Cross-seeding of IAPP and Aβ42: A review of the molecular link between type 2 diabetes and Alzheimer’s disease

Alzheimer’s Disease (AD) and Type 2 Diabetes Mellitus (T2DM) are interconnected conditions, both marked by the aggregation of amyloidogenic proteins: amyloid-β 42 (Aβ42) in AD and islet amyloid polypeptide (IAPP) in T2DM. Emerging evidence suggests that IAPP can cross the blood–brain barrier and interact with Aβ42, forming heterocomplexes that promote aggregation. This narrative review aims to describe the molecular mechanisms underlying IAPP and Aβ42 cross-seeding and evaluate its contribution to AD pathogenesis in the context of T2DM. A systematic search of PubMed was conducted using relevant MeSH terms. IAPP-Aβ42 cross-seeding enhances amyloid aggregation and cytotoxicity, but its impact on AD progression is best understood as part of a multifactorial process rather than a single driving cause. While preclinical models suggest amyloid-targeting approaches can reduce amyloid burden, clinical trials have largely failed to show cognitive benefits, likely due to late-stage intervention and the complex pathology of AD. Future research should focus on identifying early biomarkers for AD, clarifying IAPP-Aβ42 cross-seeding mechanisms, and exploring combination therapies targeting multiple pathological pathways. Early intervention may improve treatment efficacy, particularly in patients with comorbid T2DM.