Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

Abstract

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease.

A neural signature of metabolic syndrome

“…T2DM was associated with a twofold increased risk of developing AD and all-type dementia (Ott et al, 1996). An association that has since been replicated in more recent studies (Arvanitakis, Wilson, Bienias, Evans, & Bennet, 2004;Chatterjee & Mudher, 2018). In our study we found a modest relationship between the MetS neural signature and that of AD, as shown in the BrainMap VBM meta-analysis.…”

“…Although there are numerous mechanistic hypotheses as to how these degenerative changes occur, several have gained particular notoriety. The hypothesis of AD-related central nervous system (CNS) insulin resistance, coupled with observations that T2DM is associated with an increased risk of developing AD (Ott et al, 1996;Stranahan, 2015), has led researchers ask whether peripheral metabolic biomarkers could be used to predict neurological decline (Chatterjee & Mudher, 2018;Pruzin, Nelson, Abner, & Arvanitakis, 2018). Impaired insulin receptor binding in the hippocampus, a structure known to express high levels of insulin receptors, is presumed to influence the development of AD (De Felice, Lourenco, & Ferreira, 2014).…”

“…Impaired insulin receptor binding in the hippocampus, a structure known to express high levels of insulin receptors, is presumed to influence the development of AD (De Felice, Lourenco, & Ferreira, 2014). The hypothesis of AD-related central nervous system (CNS) insulin resistance, coupled with observations that T2DM is associated with an increased risk of developing AD (Ott et al, 1996;Stranahan, 2015), has led researchers ask whether peripheral metabolic biomarkers could be used to predict neurological decline (Chatterjee & Mudher, 2018;Pruzin, Nelson, Abner, & Arvanitakis, 2018). Besides brain insulin resistance, other mechanisms such as neuroinflammation, oxidative stress, and abnormal brain lipid metabolism have been proposed as pathophysiological contributors to neurocognitive decline in the MetS brain (Yates et al, 2012).…”

The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers

“…Inside the cells, hyperphosphorylated tau protein accumulate up to formation of neurofibrillary tangles (NFTs). The formation of deposits of insoluble amyloid β (Aβ) protein is observed extracellularly leading to the formation of senile plaques [1][2][3]. The senile plaques located in the brains of AD victims consist mainly of insoluble, densely packed, toxic forms of Aβ.…”

“…The insulin-degrading enzyme, which is zinc-thiol-dependent metalo-endopeptidase, is also responsible for the degradation of Aβ. If insulin concentration in T2DM is too high, it acts as a competitive IDE substrate and inhibits the degradation of Aβ, which gradually accumulates, forming insoluble plaques [1]. Studies indicate that IDE gene deletion in mice (IDE −/− ) caused a 50% decrease in Aβ clearance in brain homogenates and primary neuronal cultures.…”