Treatment‐Induced Epigenetic Modifications in MCI and Probable Alzheimer’s Disease

• Published in: Alzheimer's & dementia Vol. 19; no. S12
• Main Authors: Reading, Christopher Lewis, Gordevicius, Juozas, Haroon, Jonathan, Jordan, Kaya, Rindner, Elisabeth, Ahlem, Clarence N, Mahdavi, Kennedy D, Surya, Rama, Venkatraman, Victoria, Yuan, Harvey, Becerra, Sergio A, Pourat, Bijan, Kuhn, Taylor P, Palumbo, Joseph, Brooke, Robert, Jordan, Sheldon E
• Format: Journal Article
• Language: English
• Published: 01.12.2023
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.071981

Background NE3107 is an oral small molecule, blood‐brain permeable anti‐inflammatory insulin sensitizer that binds ERK, inhibits inflammatory NFkB and TNF signaling in macrophage lineage cells, and in clinical studies for AD (NCT04669028) and Parkinson’s disease (NCT05083260). NE3107 does not inhibit homeostatic activity of ERK or NFkB, and has a good safety profile in preclinical, non‐clinical and clinical studies. Safety, clinical, biomarker and neuroimaging results from a 3‐month open‐label phase 2 study of NE3107 treatment of mild dementia (NCT05007820) were reported at CTAD 2022. We report here results of epigenetic clock studies from NCT05007820. Method Subjects with CDR 0.5‐1 were consented, and blood was drawn, frozen and shipped for Horvath Clock DNA methylation (DNAm) epigenetic analysis (Horvath 2018 Aging 10:1758) at baseline and 3 months. Result The subject’s DNAmSkinBloodAge clock closely matched their chronologic age at baseline (+0.7 years). After 3 months of NE3107 (20 mg BID), the DNAmSkinBloodAge decreased (‐3.3 years, Table). Leptin is lower in AD, and DNAmLeptin is positively correlated with metabolic parameters waist/hip ratio, BMI, CRP, insulin, glucose and triglycerides (Lu 2022 Aging 14:9884). Dinucleotide (CpG) methylation in association with the leptin promotor (DNAmLeptin) decreased in all subjects (‐40%). DNAmPackYears is reported to be negatively correlated with time to mortality in both smokers and nonsmokers, and positively correlated with waist/hip ratio, CRP and triglycerides. DNAmPackYears also decreased (‐39%). Baseline DNAmMonocyte correlated with monocyte frequency but decreased (‐29%) after 3 months treatment without change in monocyte frequency. There were no significant changes in DNAmTcell, DNAmNK or DNAmGran. Conclusion NE3107 treatment significantly decreased biological age compared to chronological age and altered epigenetic measures correlating with metabolic parameters known to be associated with cognitive decline. DNAm decreases in monocyte/macrophage are associated with proinflammatory pathways in many disease states but aging epigenetic clocks may select for CpG methylation associated with inhibition of anti‐inflammatory pathways. NE3107 decreases in DNAmMonocyte, DNAmSkinBloodAge, DNAmLeptin and DNAmPackYears in MCI and AD subjects were associated with cognitive, biomarker and neuroimaging improvements. The data suggests that NE3107 may decrease methylation in promoters of monocyte/macrophage pathway regulators that can decrease inflammation and restore metabolic homeostasis in subjects with dementia.