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Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases amongst the aged population. The disease is multifactorial, and diabetes has been considered as one of the major risk factors for the development of AD. Chronic hyperglycemic condition in diabetes promotes non-enzymatic protein modification by glucose termed as glycation, which affects protein structure and function. Previous studies have shown that many of the enzymes, including proteases, are affected by glycation. Conversely, glycated proteins are known to become resistant to protease action. In these hypotheses, we have extended these two concepts to the regulation of amyloid-β protein precursor (AβPP) by secretases leading to amyloid-β (Aβ) accumulation. The first hypothesis deals with the glycation of α-secretases leading to its reduced activity, while in the second hypothesis, AβPP glycation may prevent α-secretases action, rendering its processing by β secretase. As diabetes is a risk factor for the development of AD, either or both these pathways may operate, leading to the manifestation of AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)