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Peer-reviewedCC BY 4.0CNS Spectrums

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

  • Serene Lee1
  • Esha Purewal2
  • Natalie Rasgon3
  • Angela Kwan4
  • Christine E. Dri1
  • Roger Ho5
  • Roger S. McIntyre6
6 affiliations
  1. 1Brain and Cognition Discovery Foundation, Canada
  2. 2Queen’s University, Canada
  3. 3Stanford University, USA
  4. 4Brain and Cognition Discovery Foundation, University Health Network, Canada
  5. 5National University of Singapore Yong Loo Lin School of Medicine, Singapore
  6. 6Department of Psychiatry, University of Toronto, Canada
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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.

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Cite

BibTeXRIS
BibTeX
@article{lee2026differences,
  title = {{Sex differences in glucagon-like peptide-1 signalling and the implications for Alzheimer’s disease: A narrative review}},
  author = {Serene Lee and Esha Purewal and Natalie Rasgon and Angela Kwan and Christine E. Dri and Roger Ho and Roger S. McIntyre},
  journal = {CNS Spectrums},
  year = {2026},
  month = oct,
  doi = {10.1017/s1092852926101291},
  url = {https://doi.org/10.1017/s1092852926101291},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Sex differences in glucagon-like peptide-1 signalling and the implications for Alzheimer’s disease: A narrative review
AU  - Serene Lee
AU  - Esha Purewal
AU  - Natalie Rasgon
AU  - Angela Kwan
AU  - Christine E. Dri
AU  - Roger Ho
AU  - Roger S. McIntyre
PY  - 2026
DA  - 2026/10/29
JO  - CNS Spectrums
DO  - 10.1017/s1092852926101291
UR  - https://doi.org/10.1017/s1092852926101291
AB  - 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.
SN  - 1092-8529
SN  - 2165-6509
ER  -