In recent decades incidences of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are rapidly increasing, becoming two major healthcare problems of aging that affect millions of people all over the world (Bellelli et al., 2025; Guzman-Martinez et al., 2021; Yu et al., 2025). The global estimates report that over 32 million people worldwide already suffer from AD (Gustavsson et al., 2023). It is estimated that there will be 315 million people with preclinical AD worldwide (Gustavsson et al., 2023). While the International Diabetes Federation estimated that about 589 million people (aged 20–79) were caught by diabetes in 2024 and beyond 853 million in 2050 (Genitsaridi et al., 2026). Over 90% of the 158.3 million elderly diabetic patients between the ages of 65 and 99 have type 2 diabetes, with the prevalence rate being highest among such individuals (Genitsaridi et al., 2026). It is expected that the incidence and prevalence of diabetes are predicted to keep rising globally, resulting in a significant burden on public health systems.

AD, the most common type of dementia, is characterized primarily by cognitive decline, loss of behavioral abilities and personality change (Wang et al., 2023). The primary pathogenesis of AD is an excessive accumulation of tau tangles and amyloid plaques, as well as increased inflammation, neuronal loss, and an elevated glial response (Wang et al., 2023). The symptoms of T2DM include hyperglycemia, hyperinsulinemia, and impaired insulin sensitivity (Roden and Shulman, 2019). Despite many factors bringing about T2DM, insulin resistance is a main etiology of T2DM (Roden and Shulman, 2019). Increased blood glucose levels and decreased blood flow to organs are caused by insulin resistance, which damages the heart, retina, blood vessels, and neurons (Roden and Shulman, 2019). Moreover, there is growing evidence that diabetes also damages the central nervous system, as evidenced by anomalies in the hippocampus, impaired neurotransmitters, impaired insulin signaling, cognitive dysfunction, and memory loss (Athanasaki et al., 2022).

Multiple studies have revealed that T2DM is regarded as one of the critical risk factors for Alzheimer's disease (Athanasaki et al., 2022; Jeong et al., 2025; Xu and Shi, 2025). Clinical and epidemiological studies have reported that patients with T2DM, both female and male, usually suffer a higher risk of cognitive impairment and dementia, indicating that diabetic patients are more susceptible to AD (Jeong et al., 2025; Raza et al., 2025; Xu and Shi, 2025; Xu et al., 2025). Besides, among individuals with diabetes 65 and older, the death rate from late-onset AD is increasing in the United States (Raza et al., 2025; Waqas et al., 2025). T2DM not only doubles the risk of AD, but AD has also been associated with a higher risk of T2DM (Xu and Shi, 2025). Approximately 80% of AD patients had impaired glucose metabolism or even T2DM (Janson et al., 2004; Xu and Shi, 2025). Notably, AD and T2DM share multiple molecular pathological mechanisms, including dysfunctional insulin signaling, impaired glucose metabolism, and chronic oxidative stress (Abdalla, 2024; Izuo et al., 2023; Xu and Shi, 2025; Xu et al., 2025). In particular, insulin resistance, high blood glucose, and long-term oxidative stress can all have a detrimental effect on brain health by causing excessive accumulation of tau tangles and amyloid plaques, as well as neurodegeneration and cognitive impairment (Abdalla, 2024; Xu and Shi, 2025; Xu et al., 2025).

Although the above epidemiological and experimental studies indicate a higher risk of AD among patients with T2DM (Jeong et al., 2025; Xu and Shi, 2025; Xu et al., 2025), the underlying detailed pathophysiological mechanisms between T2DM and AD still remain unknown. Both T2DM and AD are multifactorial diseases, caused by interactions of complex factors, and some similar etiologic contributing factors are engaged in their pathogenesis, including age, genes, neuroendocrine, metabolism, stressful environment, and psychological and social factors (Jeong et al., 2025). Notably, current research on preclinical models has shown evidence that the dysregulation of the galanin-GALR2 axis is a crucial factor in the development of both diseases and has been identified as a plausible molecular pathogenesis link between AD and T2DM (Zhang et al., 2015; Zhang et al., 2017b). In this review, we conducted literature searches in the PubMed and Web of Science databases. Articles published before 31 December 2025 were included in this review. The literature search was carried out using the search terms “diabetes”, “Alzheimer's disease”, “obesity”, “insulin resistance”, “cognitive”, “neuronal growth”, “neurotrophic”, “galanin”, “GALR2”, “spexin”, and “GALP” in different systematic combinations. During this systematic analysis, this article summarizes the results of our and other recent studies in human and animal models to provide a new insight into the multivariate relationship among galanin-GALR2, T2DM and AD, highlighting the beneficial effect of galanin/GALR2 signaling on the comorbid state of both diseases and explaining the underlying molecular mechanism in T2DM and AD pathogenesis. A better understanding of the regulation of galanin/GALR2 signaling under these pathological conditions, especially in the brain, might provide us with valid and innovative therapeutic options for both diseases.