The Mechanistic Effects of Diabetes on the Pathogenesis of Alzheimer’s Disease

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two of the leading health issues in the United States, affect millions of people worldwide, and have detrimental effects to the patient’s daily life as well as social and economic costs. Currently, more than 21 million people in the US alone have diabetes, and over five million have AD. Recent studies have shown a correlation of newly diagnosed diabetes mellitus and increased risk of future Alzheimer’s disease development (Huang et al., 2014), and prevalence of diabetes mellitus has shown to almost double the risk of general dementia. Current studies have begun to like the prevalence of T2DM and its mechanistic effects including abnormal insulin levels, high blood sugar, and chronic inflammation to increased pathogenesis of AD. AD is characterized by the accumulation of amyloid-β plaques (Aβ) and neurofibrillary tangles (NFTs) in the brain. Epigenetic studies have revealed different mechanisms of AD pathogenesis in sporadic AD versus familial AD. Familial AD is characterized by autosomal dominant mutations in specific genes that result in Aβ accumulation, while sporadic AD has some genetic factors, but also heavily relies on epigenetics and lifestyle with mechanisms still to be elucidated.              

There are some controversies about how diabetes directly affects the risk of AD, including how hypertension, dyslipidemia (high concentration of lipids in the blood), obesity, and depression might affect Alzheimer’s incidence. However, some possible mechanisms of how T2DM affects cognitive decline include the relationship between cerebrovascular dysfunction and Aβ metabolism. Increased solubility of Aβ and increased production Aβ resulting from an imbalance of the production and degradation of Aβ could result in the aggregates found in AD (Baglietto-Vargas et al., 2016). Cerebrovascular dysfunction can result from T2DM by increased dyslipidemia, which results in epithelial dysfunction (decreased blood flow to tissues in the brain, decreased protein production, neural tissue necrosis, etc.) and increased stiffness of the arteries. The link between T2DM and AD is found from high blood sugar and lipid content resulting in increased cerebrovascular dysfunction and increased Aβ production (Carlsson, 2010).

The insulin-signaling pathway is crucial for regulating glucose metabolism in the brain, as well as for the regulation of neuronal development, learning, and memory. Increased insulin resistance and glucose intolerance in T2DM has shown to overstimulate brain metabolism, and is an early and common feature of AD. Insulin and insulin-like growth factor (IGF) dysfunction can lead to the imbalance of functional enzymes and increased risk of AD pathogenesis.  One example includes overexpression of beta-secretase 1 (BACE-1) in the Aβ precursor protein (AβPP) processing pathway. Overexpression of this enzyme results in the translational upregulation of the precursor protein, and causes an accumulation of the Aβ protein as well as inhibition of the insulin degrading enzyme (IDE) (Baglietto-Vargas et al., 2016). IDE is responsible for the regulation and degradation of insulin as well as for soluble Aβ protein. IDE can also be impaired by hyperinsulinemia and by high blood glucose levels, resulting in increased levels of the Aβ protein (Farris et al., 2003).

High blood glucose is a defining characteristic of T2DM. Excess glucose in the blood stimulates glycation reactions that result in higher concentrations of AGEs (advanced glycation end products) as well as increased AGEs receptors. AGEs are proteins and lipids that become covalently bonded to sugars. Postmortem studies have revealed that AGEs are commonly associated with Aβ plaques and NFTs, and higher concentrations of AGEs were found in AD patients that had T2DM than those without (Baglietto-Vargas et al., 2016). RAGE is an AGE receptor that acts as an inflammatory intermediary as well as an inducer of oxidative stress that can contribute to the pathogenesis of T2DM as well as AD (Cai et al., 2016). RAGE also regulates the amount of Aβ protein in the brain, and is a possible contributor to synaptic and neuronal dysfunction resulting in overall cognitive impairment.

Inflammation and oxidative stress are newer possible mechanisms of AD pathogenesis. A well-known side effect of T2DM is chronic inflammation and the excess release of pro-inflammatory cytokines. Excessive activation of the innate immune system has been shown to induce both hyperglycemia and insulin resistance (Guest et al., 2008). In addition to inflammatory cytokines, vascular endothelial growth factor (VEGF) levels, which stimulate angiogenesis (the development of new blood cells), have shown to be higher in both AD patients and in T2DM. VEGF expression is induced by brain hypoxia as well as chronic inflammation. Overexpression of this growth factor leads to increased angiogenesis and possibly results in the accumulation of Aβ plaques and the secretion of a neuronic peptide that kills cortical neurons and results in characteristic AD dementia (Jung et al., 2015).

Oxidative stress resulting from T2DM also plays a major role in chronic inflammation and possible AD pathogenesis. Causes of T2DM including physical inactivity and over-nutrition results in chronic reactive oxygen species (ROS) and reactive nitrogen species (RNS) production (Verdile et al., 2015). The resulting oxidative stress can induce mitochondrial dysfunction, impairing ATP synthesis and enhancing ROS generation which depletes the brain’s source of neuronal energy and results in neural degeneration (Rani et al., 2016). The increase of ROS generation and mitochondrial dysfunction have also been liked to increased Aβ production (Apelt et al., 2004).

 Interestingly, VEGF levels have also shown to be higher in Alzheimer’s patients with depression than those without (Jung et al., 2015). There are a number of studies liking depression to diabetes, dementia, and AD, however the cause-effect relationship between them is unclear. Chronic depression increases pro-inflammatory cytokines and inflammatory markers that have been linked to AD. The inflammatory cytokines IL-6, IL-1 and TNF-α have been found in higher concentrations in depression and AD, and the overexpression of IL-1 promotes the synthesis of Aβ protein. Also, the glucocorticoid theory states that chronic depression results in a smaller hippocampus (HC) as well as HC atrophy, which could contribute to the risk and progression of AD (Hermida et al., 2012). Alternatively, depression could be the result of the neuropathological changes that occur during AD pathogenesis.

These mechanisms showing the link between insulin, high blood sugar, inflammation, and AD is continuously supporting the theory that AD is “diabetes mellitus of the brain”. There are multiple studies showing the relationship between AD pathogenesis and other co-morbid medical conditions including stroke, stress, seizures, osteoporosis, and renal disease, but the increasing prevalence and relationship of diabetes and Alzheimer’s is suggesting anti-diabetic agents could be a potential treatment target for sporadic AD.

References

Apelt, J. et al., (2004). Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. Int. J. Dev. Neurosci. 22 (7) 475–484.

Baglietto-Vargas, D., Shi, J., Yaeger, D. M., Ager, R., & LaFerla, F. M. (2016). Diabetes and Alzheimer’s disease crosstalk. Neuroscience & Biobehavioral Reviews, 64, 272-287.

Cai, Z., Liu, N., Wang, C., Qin, B., Zhou, Y., Xiao, M., & ... Zhao, B. (2016). Role of RAGE in Alzheimer’s disease. Cellular And Molecular Neurobiology, 36(4), 483-495. doi:10.1007/s10571-015-0233-3

Carlsson, C. M. (2010). Type 2 Diabetes Mellitus, Dyslipidemia, and Alzheimer's Disease. Journal Of Alzheimer's Disease, 20(3), 711-722. doi:10.3233/JAD-2010-100012

De la Monte, S. M., & Wands, J. R. (2008). Alzheimer’s Disease Is Type 3 Diabetes–Evidence Reviewed. Journal of Diabetes Science and Technology (Online), 2(6), 1101–1113.

Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., … Guénette, S. (2003). Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 4162–4167. http://doi.org/10.1073/pnas.0230450100

Guest, C.B., Park, M.J., Johnson, D.R., & Freund, G.G. (2009). The implication of proinflammatory cytokines in type 2 diabetes. Frontiers in Bioscience: a Journal and Virtual Library. 13:5187-5194.

Hermida, A. P., McDonald, W. M., Steenland, K., & Levey, A. (2012). The association between late-life depression, mild cognitive impairment and dementia: is inflammation the missing link? Expert Review of Neurotherapeutics, 12(11), 1339–1350. http://doi.org/10.1586/ern.12.127

Huang, C., Chung, C., Leu, H., Lin, L., Chiu, C., Hsu, C., & ... Chan, W. (2014). Diabetes Mellitus and the Risk of Alzheimer’s Disease: A Nationwide Population-Based Study. Plos ONE, 9(1), 1-7. doi:10.1371/journal.pone.0087095

Jung, J., Kim, S., Yoon, K., Moon, Y., Roh, D., Lee, S., & ... Kim, D. (2015). The Effect of Depression on Serum VEGF Level in Alzheimer’s Disease. Disease Markers, 20151-6. doi:10.1155/2015/742612

Odegaard, A. O., Jacobs Jr., D. R., Sanchez, O. A., Goff Jr., D. C., Reiner, A. P., & Gross, M. D. (2016). Oxidative stress, inflammation, endothelial dysfunction and incidence of type 2 diabetes. Cardiovascular Diabetology, 151-12. doi:10.1186/s12933-016-0369-6

Rani, V., Deshmukh, R., Jaswal, P., Kumar, P., & Bariwal, J. (2016). Alzheimer's disease: Is this a brain specific diabetic condition? Physiology & Behavior, 164259-267. doi:10.1016/j.physbeh.2016.05.041

Tarkowski, E., Issa, R., Sjogren, M., et al., (2002). “Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia,” Neurobiology of Aging, vol. 23, no. 2, pp. 237–243.

Verdile, G., Keane, K. N., Cruzat, V. F., Medic, S., Sabale, M., Rowles, J., & Newsholme, P. (2015). Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer’s Disease. Mediators of Inflammation, 1-17. doi:10.1155/2015/105828