Molecular Linkages Between Diabetes and Alzheimer's Disease: Current Scenario and Future Prospects

Abstract

After the revolutionary Rotterdam study that suggested there was an increased risk of developing Alzheimer's disease (AD) in patients with type-2 diabetes mellitus (T2DM), a number of studies have provided direct evidence for the linkage between AD and T2DM. In recent years, AD is considered as a neuroendocrine disorder, also referred as type-3 diabetes. There is a growing list of evidence to suggest that, in addition to impaired insulin signaling, there are a number of additional factors that may act as mechanistic links between AD and T2DM. These factors mainly include hypercholesterolemia, dyslipidemia, hypercystinemia, inflammation, impaired insulin signaling and impaired central nervous response to the adipose tissue-derived hormone leptin. Increased cholesterol plays a crucial role in the abnormal metabolism of the amyloid precursor protein, leading to the accumulation of β-amyloid. In addition to impaired insulin signaling, diabetes has been found to accelerate the appearance of cerebrovascular inflammation and β-amyloid peptide (Aβ) deposition. Increased oxidative stress and production of advanced glycation end products are other probable marker linkages. However, the details of many of these molecular links still require extensive investigation. It is possible that a number of common molecular linkages exist between T2DM and AD. Understanding and analyzing the various molecular linkages between AD and T2DM may shed light on new tools that can be used for the early diagnosis and treatment of AD and also accelerate the identification of T2DM patients who are at high risk of AD.

Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal

“…Insulin resistance in T2DM causes mitochondrial dysfunction, which in turn triggers inflammation response [82, 83]. In these conditions, insulin resistance increases the levels of cytokines such as IL-6, IL-1β and IL-18, tumor necrosis factor-alpha (TNF-α), alpha-1-antichymotrypsin and C-reactive protein [84–86].…”

Forxiga (dapagliflozin): Plausible role in the treatment of diabetes‐associated neurological disorders

“…It has been suggested that AD and T2DM result from various metabolic abnormalities and defective insulin metabolism. Shared pathology, metabolic profiles, transcriptomics, and proteomics are the possible links between these two diseases . Insulin signaling abnormalities could be the underlying mechanism affecting the outcome of AD; insulin resistance and disordered degradation of amyloid seem to link diabetes mellitus with AD .…”

Title: Biochemical linkage of type 2 diabetes mellitus and Alzheimer’s disease

“…Due to the absence of negative feedback control of acetylcholine, the decrease of AChE concentration leads to an increase of interleukin-1 (IL-1) and tumor necrotic factor (TNF-α). Therefore, the observation that the actions of AChase and BChase are increased in the plasma and red blood cells of T2DM and AD patients suggests that these proteins may be possible biochemical markers of these diseases (Dar et al, 2014).…”