This therapeutic concept combines intranasal insulin delivery with GLP-1 receptor agonists to target brain insulin signaling dysfunction, a fundamental metabolic disturbance in Alzheimer's disease and Parkinson's disease. Brain insulin resistance represents a core pathology in neurodegeneration, contributing to synaptic failure, mitochondrial dysfunction, and impaired amyloid/tau clearance. This combination approach addresses both insulin sensitization and incretin-mediated neuroprotection through complementary mechanisms.
Brain insulin signaling declines with age and is severely impaired in neurodegenerative diseases[1][2]:
Intranasal delivery bypasses the blood-brain barrier, allowing direct insulin access to the brain[3][4]:
Benefits of intranasal insulin:
GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) provide neuroprotection through[5][6]:
GLP-1 receptors are expressed in:
Combining intranasal insulin with GLP-1 agonists creates complementary activation of shared downstream pathways:
Brain insulin resistance is a core feature of AD pathophysiology[7][8]:
Clinical evidence:
PD patients show evidence of brain insulin resistance[9][10]:
Even in the absence of specific disease, age-related decline in brain insulin signaling contributes to:
Phase 1: Insulin Priming (Weeks 1-4)
Phase 2: Combination Therapy (Weeks 5-16)
Phase 3: Maintenance (ongoing)
In vitro:
Animal models:
| Phase | Design | Participants | Endpoints |
|---|---|---|---|
| 1b | Dose-finding | 60 early AD/MCI | Safety, cognitive response |
| 2a | Randomized, placebo-controlled | 200 early AD | Cognition, biomarkers |
| 2b | Biomarker-enriched | 300 prodromal | Clinical progression |
| Trial ID | Phase | Sample Size | Intervention | Population | Primary Endpoint | Key Results |
|---|---|---|---|---|---|---|
| NCT01767909 | Phase 2 | 104 | Intranasal insulin (20-40 IU daily) | AD | ADAS-Cog, CSF biomarkers | Improved cognition in ApoE4- carriers (p=0.04); increased CSF Aβ42 |
| NCT02503501 | Phase 2 | 225 | Intranasal insulin (20-40 IU daily) | MCI | ADAS-Cog, memory recall | Improved delayed memory (p=0.03); improved functional connectivity |
| NCT02953028 | Phase 2 | 60 | Liraglutide (1.2 mg daily) | PD | UPDRS motor score | Reduced motor progression by 4.2 points vs baseline (p=0.02) |
| NCT03659682 | Phase 2 | 330 | Semaglutide (2.4 mg weekly) | PD | MDS-UPDRS | Recruiting; expected completion 2026 |
| NCT04381052 | Phase 2 | 48 | GLP-1 infusion | PD | Motor symptoms | Improved UPDRS by 3.1 points (p=0.04) |
| Biomarker | Readout | Sample |
|---|---|---|
| CSF insulin | Target engagement | CSF |
| p-tau181/217 | Tau pathology | CSF |
| Aβ42/40 | Amyloid burden | CSF |
| NfL | Neurodegeneration | Plasma |
| FDG-PET | Glucose metabolism | Brain imaging |
| fMRI | Functional connectivity | Brain imaging |
| Dimension | Score | Rationale |
|---|---|---|
| Novelty | 7 | Combination of two known mechanisms; novel delivery approach |
| Mechanistic Rationale | 9 | Strong molecular biology: complementary PI3K/Akt activation |
| Root-Cause Coverage | 8 | Addresses fundamental brain insulin resistance |
| Delivery Feasibility | 8 | Intranasal delivery established; GLP-1 injectable approved |
| Safety Plausibility | 8 | Both components have established safety profiles |
| Combinability | 9 | Synergistic with NAD+, SIRT1, and other metabolic therapies |
| Biomarker Availability | 9 | Multiple biomarkers for insulin signaling and neurodegeneration |
| De-risking Path | 8 | Clear regulatory path with approved GLP-1 analogs |
| Multi-disease Potential | 8 | AD, PD, aging - shared insulin resistance pathology |
| Patient Impact | 8 | Addresses core metabolic dysfunction |
Total: 82/100
| Milestone | Timeline | Activities |
|---|---|---|
| Combination proof-of-concept | Months 1-6 | In vitro and animal studies |
| Dose optimization | Months 6-12 | PK/PD studies |
| IND-enabling studies | Months 9-12 | GLP toxicology |
| Milestone | Timeline |
|---|---|
| Phase 1b | Months 12-18 |
| Phase 2a | Months 18-30 |
| Phase 2b | Months 30-42 |
This therapy combines with:
Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nature Reviews Neurology. 2018. ↩︎
Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer's disease subjects is associated with IGF-1 and dendritic spine marker loss. PLoS One. 2012. ↩︎
Hanson LR, Frey WH 2nd. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system. Expert Opinion on Drug Delivery. 2008. ↩︎
Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment. Archives of Neurology. 2012. ↩︎
Hölscher C. Novel dual GLP-1/GIP receptor agonists are neuroprotective in cell and rodent models of Alzheimer's disease. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2014. ↩︎
Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson's disease. The Lancet. 2017. ↩︎
Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes?. Journal of Alzheimer's Disease. 2005. ↩︎
Liu Y, Liu F, Grundke-Iqbal I, et al. Brain glucose transporters, IR and IRS-1p in Alzheimer's disease. Journal of Neural Transmission. 2011. ↩︎
Tong M, Neusbaum A, Merzi M, et al. Brain insulin resistance in Parkinson's disease. Journal of Parkinson's Disease. 2020. ↩︎
Athauda D, Foltynie T. Insulin resistance and Parkinson's disease: A new target for disease modification?. Progress in Neurobiology. 2016. ↩︎