Bridging pathologies: Mechanistic insights into the diabetes-Alzheimer's nexus.

Mar 16, 2026EXCLI journal

Understanding the biological links between diabetes and Alzheimer's disease

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Abstract

Type 2 diabetes mellitus (T2DM) is associated with multiple biological links to Alzheimer's disease (AD).

Key overlapping pathways include impaired insulin signaling and chronic inflammation.
Oxidative stress and mitochondrial dysfunction are noted in both conditions.
Amyloid-beta accumulation and tau hyperphosphorylation may contribute to neurodegeneration.
Disruption of insulin signaling in the brain could lead to synaptic loss.
Antidiabetic treatments targeting the gut-brain axis may influence AD progression.
Challenges exist in translating mechanistic knowledge into effective therapies.

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Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for Alzheimer's disease (AD), with mounting evidence highlighting shared pathophysiological mechanisms. This review explores the intricate biological and molecular links between these two chronic disorders. Key overlapping pathways include impaired insulin signaling, chronic inflammation, oxidative stress, mitochondrial dysfunction, amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and the formation of advanced glycation end-products (AGEs). Disruption of insulin signaling in the brain contributes to synaptic loss and neurodegeneration, while systemic metabolic disturbances aggravate blood-brain barrier dysfunction and neurovascular damage. Emerging studies also underscore the role of antidiabetic treatments, especially newer agents targeting the gut-brain axis, in modulating AD progression. The review further examines preclinical models, clinical observations, and the development of biomarkers to improve early detection and intervention. Despite growing insights, challenges remain in translating mechanistic knowledge into effective therapies. A multidisciplinary approach integrating metabolic control and neuroprotective strategies is essential for addressing the comorbid burden of T2DM and AD. See also the graphical abstract(Fig. 1).

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Bridging pathologies: Mechanistic insights into the diabetes-Alzheimer's nexus.

Abstract

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