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Review
. 2025 Jul 24:17:1601602.
doi: 10.3389/fnagi.2025.1601602. eCollection 2025.

GLP-1R as a potential link between diabetes and Alzheimer's disease

Shujun Li #  1 , Nanqu Huang #  2   3 , Mei Wang  2   3 , Wendi Huang  2   3 , Jingshan Shi  1   4 , Yong Luo  2   3 , Juan Huang  1
Affiliations
Review

GLP-1R as a potential link between diabetes and Alzheimer's disease

Shujun Li et al. Front Aging Neurosci. .

Abstract

There is growing interest in the relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the glucagon-like peptide-1 receptor (GLP-1R) may be an important link between these two diseases. The role of GLP-1R in DM is principally to regulate glycemic control by stimulating insulin secretion, inhibiting glucagon secretion, and improving insulin signaling, thereby reducing blood glucose levels. In AD, GLP-1R attenuates the pathological features of AD through mechanisms such as anti-inflammatory effects, the reduction in amyloid-beta (Aβ) deposition, the promotion of Aβ clearance, and improvements in insulin signaling. Notably, AD and DM share numerous pathophysiological mechanisms, most notably the disruption of insulin signaling pathways in the brain. These findings further underscore the notion that GLP-1R plays pivotal roles in both diseases. Taken together, these findings lead us to conclude that GLP-1R not only plays an important role in the treatment of DM and AD but also may serve as a bridge between these two diseases. Future research should focus on elucidating the detailed molecular mechanisms underlying the actions of GLP-1R in both diseases and exploring the development of GLP-1R agonists with dual therapeutic benefits for AD and DM. This could pave the way for innovative integrated treatment strategies to improve outcomes for patients affected by these intertwined conditions.

Keywords: Alzheimer’s disease; diabetes mellitus; glucagon-like peptide-1 receptor; insulin resistance; neuroinflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Diagram illustrating the role of GLP-1 and GLP-1R in the brain, impacting amyloid precursor protein processing and Aβ plaque aggregation reduction. Shows tau protein transformation into neurofibrillary tangles, reduced by GLP-1R agonists. Highlights reduced ROS generation, mitochondrial protection, and microglia activation reduction, indicating a role in combating neuroinflammation and promoting GLP-1 secretion.
FIGURE 1
Simplified schematic of the four major pathological changes present in the brains of patients with AD and the role of GLP-1R. Multiple pathological changes, including Aβ deposition, tau protein hyperphosphorylation, neuroinflammation, and mitochondrial dysfunction, occur in the brains of patients with AD. GLP-1R activation plays significant modulatory roles in all these pathological mechanisms.
Diagram showing the GLP-1 and GLP-1R signaling pathway. GLP-1R activation influences cAMP, PI3K, and Ca2+/CaMKK2 pathways affecting insulin sensitivity and glucose metabolism. Key elements include PKA, AKT, AMPK, NF-κB, and BACE1, leading to outcomes like improved energy metabolism, reduced Aβ toxicity, decreased blood glucose, and enhanced neuronal survival. Pathways also involve SIRT1 and PGC1α improving insulin resistance and reducing neuroinflammation. Activation and inhibition are marked with arrows, indicating up-regulation or down-regulation effects. A mitochondrion is shown with ROS indicated.
FIGURE 2
Schematic representation of signaling pathways common to AD and DM induced by GLP-1R agonism. These include AMPK, PI3K/AKT, CaMKK2-AMPK, NF-κB, insulin/IGF-1 R and the mitochondrial signaling pathway.
See this image and copyright information in PMC

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