Jie Shen is Professor of Neurology at Harvard Medical School. She received her Ph.D. in molecular biology from the University of Virginia in 1995 studying the mechanisms of alternative splicing in Drosophila. As a postdoctoral fellow at MIT, she began the investigation of the molecular basis of Alzheimer’s disease (AD) using mouse genetic approaches. Since 1998, she has directed a molecular neurobiology laboratory focusing on the elucidation of pathogenic mechanisms of AD and Parkinson’s disease (PD). Their earlier genetic findings led to the proposal of the presenilin hypothesis in 2006, which posited that loss of presenilin function underlies neurodegeneration and dementia in familial AD. They also predicted correctly that inhibition of g-secretase would make AD patients worse. Subsequent studies in cell culture, in vitro biochemical systems, knockin mice from her lab and others further substantiated the presenilin hypothesis and demonstrated that PSEN mutations are loss of function mutations, impairing g-secretase activity, learning and memory, synaptic function, and neuronal survival. Their recent preclinical testing in mice provided proof-of-concept data in support of presenilin-based gene therapy for familial AD carrying PSEN mutations. Their latest genetic modifier screen in Drosophila uncovered that genes involved in lipid homeostasis interact with Psn and are potent modulators of neurodegeneration in the aging brain. They continue using multidisciplinary approaches to elucidate molecular and cellular mechanisms underlying cortical neurodegeneration in hope to develop novel therapies to combat dementia in AD.