NFκB1: A Common Biomarker Linking Alzheimer's and Parkinson's Disease Pathology

Adam Cunningham¹Emma Barrett¹Sebastian Risch¹Peter Lee²Chan Lee³Abhay Moghekar⁴Prabir Patra¹Joon W Shim^1*

• ¹Marshall University, Huntington, United States
• ²Brown University, Providence, Rhode Island, United States
• ³Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ⁴Johns Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, United States

Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders marked by mitochondrial dysfunction and chronic inflammation. The transcription factor NF-κB1 plays a dual role-promoting neuroprotection or neuroinflammation depending on its activity in neurons versus glial cells. While our previous work examined genetic and epigenetic contributions to these polygenic diseases, the infection hypothesis is gaining renewed interest as a framework for identifying disease biomarkers. In this study, we performed bulk RNA sequencing on human postmortem caudate nucleus samples from controls (n=5), AD patients (n=6), and PD patients (n=3). TNFα signaling via NF-κB emerged as a key dysregulated pathway. Elevated levels of transcription factors NFE2L2 (NRF2) and NF-κB1 were associated with reduced SLC25A6 expression, suggesting a compensatory response to oxidative stress. Increased PLCG2 expression in microglia indicated enhanced immune signaling and inflammation. Notably, we observed a 10-fold reduction in hemoglobin subunit alpha (HbA1) RNA in both AD and PD samples, pointing to impaired oxygen transport and heightened cellular stress. These findings identify candidate biomarkers and suggest therapeutic strategies targeting inflammation and mitochondrial function in AD and PD.