Type 2 Diabetes Mellitus and Alzheimer’s Disease: Overlapping Biologic Mechanisms and Environmental Risk Factors
Purpose of Review
A number of studies over the past two decades have suggested that type 2 diabetes mellitus (T2DM) patients are at an increased risk of Alzheimer’s disease (AD). Several common molecular pathways to cellular and metabolic dysfunction have been implicated in the etiology of both diseases. Here, we review the emerging evidence from observational studies that investigate the relationship between T2DM and AD, and of shared environmental risk factors, specifically air pollution and pesticides, associated with both chronic disorders.
Particulate matter and traffic-related air pollution have been widely associated with T2DM, and multiple studies have associated exposures with AD or cognitive function. Organochlorine (OC) and organophosphate (OP) pesticides have been associated with T2DM in multiple independent populations. Two populations have observed increased risks for OC and OP exposures and AD. Other studies, limited in exposure assessment, have reported increased risk of AD with any pesticide exposure assessments.
This may suggest shared pathogenic pathways between environmental risk factors, T2DM, and AD. Research focusing on exposures related to both T2DM and AD could provide new disease insights on shared mechanisms and help shape innovative preventative measures and policy decisions.
KeywordsType 2 diabetes mellitus Alzheimer’s disease Environment Air pollution Pesticides
Parts per billion
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 1.United Nations. Report of the Second World Assembly on Ageing: Madrid, 8-12 April 2002. United Nations Publications; 2002. http://www.un.org/en/ga/search/view_doc.asp?symbol=A/CONF.197/9.
- 11.Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100(7):4162–7. https://doi.org/10.1073/pnas.0230450100. CrossRefPubMedCentralPubMedGoogle Scholar
- 15.• de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes—evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101–13. https://doi.org/10.1177/193229680800200619. This article reviews the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration.CrossRefPubMedCentralPubMedGoogle Scholar
- 17.Bass V, Gordon CJ, Jarema KA, MacPhail RC, Cascio WE, Phillips PM, et al. Ozone induces glucose intolerance and systemic metabolic effects in young and aged brown Norway rats. Toxicol Appl Pharmacol. 2013;273(3):551–60. https://doi.org/10.1016/j.taap.2013.09.029.CrossRefPubMedCentralPubMedGoogle Scholar
- 23.Xu WL, Qiu CX, Wahlin A, Winblad B, Fratiglioni L. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology. 2004;63(7):1181–6. https://doi.org/10.1212/01.WNL.0000140291.86406.D1.CrossRefPubMedGoogle Scholar
- 24.Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005;65(4):545–51. https://doi.org/10.1212/01.wnl.0000172914.08967.dc.CrossRefPubMedCentralPubMedGoogle Scholar
- 27.Al-Emam A, Elhaddad AA, Ramadan E. The risk of clinically diagnosed alzheimer disease in patients with non insulin dependent diabetes mellitus. Egypt J Neurol Psychiatry Neurosurg. 2010;47(3):419–24.Google Scholar
- 29.Kimm H, Lee PH, Shin YJ, et al. Mid-life and late-life vascular risk factors and dementia in Korean men and women. Arch Gerontol Geriatr 2011;52(3). https://doi.org/10.1016/j.archger.2010.09.004.
- 38.Raaschou-Nielsen O, Andersen ZJ, Beelen R, Samoli E, Stafoggia M, Weinmayr G, et al. Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Lancet Oncol. 2013;14(9):813–22. https://doi.org/10.1016/S1470-2045(13)70279-1.CrossRefPubMedGoogle Scholar
- 41.• Zaganas I, Kapetanaki S, Mastorodemos V, et al. Linking pesticide exposure and dementia: what is the evidence? Toxicology. 2013;307:3–11. https://doi.org/10.1016/j.tox.2013.02.002. This article reviews the epidemiological links between dementia and pesticide exposure and discusses the possible pathophysiological mechanisms and clinical implications of this association.CrossRefPubMedGoogle Scholar
- 43.Coogan PF, White LF, Jerrett M, et al. Air pollution and incidence of hypertension and diabetes in African American women living in Los Angeles. Circulation. 2012. https://doi.org/10.1161/CIRCULATIONAHA.111.052753.
- 46.G W, K F, F H, et al. Industry and traffic related air pollution and diabetes type two incidence: results from a German cohort study. Eur J Epidemiol. 2012;27(1 SUPPL. 1):S12. http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed14&NEWS=N&AN=71302821 Google Scholar
- 50.Chen H, Burnett RT, Kwong JC, Villeneuve PJ, Goldberg MS, Brook RD, et al. Risk of incident diabetes in relation to long-term exposure to fine particulate matter in Ontario, Canada. Environ Health Perspect. 2013;121(7):804–10. https://doi.org/10.1289/ehp.1205958.CrossRefPubMedCentralPubMedGoogle Scholar
- 52.Weinmayr G, Hennig F, Fuks K, et al. Long-term exposure to fine particulate matter and incidence of type 2 diabetes mellitus in a cohort study: effects of total and traffic-specific air pollution. Environ Health. 2015;14(1):53. https://doi.org/10.1186/s12940-015-0031-x. CrossRefPubMedCentralPubMedGoogle Scholar
- 56.Loop MS, Kent ST, Al-Hamdan MZ, Crosson WL, Estes SM, Estes MG, et al. Fine particulate matter and incident cognitive impairment in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. PLoS One. 2013;8(9):e75001. https://doi.org/10.1371/journal.pone.0075001.CrossRefPubMedCentralPubMedGoogle Scholar
- 61.Chang K-H, Chang M-Y, Muo C-H, Wu T-N, Chen C-Y, Kao C-H. Increased risk of dementia in patients exposed to nitrogen dioxide and carbon monoxide: a population-based retrospective cohort study. PLoS One. 2014;9(8):e103078. https://doi.org/10.1371/journal.pone.0103078.CrossRefPubMedCentralPubMedGoogle Scholar
- 66.Bro-Rasmussen F. Contamination by persistent chemicals in food chain and human health. Sci Total Environ. 1996;188 https://doi.org/10.1016/0048-9697(96)05276-X.
- 67.Committee to review the health effects in Vietnam Veterans of exposure to herbicides (Tenth Biennial Update) C, on the Health of select populations B, of Medicine I, of Sciences Engineering, Medicine. Veterans and Agent Orange: Update 2014.; 2016. https://doi.org/10.17226/21845.
- 68.Taylor KW, Novak RF, Anderson HA, Birnbaum LS, Blystone C, DeVito M, et al. Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a national toxicology program workshop review. Environ Health Perspect. 2013;121(7):774–83. https://doi.org/10.1289/ehp.1205502.CrossRefPubMedCentralPubMedGoogle Scholar
- 70.Lee D-H, Lee I-K, Song K, Steffes M, Toscano W, Baker BA, et al. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999-2002. Diabetes Care. 2006;29(7):1638–44. https://doi.org/10.2337/dc06-0543.CrossRefPubMedGoogle Scholar
- 74.Lee DH, Lind PM, Jacobs DR, Salihovic S, Van Bavel B, Lind L. Polychlorinated biphenyls and organochlorine pesticides in plasma predict development of type 2 diabetes in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Diabetes Care. 2011;34(8):1778–84. https://doi.org/10.2337/dc10-2116.CrossRefPubMedCentralPubMedGoogle Scholar
- 84.Lin J-N, Lin C-L, Lin M-C, Lai CH, Lin HH, Yang CH, et al. Increased risk of dementia in patients with acute organophosphate and carbamate poisoning: a Nationwide population-based cohort study. Medicine (Baltimore). 2015;94(29):e1187. https://doi.org/10.1097/MD.0000000000001187.CrossRefGoogle Scholar
- 89.McGuire V, Nelson LM, Koepsell TD, Checkoway H, Longstreth WT. Assessment of occupational exposures in community-based case-control studies. Annu Rev Public Health. 1998;19(19):35–53. https://doi.org/10.1146/annurev.publhealth.19.1.35.CrossRefPubMedGoogle Scholar
- 90.• Brouwer M, Kromhout H, Vermeulen R, et al. Assessment of residential environmental exposure to pesticides from agricultural fields in the Netherlands. J Expo Sci Environ Epidemiol. 2017. This article describes a spatio-temporal model to estimate lifetime exposure to pesticides in the Netherlands based on residential histories.Google Scholar