Examining Effects of New Drugs for Alzheimer’s Disease

What biomedical issue did you address in your research, and what did your studies find?

My work focused on the role the immune system plays in Alzheimer's disease and how it can be harnessed for treatments. The newest and most promising class of drugs, anti-amyloid immunotherapies, reduce brain levels of amyloid-beta protein, which is thought to be an initiator of Alzheimer's disease.

In a preclinical model, I studied the effects of aducanumab, the first FDA-approved anti-amyloid immunotherapy, on microglia, the immune cells of the brain. I was interested in the effects during and after discontinuation of treatment. Not all patients will stay on immunotherapies, so researching the effects of the drug is crucial. My studies used a combination of classical molecular biology and immunology techniques, histology and next-generation RNA sequencing (bulk RNAseq and single-cell RNAseq) to produce a detailed picture of microglial and immune response to immunotherapy, amyloid levels and neuronal damage.

I found that aducanumab engages microglia and the immune system in a concerted program that likely aids in amyloid clearance. Microglia are recruited to amyloid plaques, where they can form a physical barrier to limit the spread of the toxic amyloid and neuronal damage. They may also reduce amyloid levels by phagocytosing, or "eating" the plaques.

While these findings were important and exciting, the effects of aducanumab withdrawal were even more surprising. We found that after cessation of treatment, the effect of aducanumab on microglia reverses, making the cells less responsive to increasing levels of amyloid. The findings suggest that, despite early benefits, discontinuation of the drug may impair long-term microglia response in the brain. The lab will continue to investigate the effects of aducanumab and other similar drugs.

How did Mayo's culture and approach to training help you grow as a scientist and as a thinker?

The graduate school funds student stipends, which provide students the opportunity to join any lab that interests them. I was very fortunate to join the lab of Dr. Fryer, who is both an excellent scientist and mentor. He encourages his trainees to think rigorously and creatively about scientific problems that are interesting to them. In his lab, I was granted a degree of freedom and independence that I think is unusual for most mentors to provide. I had the opportunity to conceptualize and propose projects, all while receiving valuable feedback from him, my thesis committee and other faculty in the Neuroscience department.

What's next?

My next step will be a postdoctoral fellowship at Weill Cornell Medicine at Cornell University, focusing on neuroimmunology in neurodegenerative disease. My long-term goal is to join the faculty at an academic institution and establish my own research lab.