	China	Ecological study	22 provinces and 3 municipal districts in mainland China	As, Pb, Cd, and Hg	As- concentrations in soil in 1990 obtained from the China State Environmental Protection Bureau and data on annual mortality of AD from 1991 to 2000 obtained from the National Death Cause Surveillance Database of China	As concentrations in soil and AD mortality	AD mortality was increased by soil As concentration, the Spearman correlation coefficient between As concentration and AD mortality was 0.552 (p = 0.004), 0.616 (p = 0.001), and 0.622 (p = 0.001) in the A soil As (eluvial horizon), the C soil As (parent material horizon), and the total soil As (A soil As + C soil As), respectively. Evidence was found of a possible causal association between As exposure and the death risk from AD. No association was detected between Pb, Cd, and Hg soil concentrations and AD mortality.	⇧ for As ⇩ for Pb, Cd, and Hg
Siblerud et al., 2019 [46]	Not specified	Hypothesis	-	Hg	70 factors were identified as occurring in AD; factors were investigated in relation to Hg exposure	AD	All 70 factors associated with AD were examined and all of them could be explained by Hg toxicity. The hallmark changes of AD: plaques, beta amyloid protein, neurofibrillary tangles, phosphorylated tau protein, and loss of memory could all be changes caused by Hg. Neurotransmitters such as acetylcholine, serotonin, dopamine, glutamate, and norepinephrine are inhibited in AD patients, and same inhibition occurs in Hg toxicity. It was strongly suggested that Hg can cause AD.	⇧
Azar et al., 2021 [47]	Not specified	Review	Both animal and epidemiological studies	Hg	-	AD	Hg was involved in the process of amyloid beta deposition and tau tangles formation, which contributed to the development of AD.	⇧
Bakulski et al., 2020 [48]	Not specified	Review	Both experimental and epidemiological studies, partly in occupational settings	Pb and Cd	Pb in blood or in bone (tibia or patella) and Cd in brain tissues (postmortem studies), in circulation concentrations (whole blood, serum, or plasma), or in urine	AD, dementia, and cognitive decline	Pb exposure was associated with lower cognitive status and longitudinal declines in cognition in older adults. Cd may be associated with decreased cognitive function and clinical AD specifically in human aging studies. The pathophysiologic link between environmental Cd exposure and AD was limited due to the uncertainty in Cd transport to the brain.	⇧ for Pb ⇔ for Cd
Loef et al., 2011 [49]	Not specified	Systematic review	N of studies: - Setting: both animal and epidemiological studies, human studies: longitudinal cohort, cross-sectional, and case-control studies, as well as case-report and post-mortem analysis Target group: e.g., occupational and non-occupational cohorts, AD patients, and healthy subjects	Pb	Pb in blood, bone (tibia, patella, or calcaneus), CSF, dentate gyrus, temporal cortex, or in protein fraction from cortical gray and subcortical white matter	cognitive decline, AD, and dementia	Pb had a potential role in the development of AD, and was a risk factor for AD. An effect of long-term Pb exposure on cognitive decline in elderly subject was suggested. A scarcity of conclusive studies including patients with validated AD diagnoses was detected.	⇧

* ⇧ association observed, ⇩ negative association or no association observed, ⇔ inconsistent associations/results observed.