**Background:** Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-amino acid hormone co-secreted with insulin from pancreatic β-cells. Under physiological conditions, hIAPP regulates gastric emptying, satiety, and insulin/glucagon secretion. However, in type 2 diabetes mellitus (T2DM), hIAPP aggregates into toxic oligomers and non-soluble fibrils that induce β-cell apoptosis, contributing to progressive β-cell loss and insulin resistance. Notably, hIAPP shares 25% amino acid sequence identity with amyloid-beta (Aβ), the hallmark protein of Alzheimer's disease (AD), and both peptides are degraded by the same enzymes (insulin-degrading enzyme IDE and neprilysin NEP). This structural and biochemical overlap has led to the hypothesis that hIAPP acts as a molecular link between T2DM and AD. The present narrative review aims to elucidate the mechanistic role of both pancreatic-derived and brain-derived hIAPP in the pathogenesis of T2DM and AD.
**Methods:** This is a narrative review synthesizing evidence from in vitro studies, animal models, human observational studies (case-control and cohort), and clinical trials. The authors discuss the physiological functions of hIAPP, its aggregation mechanisms, cytotoxic pathways, and the bidirectional interactions between hIAPP and Aβ/tau proteins. They also review the effects of anti-diabetic drugs (metformin, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists) on hIAPP aggregation and AD neuropathology. No systematic search strategy or inclusion/exclusion criteria are reported.
**Key Results:** The review reports that hIAPP aggregation is driven by several factors: the S20G mutation and F15 mutation increase toxic fibril formation; absence of proprotein convertase 2 enhances toxic oligomer generation; copper ions and heparin promote aggregation; zinc deficiency (documented in T2DM patients) reduces the lag-time for hIAPP aggregation. Cytotoxicity is mediated through oxidative stress, endoplasmic reticulum (ER) stress, aberrant Ca2+ release, and activation of calpain, leading to β-cell loss. The immune response involves toll-like receptor 2 (TLR2) activation, NF-κB expression, and IL-1β release; blocking IL-1β attenuates hIAPP-induced cytotoxicity. In AD, hIAPP deposits have been found in brain tissue, and hIAPP cross-seeds with Aβ to form hybrid amyloid fibrils. A longitudinal cohort study (up to 9 years) found that the risk of developing AD was 65% higher in T2DM patients versus non-diabetic controls. A community-based study reported that T2DM was present in 35% and glucose intolerance in 46% of AD patients, with up to 80% of AD patients having either condition. The incidence of dementia was 14.9% in diabetic subjects versus 10.3% in non-diabetic subjects (hazard ratio 1.62 for AD). Cerebrospinal fluid (CSF) hIAPP levels are elevated in AD patients with or without T2DM, and hIAPP colocalizes with pathological tau in AD brains. hIAPP binds tau and promotes its aggregation into a more toxic strain with increased seeding activity and neurotoxicity in vitro. Intra-hippocampal injection of IAPP-modified tau fibrils into tau transgenic mice induced more severe tau pathology and cognitive deficits. Regarding therapeutics, metformin and rosiglitazone reduced both the prevalence and severity of islet amyloid in hIAPP transgenic mice. A systematic review found that insulin sensitizers (metformin, TZDs) reduced Aβ pathology. DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin) and GLP-1 receptor agonists showed neuroprotective effects in AD models, reducing Aβ deposition, tau phosphorylation, and neuroinflammation.
**Clinical Implications:** The review suggests that hIAPP represents a promising therapeutic target for both T2DM and AD. Strategies to prevent hIAPP aggregation—such as restoring zinc homeostasis, enhancing chaperone-mediated autophagy (e.g., via Hsp70 activators), blocking IL-1β, and using copper chelating agents—may reduce β-cell toxicity and AD neuropathology. Anti-diabetic drugs that reduce secretory demand on β-cells (metformin, TZDs) or modulate incretin signaling (DPP-4 inhibitors, GLP-1 agonists) appear to attenuate hIAPP aggregation and may confer cognitive benefits. However, the authors caution that not all T2DM patients develop AD, and the precise mechanisms converting soluble hIAPP to toxic fibrils remain incompletely understood. They recommend retrospective and prospective studies to further elucidate the link between pancreatic hIAPP and AD neuropathology.