Clinicn Investigator, Instruct Neurology, Mass General Research Institute

Instructor in Neurology Harvard Medical School

Assistant In Neurology Massachusetts General Hospital

MD Harvard Medical School 2015

PhD 2013

alzheimer's disease; cell culture; endosomes; fluorescence confocal microscopy; neurons derived from human induced pluripotent stem cells; neuropathology; tau proteins; tauopathies I am a physician-scientist specializing in dementia, with a special interest in Alzheimer’s disease and related disorders (ADRD). My approach to investigation spans basic, translational, and clinically oriented research, all aimed at ultimately improving the diagnosis and treatment of ADRD. My main research project focuses on studying how modifications of the tau protein influence its spread in Alzheimer’s disease. The cell-to-cell propagation of tau across connected brain regions is thought to explain the stereotyped spreading of tau in Alzheimer’s disease. My research examines the influence of Alzheimer’s disease-associated tau post-translational modifications, such as phosphorylation or acetylation, on this process. I have investigated this question using genetically encoded mimics of post-translational modifications in cell-based assays with immortalized cells and induced-pluripotent stem cell (iPSC)-derived neurons. The results of these experiments have indicated that Alzheimer’s disease-associated tau post-translational modifications tend to decrease the cell-to-cell propagation of tau, likely due to reduced uptake of the modified tau by recipient cells. The modified tau has a reduced affinity for the tau uptake receptor LRP1, which may explain the reduced tau uptake. These findings may explain why certain phospho-tau species used as Alzheimer’s disease biomarkers are elevated in CSF and plasma. Ongoing experiments in the lab focus on how these modifications influence the movement of tau along the endolysosomal pathway in recipient cells, how these modifications influence the escape of tau from the endolysosomal pathway into the cytoplasm, and how these modifications influence the seeding of aggregate formation in the cytoplasm. Improved understanding of these aspects of Alzheimer’s disease pathophysiology may help identify therapeutic targets that could slow or halt disease progression. Another project focuses on understanding the pattern of tau spreading in an atypical variant of Alzheimer’s disease called posterior cortical atrophy. In this condition, tau spreads through the brain as the disease progresses, but in a different pattern than that seen in typical Alzheimer’s disease. This project uses immunohistochemistry to examine the neuropathological burden of tau aggregates in different brain regions in different stages of posterior cortical atrophy. I am also engaged in clinically oriented research related to anti-amyloid therapy for Alzheimer’s disease (e.g. lecanemab and donanemab). This includes a project to describe the initial clinical experience in the development of a novel clinical program to manage these medications, as well as a project looking at clinical outcomes in patients treated with these medications.