Lead (Pb) in Alzheimer’s Dementia: A Systematic Review of Human Case- Control Studies

Author(s): Eric E. Brown, Parita Shah, Bruce G. Pollock, Philip Gerretsen, Ariel Graff-Guerrero*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 4 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: Alzheimer’s Dementia (AD) has a complex pathophysiology that is incompletely understood. Chronic, low-level environmental lead (Pb) exposure is associated with cognitive impairment, hypertension and mortality, and has been proposed as a potential cause of AD.

Objective: We aimed to review the literature to clarify the potential role of Pb in AD and to guide future research.

Methods: Through a series of systematic reviews, we identified case-control studies comparing AD to controls on 6 measures of Pb exposure or accumulation: blood, bone, cerebrospinal fluid, hair/nail, postmortem pathology, and urine. We completed meta-analyses where possible.

Results: The number of identified case-control studies of AD, by measurement method, was: 15 by blood, 0 by bone, 5 by Cerebrospinal Fluid (CSF), 3 by hair/nail, 3 by postmortem, and 1 by urine. Two meta-analyses were possible for 7 studies reporting whole blood Pb and for 8 studies of serum Pb. Both were negative. The largest study of CSF Pb showed lower levels in AD. Similarly, lower hair Pb levels were found in AD.

Conclusion: The available case-control studies are insufficient to draw conclusions on the role of Pb in AD. Most methods do not address long-term or early-life exposure. The preferred measure of chronic Pb is in bone, which has not been utilized in case-control AD studies. Future research should measure bone Pb in AD, together with other biomarkers, such as amyloid and tau imaging, and markers of cerebrovascular pathology.

Keywords: Lead (Pb), Alzheimer's, dementia, toxicity, environmental, cognition.

Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. The Lancet 390(10113): 2673-34. (2017).
Bakulski KM, Rozek LS, Dolinoy DC, Paulson HL, Hu H. Alzheimer’s disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics. Curr Alzheimer Res 9(5): 563-73. (2012).
World Health Organization, Ed. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva, Switzerland: World Health Organization; 62 p. (2009).
McNeill FE, Fisher M, Chettle DR, Inskip M, Healey N, Bray R, et al. The decrease in population bone lead levels in Canada between 1993 and 2010 as assessed by in vivo XRF. Physiol Meas 39(1): 015005. (2017).
Satizabal CL, Beiser AS, Chouraki V, Chêne G, Dufouil C, Seshadri S. Incidence of dementia over three decades in the framingham heart study. N Engl J Med 374(6): 523-2. (2016).
Niklowitz W, Mandybur T. Neurofibrillary changes following childhood lead encephalopathy. J Neuropathol Exp Neurol 34(5): 445-55. (1975).
Reuben A, Caspi A, Belsky DW, Broadbent J, Harrington H, Sugden K, et al. Association of childhood blood lead levels with cognitive function and socioeconomic status at age 38 years and with iq change and socioeconomic mobility between childhood and adulthood. JAMA 317(12): 1244. (2017).
Lanphear BP, Rauch S, Auinger P, Allen RW, Hornung RW. Low-level lead exposure and mortality in US adults: a population-based cohort study. Lancet Public Health 3(4): e177-84. (2018).
Bihaqi SW, Alansi B, Masoud AM, Mushtaq F, Subaiea GM, Zawia NH. Influence of early life lead (pb) exposure on alpha-synuclein, GSK-3beta and caspase-3 mediated tauopathy: implications on Alzheimer’s disease. Curr Alzheimer Res Curr Alzheimer Res 15(12): 1114-22. (2018).
Shih RA, Hu H, Weisskopf MG, Schwartz BS. Cumulative lead dose and cognitive function in adults: a review of studies that measured both blood lead and bone lead. Environ Health Perspect 115: 483-92. (2007).
Farooqui Z, Bakulski KM, Power MC, Weisskopf MG, Sparrow D, Spiro A, et al. Associations of cumulative Pb exposure and longitudinal changes in Mini-Mental Status Exam scores, global cognition and domains of cognition: The VA Normat Aging Study. Environ Res 152: 102-8. (2017).
Bandeen-Roche K, Glass TA, Bolla KI, Todd AC, Schwartz BS. Cumulative lead dose and cognitive function in older adults. Epidemiol Camb Mass 20(6): 831-9. (2009).
Power MC, Korrick S, Tchetgen Tchetgen EJ, Nie LH, Grodstein F, Hu H, et al. Lead exposure and rate of change in cognitive function in older women. Environ Res 129: 69-75. (2014).
Weuve J, Korrick SA, Weisskopf MG, Ryan LM, Schwartz J, Nie H, et al. Cumulative exposure to lead in relation to cognitive function in older women. Environ Health Perspect 117(4): 574-80. (2009).
Arksey H, O’Malley L. Scoping studies: towards a methodological framework. Int J Soc Res Methodol 8(1): 19-32. (2005).
Esteban-Vasallo MD, Aragonés N, Pollan M, López-Abente G, Perez-Gomez B. Mercury, cadmium, and lead levels in human placenta: a systematic review. Environ Health Perspect 120(10): 1369-77. (2012).
Schwarzer G. Meta: an R package for meta-analysis. R News 7(3): 40-5. (2007).
Xu L, Zhang W, Liu X, Zhang C, Wang P, Zhao X. Circulatory levels of toxic metals (aluminum, cadmium, mercury, lead) in patients with Alzheimer’s disease: a quantitative meta-analysis and systematic review. J Alzheimers Dis 62(1): 361-72. (2018).
Bocca B, Forte G, Petrucci F, Pino A, Marchione F, Bomboi G, et al. Monitoring of chemical elements and oxidative damage in patients affected by Alzheimer’s disease. Ann Ist Super Sanita 41(2): 197-203. (2005).
Bocca B, Alimonti A, Bomboi G, Giubilei F, Forte G. Alterations in the level of trace metals in Alzheimer’s disease. Trace Elem Electrolytes 23(4): 270-6. (2006).
Alimonti A, Ristori G, Giubilei F, Stazi MA, Pino A, Visconti A, et al. Serum chemical elements and oxidative status in Alzheimer’s disease, Parkinson disease and multiple sclerosis. Neurotoxicology 28(3): 450-6. (2007).
González-Domínguez R, García-Barrera T, Gómez-Ariza JL. Characterization of metal profiles in serum during the progression of Alzheimer’s disease. Metallomics 6(2): 292-300. (2014).
Paglia G, Miedico O, Cristofano A, Vitale M, Angiolillo A, Chiaravalle AE, et al. Distinctive pattern of serum elements during the progression of Alzheimer’s disease. Sci Rep [Internet]. 2016 Sep [cited 2018 Aug 28];6(1). Available from: http://www.nature.com/articles/srep22769
Fathabadi B, Dehghanifiroozabadi M, Aaseth J, Sharifzadeh G, Nakhaee S, Rajabpour-Sanati A, et al. Comparison of blood lead levels in patients with Alzheimer’s disease and healthy people. Am J Alzheimers Dis Other Demen 33(8): 541-7. (2018).
Giacoppo S, Galuppo M, Calabro RS, D’Aleo G, Marra A, Sessa E, et al. Heavy metals and neurodegenerative diseases: an observational study. Biol Trace Elem Res 161(2): 151-60. (2014).
Hare DJ, Faux NG, Roberts BR, Volitakis I, Martins RN, Bush AI. Lead and manganese levels in serum and erythrocytes in Alzheimer’s disease and mild cognitive impairment: results from the Australian imaging, biomarkers and lifestyle flagship study of ageing. Met Integr Biometal Sci 8(6): 628-32. (2016).
Pino A, Brescianini S, D’Ippolito C, Fagnani C, Alimonti A, Stazi MA. Discriminant analysis to study trace elements in biomonitoring: an application on neurodegenerative diseases. Ann Ist Super Sanita 41(2): 6. (2005).
Gerhardsson L, Lundh T, Minthon L, Londos E. Metal concentrations in plasma and cerebrospinal fluid in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 25(6): 508-15. (2008).
Gerhardsson L, Blennow K, Lundh T, Londos E, Minthon L. Concentrations of metals, β-amyloid and tau-markers in cerebrospinal fluid in patients with alzheimer’s disease. Dement Geriatr Cogn Disord 28(1): 88-94. (2009).
Gerhardsson L, Lundh T, Londos E, Minthon L. Cerebrospinal fluid/plasma quotients of essential and non-essential metals in patients with Alzheimer’s disease. J Neural Transm 118(6): 957-62. (2011).
Basun H, Forssell LG, Wetterberg L, Winblad B. Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer’s disease. J Neural Transm Park Dis Dement Sect 3(4): 231-58. (1991).
Hershey CO, Hershey LA, Varnes A, Vibhakar SD, Lavin P, Strain WH. Cerebrospinal fluid trace element content in dementia: clinical, radiologic, and pathologic correlations. Neurology 33(10): 1350-50. (1983).
Koseoglu E, Koseoglu R, Kendirci M, Saraymen R, Saraymen B. Trace metal concentrations in hair and nails from Alzheimer’s disease patients: Relations with clinical severity. J Trace Elem Med Biol Organ Soc Miner Trace Elem GMS 39: 124-8. (2017).
McIntosh KG, Cusack MJ, Vershinin A, Chen ZW, Zimmerman EA, Molho ES, et al. Evaluation of a prototype point-of-care instrument based on monochromatic x-ray fluorescence spectrometry: potential for monitoring trace element status of subjects with neurodegenerative disease. J Toxicol Environ Health A 75(21): 1253-68. (2012).
Szabo ST, Harry GJ, Hayden KM, Szabo DT, Birnbaum L. Comparison of metal levels between postmortem brain and ventricular fluid in alzheimer’s disease and nondemented elderly controls. Toxicol Sci Off J Soc Toxicol 150(2): 292-300. (2016).
Uitti RJ, Rajput AH, Rozdilsky B, Bickis M, Wollin T, Yuen WK. Regional metal concentrations in Parkinson’s disease, other chronic neurological diseases, and control brains. Can J Neurol Sci J Can Sci Neurol 16(3): 310-4. (1989).
Lahiri DK, Maloney B, Zawia NH. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry 14(11): 992-1003. (2009).
Maloney B, Lahiri DK. Epigenetics of dementia: understanding the disease as a transformation rather than a state. Lancet Neurol 15(7): 760-74. (2016).
Basha MR. The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and -amyloid in the aging brain. J Neurosci 25(4): 823-9.
Rodushkin I, Ödman F. Assessment of the contamination from devices used for sampling and storage of whole blood and serum for element analysis. J Trace Elem Med Biol 15(1): 40-5. (2001).
Ayton S, Lei P, Bush AI. Biometals and their therapeutic implications in Alzheimer’s disease. Neurotherapeutics 12(1): 109-20. (2015).
Yang Y-W, Liou S-H, Hsueh Y-M, Lyu W-S, Liu C-S, Liu H-J, et al. Risk of Alzheimer’s disease with metal concentrations in whole blood and urine: a case–control study using propensity score matching. Toxicol Appl Pharmacol 356: 8-14. (2018).
Grashow R, Sparrow D, Hu H, Weisskopf MG. Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The normative aging study. Neurotoxicology 49: 158-64. (2015).
Keil DE, Berger-Ritchie J, McMillin GA. Testing for toxic elements: a focus on arsenic, cadmium, lead, and mercury. Lab Med 42(12): 735-42. (2011).
Prince M. Is chronic low-level lead exposure in early life an etiologic factor in Alzheimer’s disease? Epidemiology 9(6): 618-21. (1998).
Zawia NH, Basha MR. Environmental risk factors and the developmental basis for Alzheimer’s disease. Rev Neurosci 16(4): 325-37. (2005).
Lee J-Y, Kim J-H, Choi D-W, Lee D-W, Park J-H, Yoon H-J, et al. The association of heavy metal of blood and serum in the Alzheimer’s diseases. Toxicol Res 28(2): 93-8. (2012).
Park J-H, Lee D-W, Park KS, Joung H. Serum trace metal levels in Alzheimer’s disease and normal control groups. Am J Alzheimers Dis Other Demen 29(1): 76-83. (2014).

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 23 April, 2019
Page: [353 - 361]
Pages: 9
DOI: 10.2174/1567205016666190311101445
Price: $65

Article Metrics

PDF: 47
PRC: 1