The overarching goal of this application is to provide Dr. Jesse Mez, M.D., M.S. with additional training in the field of Alzheimer's disease (AD) genetics so that he may develop into an independent investigator and skilled future leader of a multidisciplinary research team. Dr. Mez, his mentors and the consultants on the application have designed a research plan and complementary training plan that will engage him in several new areas of study and provide him with the skills necessary for leading a research team with diverse expertise. Patients with AD can present with substantial variation in clinical presentation While a considerable number of genetic risk factors have been identified for the incidence of AD, few genetic risk factors have been identified for the variation in clinical presentation of AD. Genetic risk factors provide insight into underlying AD pathophysiology and offer potential targets for disease-modifying therapies. The research plan will focus on identifying genetic risk factors for the variation in neuropsychological profile of patients with AD. The major research aims of the application are 1) to identify common genetic variants associated with the difference between memory and non-memory function in AD using genome wide association (GWA), 2) to identify causal variants in genes implicated by the GWA in Aim 1 using whole exome sequencing (WES) data and 3) to identify A) gene x gene interactions among variants identified in aim 1 and variants previously found to be associated with incident AD and B) gene x environment interactions among variants identified in aim 1 and AD risk factors with environmental influences: education, hypertension and type 2 diabetes mellitus. The plan makes use of a large volume of genetic and neuropsychological data already obtained or in the process of being obtained through the AD Genetic Consortium, the National AD Sequencing Project, their associated parent studies and several additional studies. Sophisticated genetic and psychometric approaches will be employed to combine and analyze the datasets. The major training goals for Dr. Mez are 1) to develop proficiency in analyzing large-scale genetic data, especially WES data and 2) to learn and apply modern psychometric approaches, including item response theory, to analyze neuropsychological data. Dr. Mez is surrounded by a rich training environment at Boston University (BU). He is a member of the BU Alzheimer's Disease Center and is co-mentored by Dr. Neil Kowall, head of the center. He also is affiliated with the Biomedical Genetics Division in the Department of Medicine, headed by Dr. Lindsay Farrer, who serves as his primary mentor. Lastly he will receive training in psychometrics via frequent contact with Paul Crane, an expert in modern psychometric approaches, at the University of Washington, who will also serve as a co-mentor. The combination of Dr. Mez's current and growing expertise in dementia and the skills he will develop through this training grant will be rare for a clinician researcher, will greatly enhance his prospects for future R01 funding and will position him to lead a future multidisciplinary team focused on the genetics of dementing illnesses.

Public Health Relevance

The aim of this project is to further the understanding of the genetics of memory and non- memory functioning in Alzheimer's disease patients. A better understanding of the genetic architecture of Alzheimer's disease will provide new insights into Alzheimer's disease pathophysiology and may offer potential targets for drug development.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Institute on Aging Initial Review Group (NIA)
Program Officer
Miller, Marilyn
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Boston University
Schools of Medicine
United States
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Chung, Jaeyoon; Zhang, Xiaoling; Allen, Mariet et al. (2018) Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease. Alzheimers Res Ther 10:22
Alosco, Michael L; Tripodis, Yorghos; Fritts, Nathan G et al. (2018) Cerebrospinal fluid tau, A?, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration. Alzheimers Dement 14:1159-1170
Alosco, Michael L; Sugarman, Michael A; Besser, Lilah M et al. (2018) A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. J Alzheimers Dis 63:1347-1360
Cherry, Jonathan D; Mez, Jesse; Crary, John F et al. (2018) Variation in TMEM106B in chronic traumatic encephalopathy. Acta Neuropathol Commun 6:115
Chung, Jaeyoon; Wang, Xulong; Maruyama, Toru et al. (2018) Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages. Alzheimers Dement 14:623-633
Mez, Jesse; Daneshvar, Daniel H; Kiernan, Patrick T et al. (2017) Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA 318:360-370
Crane, Paul K; Trittschuh, Emily; Mukherjee, Shubhabrata et al. (2017) Incidence of cognitively defined late-onset Alzheimer's dementia subgroups from a prospective cohort study. Alzheimers Dement 13:1307-1316
Zahodne, Laura B; Gilsanz, Paola; Glymour, M Maria et al. (2017) Comparing Variability, Severity, and Persistence of Depressive Symptoms as Predictors of Future Stroke Risk. Am J Geriatr Psychiatry 25:120-128
Montenigro, Philip H; Alosco, Michael L; Martin, Brett M et al. (2017) Cumulative Head Impact Exposure Predicts Later-Life Depression, Apathy, Executive Dysfunction, and Cognitive Impairment in Former High School and College Football Players. J Neurotrauma 34:328-340
Alosco, M L; Kasimis, A B; Stamm, J M et al. (2017) Age of first exposure to American football and long-term neuropsychiatric and cognitive outcomes. Transl Psychiatry 7:e1236

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