Caghan Kizil, PhD

Catalyst CURE ONE, CURE MANY AWARD IN Neuroinflammation

Resilience-by-Design: Targeting Fibronectin-Induced Neuroinflammation in APOE–ε4–Driven Alzheimer’s Disease 

Institution: Columbia University Medical Center, New York, NY 

Co-Principal Investigators and Institutions: Badri Vardarajan, PhD and Richard Mayeux, MD, Columbia University

Around 40% of Alzheimer’s disease patients carry one or more copies of the APOE-ε4 allele, or a variant of the APOE gene. This gene variant is the strongest genetic risk factor for late-onset Alzheimer’s. Individuals who carry the APOE-ε4 allele are often excluded from current monoclonal antibody therapies because they are susceptible to associated risks of brain swelling and hemorrhage. This high-risk population urgently needs tailored, safer interventions.  

Fibronectin is a protein that accumulates in the brain and typically causes neuroinflammation. However, a rare variant in FN1, the gene that provides instructions for making fibronectin, protects APOE-ε4 allele carriers by helping to clear out toxic protein accumulations. This helps prevent inflammatory damage and its consequences at the blood–brain barrier, the protective layer that prevents harmful bloodborne pathogens from entering the brain. In this way, the variant FN1 gene helps to reduce Alzheimer’s risk. Building on this natural resilience, the team will develop a first-in-class precision therapy that targets fibronectin accumulation and subsequent neuroinflammation at its source before irreversible damage and cognitive decline occur. This therapy could offer safer, genetically informed, and personalized treatment options for patients. 

This $500,000 Catalyst award is funded in collaboration with the National MS Society, Gates Ventures, NFL Players Association, Genentech, and WoodNext Foundation.