Glucose Metabolism and AD: Evidence for a Potential Diabetes Type 3

Background: Alzheimer's disease is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.

Methods: We provide a thread regarding the influence of glucose metabolism in AD from three different perspectives: (i) as a regulator of the energy source, (ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence activation of the immune system (e.g., insulin resistance, diabetes, etc.), and (iii) as modulators of various key post-translational modifications for protein aggregation, for example, influence on tau hyperphosphorylation and other important modifications, which determine its self-aggregating behavior and hence Alzheimer's pathogenesis.

Conclusions: In this revision, we observed a 3 edge-action in which glucose metabolism impairment is acting in the progression of AD: as blockade of energy source (e.g., mitochondrial dysfunction), through metabolic dysregulation and post-translational modifications in key proteins, such as tau. Therefore, the latter would sustain the current hypothesis that AD is, in fact, the novel diabetes type 3.