Sex differences in glucagon-like peptide-1 signalling and the implications for Alzheimer’s disease: A narrative review

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia. Women are differentially affected by AD, and several sex-specific mechanisms have been explored, including hormonal differences (eg, estrogen). Glucagon-like peptide-1 (GLP-1R) are located in brain regions implicated in the pathogenesis of AD and shows preliminary evidence of modulating sex-specific pathways that may underlie differential disease risk and progression. Herein, we synthesize the extant literature on the mechanisms of GLP-1 in neurobiological systems relevant to AD pathology. Metabolic signalling (eg, GLP-1, insulin) intersects with known sex-specific pathways hypothesized to subserve AD progression in women. The preceding effects may be attributable to the disruption of estrogen signalling during the postmenopausal period, which impairs hippocampal insulin receptor function and exacerbates mitochondrial dysfunction. In addition, these mechanisms provide an explanation for AD comorbidities (eg, type 2 diabetes mellitus [T2DM]). The multidimensional effects demonstrated in GLP-1 paradigms provide a compelling rationale for further investigation of the role of metabolic signalling on sex-specific alterations in AD. Evidence across preclinical and early clinical studies suggests that GLP-1RAs may differentially influence neurobiological pathways implicated in AD pathogenesis, particularly those that interact with hormonal and metabolic systems.