Can GLP-1 drugs slow neurodegeneration? New review finds promising signals but limited clinical proof

Emerging evidence suggests widely used metabolic drugs could influence brain aging pathways, yet large clinical trials are still needed to confirm whether they truly alter the course of neurodegenerative disease.

Study: The promise of GLP-1 receptor agonists for neurodegenerative diseases. Image Credit: Antonio Marca / Shutterstock

In a recent review published in the Journal of Clinical Investigation, the authors examined the biological mechanisms, translational evidence, and clinical potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as disease-modifying therapies for neurodegenerative diseases (NDDs).

Background

By 2040, NDDs are projected to become the second leading cause of death worldwide, based on epidemiological modelling projections. Rates of Alzheimer’s disease, Parkinson’s disease, and related conditions have increased in the aging global population, yet only a limited number of pharmacological treatments can modify disease course. Diabetes mellitus is associated with increased risk of developing these disorders, highlighting links between metabolism and neurodegeneration. Drugs originally designed for diabetes target several of these pathways simultaneously. Determining whether they can protect the brain requires rigorous, biomarker-driven research.

What Is Brain Insulin Resistance?

NDDs such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis differ clinically but share overlapping biological hallmarks to varying degrees. Key molecular processes linking several of these conditions include brain insulin resistance, mitochondrial dysfunction, inflammation, and toxic protein accumulation, although the relative contributions of these pathways vary across disorders.

Brain insulin resistance is a central mechanism connecting these processes. In a healthy brain, insulin regulates synaptic plasticity, mitochondrial function, and neuronal survival. When insulin signaling is disrupted by alterations in phosphoinositide 3-kinase/protein kinase B signaling, neurons lose the ability to use glucose efficiently. This contributes to tau hyperphosphorylation, amyloid-beta accumulation, alpha-synuclein aggregation, and microglial activation. Clinically, these processes manifest as progressive cognitive and motor decline.

GLP-1RAs, widely used for type 2 diabetes mellitus and obesity, activate pathways that overlap with insulin signaling. By restoring metabolic balance, they may interrupt the cycle linking insulin resistance and neurodegeneration, leading some researchers to describe these agents as partial pharmacological mimics of exercise-related metabolic signaling.

Restoring Mitochondrial Function and Cellular Energy

Mitochondria generate cellular energy, but dysfunction occurs early in many NDDs. Impaired mitochondria produce less adenosine triphosphate and excessive reactive oxygen species, contributing to neuronal injury over time. Imaging studies using fluorodeoxyglucose positron emission tomography suggest that some treated patients maintain cerebral glucose metabolism longer. These metabolic improvements provide a biological rationale for therapeutic potential; however, whether these effects reflect direct brain penetration or systemic metabolic changes remains uncertain, and consistent cognitive benefits have not been established.

Reducing Protein Aggregation and Enhancing Autophagy

Improperly folded proteins characterize many NDDs. Amyloid-beta and tau accumulation are hallmarks of Alzheimer’s disease. Alpha-synuclein aggregates contribute to Parkinson’s disease and multiple system atrophy. Mutant huntingtin drives Huntington’s disease, and TAR DNA-binding protein 43 accumulation is implicated in amyotrophic lateral sclerosis.

Activation of the glucagon-like peptide-1 receptor stimulates cyclic adenosine monophosphate/protein kinase A and phosphoinositide 3-kinase/protein kinase B pathways, enhancing autophagy and proteostasis. Preclinical studies show reduced toxic protein burden and preserved neuronal integrity, although definitive disease-modifying effects in humans remain unproven.

Because protein accumulation begins years before symptom onset, earlier intervention could theoretically delay disability.

Controlling Neuroinflammation

Chronic neuroinflammation accelerates neurodegeneration. Activated microglia release tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6, perpetuating tissue injury.

GLP-1RAs inhibit NOD-like receptor family pyrin domain-containing 3 inflammasome activity and suppress nuclear factor kappa B signaling. They promote anti-inflammatory immune phenotypes and reduce oxidative stress. Benefits have been observed in experimental models of multiple sclerosis, though consistent clinical translation has not yet been demonstrated.

Given the increasing recognition of inflammation’s role in aging and chronic disease, immunomodulatory therapies remain of interest.

Protecting Synapses and Neural Networks

Synaptic dysfunction often precedes neuronal death. Impaired long-term potentiation disrupts learning and memory before structural brain changes become apparent. GLP-1RAs increase brain-derived neurotrophic factor, stabilize dendritic spines, and enhance synaptic resilience via cyclic adenosine monophosphate/protein kinase A/cAMP response element-binding protein signaling. Restoration of suppressed long-term potentiation has been demonstrated primarily in preclinical models.

Preserving synaptic integrity may help maintain daily functioning for longer periods.

The Gut-Immune-Brain Axis

Dysbiosis of gut microbiota has been associated with neurodegeneration. Increased intestinal permeability and blood-brain barrier disruption may allow inflammatory signaling to influence the central nervous system.

GLP-1RA treatment has been associated with improved epithelial barrier function, reduced lipopolysaccharide-driven inflammation, and increased beneficial microbial taxa, largely in experimental or associative studies rather than definitive clinical trials. GLP-1RAs may also help stabilize the blood-brain barrier, potentially limiting harmful gut-brain interactions.

Clinical Evidence Across Disorders

In Alzheimer’s disease, small trials suggest preserved cerebral glucose metabolism and slower cortical atrophy, although cognitive outcomes remain mixed. Large phase III trials of semaglutide are ongoing. In Parkinson’s disease, early studies of exenatide suggested motor benefit, but a recent phase III trial reported negative clinical findings. A phase II trial of lixisenatide suggested modest slowing of motor progression.

Observational studies report a lower incidence of dementia and Parkinson’s disease among long-term GLP-1RA users, although causality is not established. Evidence in multiple system atrophy, amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis remains limited and inconsistent, with generally modest effect sizes where observed.

Conclusion

GLP-1RAs demonstrate broad neuroprotective potential across mechanistic, preclinical, and early clinical domains. By targeting insulin resistance, mitochondrial dysfunction, inflammation, and protein aggregation simultaneously, they address biological drivers shared among NDDs. Mechanistic and early clinical evidence is strongest in Alzheimer’s disease and Parkinson’s disease, but findings remain inconclusive. Interpretation is complicated by variability in central nervous system penetration, patient selection, outcome measures, tolerability, adherence, and potential effects on body weight and frailty in older adults.

Carefully designed, biomarker-guided trials in earlier disease stages are required to determine whether these therapies meaningfully alter long-term neuropathology and functional outcomes, particularly given the heterogeneity of neurodegenerative disorders.