Table 3.

Metals in Alzheimer's disease.

Metal	Study	Levels of metal	Findings	Ref.
Essential
Manganese (Mn)	Patients and age-matched controls	Mn in blood, CDR (Controls) 0 = 11.20 ± 0.95 ng/ml. CDR 0.5 (mild cognitive impairment) = 12.37 ± 1.08 ng/ml. CDR 1 (mild dementia) = 9.63 ± 1.11 ng/ml. CDR > 2 (dementia) = 13.98 ± 0.88 ng/ml	Significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score (CDR); plasma Aβ also increased with elevated Mn	[170]
Iron (Fe)	Study 37 participants aged between 62 and 89 years (22 cognitively normal, 15 MCI)	Levels of iron in the brain Controls = 1.16 ± 0.08 MCI = 1.5 ± 0.17	Confirmed the colocalization of brain Fe and Aβ plaques and promoted the development of the disease	[171]
Cooper (Cu)	Meta-analysis comparison between AD subjects and 200 controls	----	Confirmed higher levels of total Cu in AD subjects than in healthy controls (p < 0.0001)	[173]
	Frozen prefrontal brain tissues from patients with AD Braak stages V-VI	Control patients (δ65Cu = 0.60) AD brains (δ65Cu = 0.35)	Cu compositions of AD brains are statistically different compared to controls and correlate with Braak stages	[172]
Zinc (Zn)	Frozen prefrontal brain tissues from patients with AD Braak stages V-VI	Control patients (δ66 Zn = −0.6) AD brains (δ66 Zn = −0.4)	Zn of AD brains are statistically different compared to controls and correlate with Braak stages	[172]
	Nine AD subjects. Five controls	AD neutrophil = 51.4 ± 11.0 μg/g Control neutrophil = 22.6 ± μg/g	Zn levels are increased in senile plaque derived from patients diagnosed with AD	[123]
Cobalt (Co)	A 56-year-old woman with mental neuropathy	Co blood concentrations (>400 μg/L; standard control: 0.18 ± 0.10 μg/L). Co in the sural nerve was also elevated; Co (6.7 μg/g vs. neuropathy controls <3.0 μg/g)	Developed progressive sensory disturbance, hearing loss, and hypothyroidism. A sural nerve biopsy indicated axonopathy	[174]
	247 consecutive patients presented to an orthopedic clinic with an arthroprosthetic joint containing cobalt-chromium	Symptomatic patients with a blood Co level above 0.4 mcg/L or urine Co greater than 1 mcg/L underwent F-18 FDG PET brain imaging	All scanned patients had regions of significant hypometabolism. Neurological toxicity from elevated systemic Co	[175]
Nonessential
Lead (Pb)	Case-control study, patients with AD	AD group = 22.22 + 28.57 mg/dL. Control group = 7.88 + 6.63 mg/dL	Pb levels were significantly higher in the patients with AD than in the controls	[176]
Aluminum (Al)	Human tissue was collected from deceased patients with AD	Al concentrations approach 12 μg/g in some regions	Al levels have been traditionally linked to the pathogenesis of AD by its accumulation in the brain	[177]
	A 43-year-old man was exposed to high concentrations of Al	Al levels in the brain, especially the parietal and occipital lobes, were up to 5.58 and 4.45 μg/g dry weight	The histology showed extensive and widespread hyperphosphorylated tau deposition in the neuritic plaques	[178]
	69-year-old man	Al content in each brain region varied from 0.45 (0.84) μg/g dry wt. in the hippocampus to 1.75 (1.43) μg/g dry wt. in the occipital lobe	Al content was high in occipital and parietal lobes and coincided with significant AD-related neuropathology	[180]
	12 donors diagnosed with familial AD	Al was found in all 144 tissues, and its concentration ranged from 0.01 to 35.65 μg/g dry wt.	Supported by visual evidence of Al in brain tissue, it raises the possibility that genetic predisposition to AD is accompanied by a higher propensity to accumulate and retain Al in the brain	[179]
	A woman who is in 1998 had been exposed to very high and sustained levels of Al	----	Al was almost found intracellular in microglia, astrocytes, lymphocytes, and cells lining the choroid plexus	[181]
	Brain tissues	The Al content in the control (mean = 0.95) was significantly lower (p = 0.0006) than AD (mean = 1.69 μg/g dry weight of tissue)	Al content of brain tissue in AD, autism spectrum disorder, and multiple sclerosis is significantly elevated	[182]
Cadmium (Cd)	Brain tissue (hippocampus and cerebral cortex) from AD and controls	Control hippocampus: 0.472. Control cortex: 0.496. AD hippocampus: 0.547. AD cortex: 0.518 μg/g dry weight of tissue	Found that the AD brain had a higher concentration of Cd in the hippocampus and cerebral cortex	[184]
	Post-mortem frontal cortex samples from patients with AD	Control: 30 ng/g, AD: 20 ng/g	AD-related differences in metal levels with an elevation in Fe and a decrease in Cd	[185]
	Meta-analyses were used as the summary statistic for the difference in AD patients' toxic metals (Al, Hg, Cd, and Pb) compared to the controls	Circulatory Cd levels were significantly elevated in patients with AD (SMD = 0.62, 95% CI: 0.12, 1.11; p = 0.0144) compared to control subjects	Circulatory Cd levels were significantly elevated in patients with AD compared to control subjects	[186]