Table 3.

Epidemiology literature summary for manganese exposure and Alzheimer’s disease or cognitive decline

Reference	Study Design	Population	Exposure	Outcome	Main Findings
Alzheimer’s Disease
Emard, 1994 [63]	Retrospective ecological	129 definite or probable AD cases born in the Saguenay-Lac-Saint-Jean territory of Quebec	Difference between birthplace residential and municipal average levels of Mn in soil	AD clinical diagnosis	Number of cases with higher average Pb concentration near residence at birth in comparison to municipal average (n = 35) differs from number of cases with lower average Pb concentrations near residence at birth in comparison to municipal average (n = 12) p < 0.05
Tong, 2014 [186]	Case-control	Patients and age-matched controls from Beijing Geriatric Hospital 10 with CDR = 0 (mean age 75.0, SD: 5.2) 10 with CDR = 0.5 (mean age 7.2, SD: 4.1) 4 with CDR = 1 (mean age = 75.2, SD: 2.7) 16 with CDR > 2 (mean age 75.9, SD: 7.7)	Blood Mn	MMSE, CDR	Inverse correlation between MMSE score and Mn level, positive correlation between CDR and Mn level in unadjusted analysis, though selection criteria not defined.
Du, 2017 [206]	Meta-analysis	17 studies of Mn exposure and AD and/or MCI	Serum Mn	AD diagnosis, MCI	AD patients had lower Mn levels than controls (SMD −0.39, 95% CI −0.71, −0.08), and AD + MCI individuals also had lower Mn levels than controls (SMD −0.37, 95% CI −0.6, −0.13).
Cognitive function
Mergler, 1999 [200]	Cross-sectional	273 randomly sampled residents (mean age 43.4 (SD 13.9) for women, 45.1 (SD 14.4) for men) living near former Mn alloy plant in SW Quebec	Blood Mn (μg/L)	Scores on neuropsychological battery including: learning and recall, visuo-perceptive speed, verbal naming, cognitive flexibility.	Higher MnB (≥7.5 μg/L) associated with poorer learning and recall aggregate score, within which MAS acquisition, delayed recall, visual recognition, and visual reproduction scores were significantly different
Santos-Burgoa, 2001 [201]	Cross-sectional	73 randomly sampled residents (mean age 43.35, SD: 18.36) of two towns in Hidalgo, Mexico near primary ore refineries	Blood Mn (μg/L)	Scores on neuropsychological battery including: MMSE, digit span, verbal fluency, trail making, neurological exam	OR of low (≥17) MMSE adjusted for schooling was 4.92 (90% CI 1.39–17.38) for blood Mn above the median versus below.
Bowler, 2007 [202]	Cross-sectional	43 confined-space welders (mean age 43.8, SD: 10) on SF-Oakland Bay Bridge who had worked with inadequate PPE, all males	Blood Mn (μg/L), plasma Mn, urine Mn, Cumulative Exposure Index (CEI) based on Mn-air duration and type of welding	Comprehensive neuropsych exam including WAIS-III, WMS	Inverse dose-response relationship between CEI and/or blood Mn and IQ, executive function, sustained concentration and sequencing, verbal learning, working memory, and immediate memory.
Solis-Vivanco, 2009 [204]	Cross-sectional	Proportional sample (n = 288) of residents (mean age 44.7) from 8 communities in Hidalgo, Mexico near Mn deposits and refineries	Blood Mn (μg/L), air Mn concentration from nearest monitor (μg/m3)	Cognitive battery including MMSE, digit span, world list test, word association test	OR of 1.75 (95% CI 1.01 – 3.06) for poor performance on digit span in those with air Mn of >0.1 μg/m3 vs <0.1 μg/m3. Blood Mn not significantly associated with any neuropsychological tests.
Menezes-Filho, 2011 [203]	Cross-sectional	77 mothers of school-aged children living near ferro-manganese alloy plan in Brazil	Hair Mn (μg/g), blood Mn (μg/L)	Raven Progressive Matrix	Maternal hair Mn associated with worse performance on Raven Progressive Matrix (one log-unit of Mn associated with −2.69 points, 95% CI: −5.42 – 0.05)
de Sousa Viana, 2014 [199]	Cross-sectional	Residents living > 5 years in one of two communities (Cotegipe: n = 42, mean age 32.9, SD: 6.35, Santa Luzia: n = 47, mean age 34.2, SD: 10.8) near ferromanganese refinery in Brazil.	Scalp hair, axillary hair, fingernail, saliva Mn (all μg/g)	Neuropsychological battery including: WAIS-III, test of executive function, attention, and memory	In adjusted linear regression, inverse association between log hair Mn and IQ (−4.76, 95% CI: −9.17, −0.36) and log fingernail Mn and visual working memory (−3.33, 95% CI: −6.15, −0.52).
Bowler, 2015 [205]	Cross-sectional	86 residents (mean age 56, SD: 10.8) living > 10 years in one of two towns in Ohio with high airborne Mn	Estimated long-term air Mn (μg/m3) exposure	Neuropsychological battery including WAIS-III, tests of cognitive flexibility and executive functioning, memory, verbal skills	In linear regression, air Mn concentrations associated with working (−0.19) and visuospatial memory scores (−0.16), and verbal reasoning score (−0.19), though these were not significant at α = 0.05.

Mn, manganese; SD, standard deviation; CDR, Clinical Dementia Rating Scale (0.5 = MCI, 1 = Mild Dementia, ≥2 = Dementia); MMSE, Mini-Mental State Examination; CI, confidence interval; SMD, standardized mean difference; OR, odds ratio; WAIS-III, Wechsler Adult Intelligence Scale; WMS, Wechsler Memory Scale; RAVLT, Rey Auditory Verbal Learning Test; MCI, mild cognitive impairment.