Type 2 Diabetes and Alzheimer Disease: What's the Connection?
Diabetes and Alzheimer disease share biologic mechanisms and environmental risk factors, such as lifestyle, diet, and air pollution.
According to recent estimates, the global prevalence of type 2 diabetes (T2D) is 347 million, and Alzheimer disease (AD) and dementia affect 44.4 million people worldwide.1 A growing body of research supports an association between the 2 diseases, with some experts referring to AD as “type 3 diabetes.”2 Studies point to shared biologic mechanisms and environmental risk factors such as lifestyle, diet, and air pollution.
“This may suggest shared pathogenic pathways between T2DM and AD, with T2DM, which occurs on average earlier in life than AD, exacerbating neuronal and metabolic dysfunction, further increasing the risk of developing AD,” as stated in a review published in March 2018 in Current Environmental Health Reports.3 In a 2013 meta-analysis, the pooled adjusted risk ratio for AD among those with T2D was 1.57 (95% CI, 1.41-1.75).4
Findings suggest that insulin resistance and deficiency may increase AD risk via their influence on brain function. Insulin and leptin have been found to “regulate neuronal and synaptic function in different regions of the brain, protect neurons against neurodegeneration and cell death, and affect cognition and behavior,” and to modulate β-amyloid production and degradation.3
Other mechanistic pathways potentially connecting the 2 diseases include mitochondrial dysfunction, inflammation, increased advance glycation end products, and chronic oxidative stress and inflammation such as those caused by pollutants.5
The authors of the new review explored findings from observational studies that examined the T2D-AD link and shared risk factors. Examples of these results are highlighted below.
- Multiple longitudinal studies have demonstrated increased T2D risk with exposure to particulate matter <2.5 μm (PM2.5). In a study published in 2011, for example the hazard ratio was 1.21 per IQR (95% CI, 1.00-1.46) among female participants (n=74,412) and 1.52 per IQR (95% CI, 0.93-2.47) among male participants (n=15,048).6
- Research examining T2D risk related to particulate matter <10 μm (PM10) and nitrogen dioxide (NO2) has shown similar results, with one longitudinal Swiss cohort study (n=6392) reporting a 40% increased risk per IQR of PM10 (OR, 1.40; 95% CI, 1.17-1.69).7 A meta-analysis published in 2014 linked increased T2D risk with greater exposure to NO2 (meta-analysis RR=1.11 per 10 μg/m3 increment; 95% CI, 1.07-1.16), PM2.5 (meta-analysis RR=1.39 per 10 μg/m3 increment; 95% CI, 1.14-1.68), and PM10 (meta-analysis RR=1.34 per 10 μg/m3 increment; 95% CI, 1.22-1.47).8
- While longitudinal data on the risk of AD relative to air pollution exposure are more scarce, case-control studies on the topic and longitudinal studies pertaining to general cognitive decline suggest increased risk with exposure.
- In Taiwanese research involving 95,690 participants, those with higher PM2.5 exposures had greater than twice the risk of AD (HR=2.38 per 4.43-μg/m3 increase; 95% CI, 2.21-2.56).9 In a US study of 9.8 million Medicare patients, an association was observed between baseline PM2.5 exposure and increased risk of AD-related hospitalization (HR=1.15 per 1 μg/m3; 95% CI, 1.11-1.19).10
- In a Swedish cohort (n=1806), exposure to nitrogen oxides was positively associated with dementia risk (highest quartile of exposure vs lowest: HR=1.43, 95% CI,1.00-2.05).11
- Additionally, numerous studies conducted in recent decades have demonstrated associations between T2D and exposure to various pesticides. In a 2016 systematic review of 22 studies, the top tertile of exposure to any pesticide (vs bottom) was found to substantially increase T2D risk (OR=1.58; 95% CI, 1.32-1.90).12
- Although findings regarding the relationship between AD and pesticide exposure have been less consistent, several studies have noted a connection, including a small case-control study (n=165) that revealed an association between higher serum dichlorodiphenyldichloroethylene levels and AD risk (OR, 4.18; 95%, 2.54-5.82).13
- In a large longitudinal cohort study (n=3084) of agricultural workers, an increased risk of AD was observed with greater self-reported exposure to organophosphate (HR=1.53; 95% CI, 1.05-2.23) and organochlorine (HR=1.49; 95% CI, 0.99-2.24).14
Future research “will ideally elaborate on the role of shared environmental risk factors contributing to these disorders, including but not limited to air pollution and pesticides, and consider how metabolic dysfunction may modify the impact of these exposures on cognitive decline,” the authors of the 2018 review concluded.3
Other research supports a genetic component to the overlap between AD and T2D. A 2015 study identified 927 single nucleotide polymorphisms (SNPs) associated with both AD and T2D (P ≤.01), and 395 of these “have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D,” the researchers wrote.1 Their findings further suggest that “among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects.”
To learn more about the link between AD and T2D, Endocrinology Advisor checked in Giulio M. Pasinetti, MD, PhD, professor of neurology, psychiatry, geriatrics and palliative medicine, and neuroscience at Icahn School of Medicine at Mount Sinai; program director of the NIH-funded Mount Sinai Center for Molecular Integrative Neuroresilience; and chief of the Brain Institute Center of Excellence for Novel Approaches to Neurodiagnostics and Neurotherapeutics. Dr Pasinetti was one of the authors of the 2015 genetics study.
Endocrinology Advisor: What is known thus far about associations between Alzheimer disease and T2D?
Dr Pasinetti: Extensive epidemiologic evidence indicates that individuals with T2D are at higher risk of developing AD. In support of this, our laboratory has recently shown a number of shared genetic polymorphisms between patients with T2D and AD, indicating that these 2 diseases may involve and progress through similar mechanisms. It is important to note, however, that we have not demonstrated that T2D predisposes individuals to AD, although there is some research suggesting this link.
Endocrinology Advisor: What are the potential mechanisms underlying this connection?
Dr Pasinetti: The onset of both AD and T2D depends on the integration of multiple genetic and environmental factors. Genetic predispositions to T2D implicate the fundamental insulin signaling pathways including insulin resistance and insulin receptor expression. However, findings from various clinical and epidemiologic studies have indicated a strong lifestyle component, including excessive caloric intake, high sugar consumption, and prolonged periods of inactivity.
Similarly, the risk of AD is heightened by genetic polymorphisms including variations in amyloid precursor protein and the gamma secretases. As with diabetes, there is a very strong influence of lifestyle factors linked to AD pathologies that parallel those for diabetes. Because of these factors, the epidemiology of these 2 seemingly diverse conditions overlaps.
Endocrinology Advisor: What are the current treatment implications for clinicians?
Dr Pasinetti: Clinicians should understand that T2D is a risk factor for cognitive deterioration and potentially dementia associated with AD. They may develop an additional treatment plan for those with genetic predispositions to AD, advising them to simultaneously reduce the risk factors of diabetes to protect their neurologic health. In addition, patients with diabetes should also receive counseling to understand their elevated risk for developing dementia, and they could be tested for the genetic risk factors to inform a more effective prophylactic treatment regime.
Endocrinology Advisor: What should be the focus of future research on this topic?
Dr Pasinetti: The direction of the link between T2D and AD should be causally mapped. Studies have shown preliminary evidence that there is, to some degree, insulin resistance present in the brain of patients with AD, and further studies should be developed to understand the extent of this relationship. Understanding how T2D contributes to this physiologic observation in patients with AD is critical to elucidating their common mechanisms. Furthermore, there is still debate regarding the extent to which diabetes may or may not influence the onset of dementia, especially when considering the multifactorial nature of both AD and T2D.
- Hao K, Di Narzo AF, Ho L, et al. Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes.Mol Aspects Med. 2015;43-44:66-76.
- Kandimalla R, Thirumala V, Reddy PH. Is Alzheimer's disease a type 3 diabetes? A critical appraisal.Biochim Biophys Acta. 2017;1863(5):1078-1089.
- Paul KC, Jerrett M, Ritz B. Type 2 diabetes mellitus and Alzheimer's disease: overlapping biologic mechanisms and environmental risk factors.Curr Environ Health Rep. 2018;5(1):44-58.
- Vagelatos NT, Eslick GD. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev. 2013;35(1):152-160.
- de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes—evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101-1113.
- Puett RC, Hart JE, Schwartz J, Hu FB, Liese AD, Laden F. Are particulate matter exposures associated with risk of type 2 diabetes?Environ Health Perspect. 2011;119(3):384-389.
- Eze IC, Schaffner E, Fischer E,et al. Long-term air pollution exposure and diabetes in a population-based Swiss cohort.Environ Int. 2014;70:95-105.
- Wang B, Xu D, Jing Z, Liu D, Yan S, Wang Y. Effect of long-term exposure to air pollution on type 2 diabetes mellitus risk: a systemic review and meta-analysis of cohort studies. Eur J Endocrinol. 2014;171(5):R173-182.
- Jung C-R, Lin Y-T, Hwang BF. Ozone, particulate matter, and newly diagnosed Alzheimer's disease: a population-based cohort study in Taiwan.J Alzheimers Dis. 2015;44(2):573-584.
- Kioumourtzoglou MA, Schwartz JD, Weisskopf MG, et al. Long-term PM exposure and neurological hospital admissions in the northeastern United States.Environ Health Perspect. 2015; 124(1): 23–29.
- Oudin A, Forsberg B, Adolfsson AN, et al. Traffic-related air pollution and dementia incidence in Northern Sweden: a longitudinal study.Environ Health Perspect. 2016;124(3):306-312.
- Evangelou E, Ntritsos G, Chondrogiorgi M, et al. Exposure to pesticides and diabetes: a systematic review and meta-analysis.Environ Int. 2016;91:60-68.
- Richardson JR, Roy A, Shalat SL, et al. Elevated serum pesticide levels and risk for Alzheimer disease.JAMA Neurol. 2014;71(3):284-290.
- Hayden KM, Norton MC, Darcey D, et al; for the Cache County Study Investigators. Occupational exposure to pesticides increases the risk of incident AD: the Cache County study.Neurology. 2010;74(19):1524-1530.