I am an early career clinician-scientist interested in basic and translational research on the alterations in hypo- thalamic function and systemic metabolism occurring in aging and Alzheimer's disease (AD), and I am applying for the Paul B. Beeson Clinical Scientist Development Award in Aging. This award will provide me with the protected time for additional training needed to develop: (a) research expertise in normal aging and aging-related neurodegenerative disorders, (b) expertise in epidemiological study design, and (c) clinical skills in aging-related neurological disorders. These skills will help me fulfill y long-term career goal to become an independent clinician-scientist in the field of neurological disorders of aging. I propose to test the central hypothesis that alterations in leptin signaling i specific hypothalamic neurons is a key factor in the metabolic dysfunction and weight loss observed in the preclinical stages of AD, compared to normal aging. This central hypothesis will be investigated in three specific aims. Aim 1 will use mouse models with increased brain levels of amyloid- (A), a key pathogenic factor in AD, to test the hypothesis that excess A direcly disrupts hypothalamic signaling, and to compare the resulting dysfunction to normal age-matched function. Aim 2 will use an unbiased molecular profiling assay to identify the hypothalamic cell types and signaling pathways that are affected by A compared to normal controls, and determine if restoration of identified targets ameliorates the dysfunction in mouse models. Aim 3 will use a well-characterized cohort of cognitively normal subjects, with or without biomarker positivity for AD, to test the hypothesis that significant alterations in leptin signalin occur in preclinical AD compared to normal aging, and to elucidate their evolution as the cognitive impairment develops. To pursue these training and research objectives, I have assembled a mentoring team including Dr. Costantino Iadecola (primary mentor), Director, Brain and Mind Research Institute, Weill Cornell Medical College, Dr. Jeffrey Friedman (co-mentor), HHMI Investigator, Rockefeller University, and Dr. Richard Mayeux (co-mentor), Chair of Neurology, Columbia University. In addition, an advisory committee comprised of academic leaders in neurology, gerontology, epidemiology, and AD will ensure my progress in all training and research areas. The proposed research is significant because it fills an obvious knowledge gap in the metabolic dysfunction of aging and AD, a priority area for the National Institute of Aging, and may lead to novel therapies and biomarker development based on leptin signaling. Furthermore, the proposed research is innovative because it uses newly developed genetic and molecular approaches to elucidate novel aspects of the molecular and cellular bases of aging and AD-related disruption of systemic metabolism and other hypothalamic functions. The Beeson award will be a defining step in my career, as it will allow me to gain the specialized training and research experience needed to become an independent clinician-scientist in this understudied area of research.