Abstract The repressor element 1-silencing transcription factor/neuron-restrictive silencer factor, (REST/NRSF), a transcriptional regulator of neuronal genes during development, has a crucial neuroprotective function in the adult brain. Downregulated in mature neurons, REST is reactivated with normal aging and with cellular stress, regulating a gene network that promotes neuronal survival and reducing the expression of genes related to the amyloid and tau neuropathology of Alzheimer’s disease and Down syndrome. Moreover, REST activity has been shown to be diminished in Alzheimer’s disease and Down syndrome brains. We will evaluate whether genetically encoding high levels of REST activity and responsiveness results in neuroprotection from stress in induced pluripotent stem cell (iPSC)-derived neurons generated from a large group of deeply phenotyped humans from three cohorts: aged individuals with high amyloid and tau pathology and severe dementia at death, age-matched controls, and aged individuals who died with substantial amyloid neuropathology but no cognitive impairment. We also will examine the ability of REST to alleviate neurodegenerative phenotypes in Down syndrome and Alzheimer’s disease human iPSC-derived neurons. Last, we will examine if REST can rescue neurons from the synapse-damaging environment of the aged, demented brain. Our proposed studies will probe intrinsically encoded REST activity and its role in neuroprotection in human neurons encompassing diverse genetic backgrounds and phenotypes. These studies also will interrogate REST’s potential as a therapeutic target in neurodegenerative diseases and will examine the importance of REST function in synaptic plasticity. Completion of this research plan will provide training in key technical areas in which I have no previous research experience: collecting and analyzing -omics-level data, gene editing, and measuring and analyzing synaptic activity. This research and training in new techniques will occur in concert with an ambitious career development plan. This will include coursework in neuroscience and bioinformatics, mentoring, grant writing, and scientific presentations. Mentored training in these scientific areas along with execution of my plans for further career development will be instrumental for my advancement to the position of independent investigator and for achieving my future scientific goals in the field of neuroscience and neurological disease.