Role of glucagon-like peptide-1 receptor agonists in Alzheimer's disease and Parkinson's disease

Abstract

Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common complications of diabetes, arising from insulin resistance, inflammation, and other pathological processes in the central nervous system. The potential of numerous antidiabetic agents to modify neurodegenerative disease progression, both preclinically and clinically, has been assessed. These agents may provide additional therapeutic benefits beyond glycemic control. Introduced in the twenty-first century, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of antidiabetic drugs noted not only for their potent glucose-lowering effects but also for their cardiovascular and renal protective benefits. Various GLP-1RAs have been demonstrated to have significant benefits in in vitro and in vivo models of neurodegenerative diseases through modulating a variety of pathogenic mechanisms, including neuroinflammation, autophagy, mitochondrial dysfunction, and the abnormal phosphorylation of pathognomonic proteins. These agents also have substantial protective effects on cognitive and behavioral functions, such as motor function. However, clinical trials investigating GLP-1RAs in diseases such as AD, PD, mild cognitive impairment, psychiatric disorders, and diabetes have yielded mixed results for cognitive and motor function. This review examines the link between diabetes and neurodegenerative diseases, explores the effects of antidiabetic agents on neurodegeneration, provides a concise overview of the GLP-1 pathway, and discusses both preclinical and clinical trial outcomes of GLP-1RAs for neurodegenerative diseases, including their effects on cognition in AD and PD. This review also proposed new strategies for the design of future clinical trials on GLP-1 RAs for both AD and PD.

Keywords: Alzheimer’s disease; Cognition; Diabetes; Glucagon-like peptide-1 receptor agonists; Neurodegenerative diseases; Neuroprotection; Parkinson’s disease.

Fig. 1

The postulated mechanism by which diabetes contributes to neurodegeneration in Alzheimer’s disease (AD) and Parkinson’s disease (PD) may involve the accumulation of advanced glycation end products (AGE) and cellular insulin resistance (IR). For the target organ, brain, these two phenomenon lead to inflammation, vascular occlusion, oxidative stress, and the aggregation of pathognomonic proteins, which, in turn, trigger neurodegeneration in the cerebral cortex for dementia, such as AD and vascular dementia (VaD), and the substantia nigra for parkinsonism, such as PD and vascular parkinsonism (VaP)

Fig. 2

This figure illustrates the neuroprotective mechanisms of GLP-1 receptor agonists (GLP-1RAs) in neurons and microglia, highlighting the key molecular pathways involved in neurodegeneration and inflammation. In neurons, the binding of GLP-1 to its receptor (GLP-1R) activates the cyclic AMP (cAMP) and protein kinase A (PKA) signaling pathway, which in turn activates PI3K/Akt signaling. This activation leads to the downstream phosphorylation and inhibition of GSK-3β, reducing tau phosphorylation—a critical event in neurodegenerative diseases such as Alzheimer’s disease. Additionally, Akt activation promotes mitochondrial biogenesis by upregulating transcription factors such as Tfam, PGC-1α, and NRF-1, leading to enhanced energy production and reduced oxidative stress. The Akt/CREB pathway also activates Bcl-2 family proteins, inhibiting apoptosis by preventing cytochrome c release. Overall, these signaling events protect neurons from oxidative stress and apoptosis, which are central to neurodegeneration. In microglia, GLP-1R activation via PI3K/Akt signaling also reduces neuroinflammation by modulating NF-κB activity. This pathway decreases the production of pro-inflammatory cytokines, including IL-1β, TNF-α, and NLRP3, and increases anti-inflammatory markers such as IL-10, IL-4, arginase, and CD206. This shift in cytokine balance promotes the transformation of microglia into an anti-inflammatory state, which is neuroprotective, reducing overall inflammation and damage in the brain. The figure highlights the dual role of GLP-1RAs in reducing neurodegeneration by improving neuronal survival and modulating microglial activity, providing a potential therapeutic approach for neurodegenerative diseases such as AD and PD. AGE advanced glycation end products, Akt protein kinase B, Bax Bcl-2 associated X protein, Bcl-2 B-cell lymphoma 2, cAMP cyclic adenosine monophosphate, CREB cAMP response element-binding protein, GSK-3β glycogen synthase kinase-3 beta, IL-1β interleukin 1 beta, IL-4 interleukin 4, IL-10 interleukin 10, IRS insulin receptor substrate, IR insulin resistance, mTOR mammalian target of rapamycin, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3 NOD-, LRR-, and pyrin domain-containing protein 3, NRF-1 nuclear respiratory factor 1, PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PI3K phosphatidylinositol 3-kinase, PKA protein kinase A, Tfam mitochondrial transcription factor A, TNF-α tumor necrosis factor alpha