Comprehending the Rationale for Repurposing Type 2 Diabetes Mellitus Medicines for Alzheimer's Disease Patients Via Gene Networks Studies and its Associated Molecular Pathways

Ravina Yadav¹, Ruchi Jakhmola Mani¹, Arun Kumar², Saif Ahmad³ and Deepshikha Pande Katare^1*

¹Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida. India.

²Department of Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana, India.

³Department of Translational Neuroscience, Barrow Neurological Institute 350 West Thomas Road Phoenix, Arizona.

Corresponding Author E-mail: dpkatare@amity.edu

Abstract: Type 2 Diabetes Mellitus (T2DM) is a known risk factor for Alzheimer’s disease (AD). Several epidemiological studies have reported a pathological association between AD and T2DM and have declared AD as a comorbidity of T2DM making T2DM a major risk factor for AD. Impaired insulin signaling elevates the risk for AD development and this can result in neurodegeneration via Aβ formation or increased inflammation in response to intraneural β amyloid. Insulin resistance, impaired glucose, carbohydrate and protein metabolism, and mitochondrial dysfunction are some characteristics common to both AD and T2DM.  These features appear much before the clinical examination of both neurodegenerative diseases. It has now become extremely crucial to know the events that appear in the prodromal phases of these neurodegenerative disorders that elevate neurodegeneration risk. This has given rise to the idea that medications designed to treat T2DM may also help to alter the pathophysiology of AD and maintain cognitive function. This review highlights the recent and past evidence that correlates AD and T2DM, focusing on the shared pathogenic processes, and then evaluates the numerous medications given at clinical stages for assessing their potential activity in AD. Few molecular processes and their associated genes, altered protein metabolism (IAPP, Fyn/ERK/S6), altered carbohydrate metabolism (GLUT1, GLUT3, GLUT4), Impaired Acetylcholine (Ach) Synthesis (ACHE, ChAT), altered cholesterol metabolism (APOE4) were some of the biological reasons which made T2DM drugs useful for AD at the molecular level. Additionally, an in-silico strategy explores and evaluates the efficiency of T2DM medications like metformin, insulin, thiazolidinediones, etc. for AD treatment. The gene receptors for these drugs in the human system were predicted to understand the molecular pathways followed by these receptors which are common in AD pathology.

Keywords: Alzheimer’s Disease; Comorbidity, Drug Repurposing; Dementia; Neurodegeneration; Type 2 Diabetes Mellitus

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