Alzheimer’s disease (AD), a neurodegenerative disorder, is the leading cause of dementia and is characterized by cognitive impairments including memory loss. Currently, more than 5 million Americans are suffering from AD and this number is projected to increase to 14 million in the next three decades (1). Clinically, AD can be divided into two categories: familial AD (starts at an early age, usually in the late 40s) and sporadic AD (starts after the age of 65). Both types of AD share similar clinical phenotypes including amyloid plaque formation, hyperpolarization of tau protein, neuroinflammation, and neuron death (2). The patients with sporadic AD, which comprise 98% of total AD cases, often have comorbidities including diabetes (2). The growing epidemiological evidence suggests that diabetes significantly increases the risk for AD development.
Diabetes, which is the most common metabolic disorder, is characterized by abnormally high blood glucose levels. The hyperglycemia occurs when beta cells of the pancreas do not produce enough insulin, or the body’s cells are not able to properly utilize the insulin (2). A study done two decades ago showed that type-2 diabetes doubles an individual’s risk of dementia (3). Diabetes can cause several brain changes that are hallmarks for AD. For instance, insulin deficiency or dysfunction has been shown to increase tau phosphorylation, amyloid plaque accumulation, and neurofibrillary degeneration (2,4,5,6). In addition, many AD patients show reduced expression of genes responsible for the synthesis of insulin in the brain (7). Hyperglycemia can also stimulate memory loss and cognitive impairment by damaging the blood vessels in the brain (2). The impaired glucose levels are suggested to exaggerate the functional and global cognitive decline and loss of whole brain volume (8). Moreover, diabetic patients also exhibited higher translation from mild cognitive impairment (MCI) to AD, suggesting that metabolic dysfunction can escalate the progression of AD (8).
The insulin receptor is highly expressed in the hippocampus and entorhinal cortex, two brain regions that are associated with learning and memory. Neuroimaging of diabetic patients suggests there is a reduction in hippocampal and cortical volume that can cause disruption of insulin signalling (2,9,10). Dysfunction of insulin signalling in these regions can result in cognitive decline and memory loss (2). Additionally, changes in the microstructure of white matter and disruption of neuron connectivity, specifically in brain regions prone to AD, are observed in diabetic patients (9,10). Along with memory impairment, type-2 diabetic patients exhibit difficulties in processing speed, attention, and visuospatial construction. In addition, impairment in the saccadic eye movement, which is characteristic of early cognitive decline, is also observed in people with chronic hyperglycemia (11,12). The above evidence suggests that impaired glucose metabolism in the body can set a platform for AD development.
Several anti-diabetic drugs are being tested as potential therapies for AD, including metformin and sulfonylureas. Metformin reduces glucose production in the liver and increases insulin sensitivity in the body, whereas sulfonylureas stimulates insulin release from pancreatic beta-cells (13). Both cell and animal based studies suggest that metformin can reduce hyperphosphorylation of tau and mitigate cognitive impairment and AD-like pathologies (13,14,15). Furthermore, the combined therapy using both sulfonylureas and metformin has been shown to reduce the incidence of dementia in diabetes patients (13,16). However, contrasting evidence also suggests there is no beneficial effect of sulfonylureas on dementia, and metformin can increase the formation of amyloid beta protein, when used as monotherapy (13,17,18). Given the contrasting evidence, further research is required to establish the therapeutic role of anti-diabetic drugs in AD or dementia.
There is strong epidemiological evidence that suggests a link between diabetes and increased risk of AD development. However, additional research is required to study the pathophysiological mechanism between the two diseases so that therapeutic interventions can be developed to slow down and/or stop the progression of cognitive decline in diabetic patients. To make therapeutic interventions more effective, the early diagnosis of AD is crucial before the significant loss of neurons. Therefore, it will be beneficial to perform risk assessment regularly on high-risk groups such as diabetic patients. Esurgi is developing a non-invasive and cost-effective diagnostic tool, Eye AD, that can analyze saccadic movements in real-time. Our novel device can aid in early detection of cognitive impairment, which can open a window for early intervention and allow care providers to adapt to dementia changes.
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- Baglietto-Vargas D, Shi J, Yaeger DM, Ager R, LaFerla FM. Diabetes and Alzheimer’s disease crosstalk. Neurosci Biobehav Rev. May 2016;64:272-87. doi:10.1016/j.neubiorev.2016.03.005
- Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. Dec 1999;53(9):1937-42. doi:10.1212/wnl.53.9.1937
- Planel E, Tatebayashi Y, Miyasaka T, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci. Dec 2007;27(50):13635-48. doi:10.1523/JNEUROSCI.3949-07.2007
- Kim B, Backus C, Oh S, Hayes JM, Feldman EL. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology. Dec 2009;150(12):5294-301. doi:10.1210/en.2009-0695
- Wang X, Yu S, Hu JP, et al. Streptozotocin-induced diabetes increases amyloid plaque deposition in AD transgenic mice through modulating AGEs/RAGE/NF-κB pathway. Int J Neurosci. Aug 2014;124(8):601-8. doi:10.3109/00207454.2013.866110
- Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis. Feb 2005;7(1):63-80. doi:10.3233/jad-2005-7107
- Morris JK, Vidoni ED, Honea RA, Burns JM, Initiative AsDN. Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol Aging. Mar 2014;35(3):585-9. doi:10.1016/j.neurobiolaging.2013.09.033
- Roberts RO, Knopman DS, Przybelski SA, et al. Association of type 2 diabetes with brain atrophy and cognitive impairment. Neurology. Apr 2014;82(13):1132-41. doi:10.1212/WNL.0000000000000269
- Moran C, Phan TG, Chen J, et al. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care. Dec 2013;36(12):4036-42. doi:10.2337/dc13-0143
- Alessandrini M, Paris V, Bruno E, Giacomini PG. Impaired saccadic eye movement in diabetic patients: the relationship with visual pathways function. Doc Ophthalmol. 1999;99(1):11-20. doi:10.1023/a:1002464316347
- Alessandrini M, Bruno E, Parisi V, Uccioli L, Giacomini PG. Saccadic eye movement and visual pathways function in diabetic patients. An Otorrinolaringol Ibero Am. 2001;28(3):269-80.
- Tumminia A, Vinciguerra F, Parisi M, Frittitta L. Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Signalling and Therapeutic Implications. Int J Mol Sci. Oct 2018;19(11)doi:10.3390/ijms19113306
- Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology. May 2011;60(6):910-20. doi:10.1016/j.neuropharm.2011.01.033
- Kickstein E, Krauss S, Thornhill P, et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci U S A. Dec 2010;107(50):21830-5. doi:10.1073/pnas.0912793107
- Hsu CC, Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis. 2011;24(3):485-93. doi:10.3233/JAD-2011-101524
- Chen Y, Zhou K, Wang R, et al. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A. Mar 2009;106(10):3907-12. doi:10.1073/pnas.0807991106
- Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J Am Geriatr Soc. May 2012;60(5):916-21. doi:10.1111/j.1532-5415.2012.03916