Joseph H. Lee, DrPH, studies genetic epidemiology of Alzheimer's Disease (AD) and other age-related diseases in several unique high-risk populations in different parts of the world. To this end, he has four areas of research. Dr. Lee and colleagues are studying families that have at least one family member who carry a mutation in the PSEN1 gene that contributes to AD risk. In these families, we observe a wide range of phenotypes (e.g., delayed age at onset of AD). One of the goals of this study is to identify protective genetic and environmental factors that allow family members to escape AD into late ages. To identify protective factors, he applies genomic and transcriptomic approaches. Once genetic variants are identified, he and his collaborators examine functional relevance of those variants by examining reprogrammed cells. Dr. Lee and colleagues are examining adults with Down syndrome (DS) to better understand the natural history of Alzheimer disease. Adults with DS are at high risk of developing AD due to having 3 copies of the APP gene. He and his colleagues examine multiomic (genomic, transcriptomic, proteomic, and metabolomics), imaging (MRI and PET), and clinical phenotypes to better understand AD disease pathways. He and colleagues are conducting a multi-site longitudinal study to determine why some individuals live to exceptionally old age and remain healthy. To this end, this study examines multiple layers of omic data including genomic, epigenomic, transcriptomic, proteomic, and metabolomic data. He and colleagues are studying an isolated inbred American-Indian cohort in Venezuela to examine the role of genetic and environmental factors on age related traits. In addition, he collaborates with colleagues in Kazakhstan to understand whether high levels of exposures to environmental pollutants affect the risk of age related diseases including AD, cardiovascular disease and cancer. (Modified 2020.11.04)
Other, 1999, University of Pennsylvania
DrPH, 1996, Columbia University
MPH, 1985, University of California at Berkeley
BS, 1983, University of California at Irvine
Professor at CUMC, Sergievsky Center
Professor at CUMC, Taub Institute
Professor at CUMC, Department of Neurology
Member, American Society of Human Genetics
Member, International Society of Genetic Epidemiology
Member, Human Genome Organization
Member, American Association of Anthropological Genetics
Member, International Society to Advance Alzheimer Research and Treatment
Member, Trisomy 21 Research Society
Areas of Expertise
Alzheimer's Disease, Healthy Aging and Longevity, Neurological Disease / Disorders, Gene-Environment Interactions, Genetic Susceptibility, Genetics, Genomics, Statistical Genetics, Global Health
Select Global Activities
Genetic epidemiology of early onset Alzheimer disease (AD): The goal of this study is to examine families that carry a PSEN1 mutation to identify novel genetic variants that may modify AD-related phenotypes, such as age at onset of AD. Once such modifiers are identified, we will apply the state-of-the-art genomic tools to understand their functions.
Genetic epidemiology of Down syndrome: This multi-center study uses multi-omic methods to understand how adults with Down syndrome age cognitively. For this purpose, we will examine genomic, proteomic, metabolomic, brain imaging (MRI & PET), and clinical evaluation data. Particularly, we are interested in adults with DS (who have 3 copies of APP gene) who are resistant to dementia in old age.
Genetic epidemiology of healthy cellular aging: Natural experiments: Three natural experiments are ongoing. The first study examines how lifestyle influences levels of metabolites in aging cohorts. For this purpose, we compare ethnic Kazakhs in Kazakhstan (urban) vs Kazakhs in China (nomadic). Subsequently, we examine the genome to identify variants that contribute to variation in levels of metabolites. The second study compares ethnic Koreans in Kazakhstan vs those in China and Korea to understand genetic and environmental factors that influence normal variations in aging traits. The third study aims to understand the biology of brain aging by examining brain imaging and genomics of highly inbred Native Indians.
Lee JH, Cheng R, Vardarajan B, Lantigua R, Reyes-Dumeyer D, Ortmann W, Graham R, Bhangale T, Behrens T, Medrano M, Jimenez-Velazquez IZ, Mayeux R. Genetic modifiers of age at onset in carriers of the G206A mutation in PSEN1 with familial Alzheimer disease in Caribbean Hispanics. JAMA Neurology. 2015 Jul 27. doi: 10.1001/jamaneurol.2015.1424
Miranda AM, Herman M, Cheng R, Nahmani E, Barrett G, Micevska E, Fontaine G, Potier M-C, Head E, Schmitt FA, Lott IT, Antonarakis SE, Di Paolo G, Lee JH, Hussaini SA, Marquer C. Excess synaptojanin1 drives age-dependent cognitive deficits, a potential unifying mechanism for individuals at high risk of Alzheimer's disease. Cell Reports 2018; 23(10):2967-2975. doi: 10.1016/j.celrep.2018.05.011
Lee JH, Kahn A, Cheng R, Reitz C, Vardarajan B, Lantigua R, Medrano M, Jimenez-Velazquez IZ, Williamson J, Nagy PL, Mayeux R. Disease-related mutations among Caribbean Hispanics with familial dementia. Molecular Genetics and Genomic Medicine doi:10.1002/mgg3.85
Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland R, Inzelberg R, Hampe W, Bujo H, Song Y, Andersen O, Willnow TE, Graff-Radford N, Petersen R, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimers Disease. Nature Genetics 2007;39(2): 168-177. PMC2657343
Schupf N, Lee AJ, Park N, Dang L-H, Pang D, Yale A, Krinsky-McHale S, Jenkins E, Luchsinger J, Zigman W, Silverman W, Tycko B, Kisselev S, Clark LN, Lee JH. Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome. Neurobiology of Aging. 2015 Jun 19. pii: S0197-4580(15)00331-0. doi: 10.1016/j.neurobiolaging.2015.06.020
Lee JH, Cheng R, Honig LS, Feitosa M, Kammerer C, Kang MS, Schupf N, Lin R, Sanders J, Bae H, Druley T, Perls T, Christensen K, Province M, Mayeux R. Genetic variants on 17q23.2 and 10q11.21 are associated with variation in telomere length: The Long Life Family Study. Frontiers in Genetics of Aging. doi: 10.3389/fgene.2013.00310.
Honig LS, Schupf N, Lee JH, Tang MX, Mayeux R. Short telomere length is associated with mortality in those with APOE4 and those with dementia. Annals of Neurology 60 181-187 2006
Terwilliger JD, Lee JH. Natural Experiments in Human Gene Mapping: The intersection of Anthropological Genetics and Genetic Epidemiology. In: Anthropological genetics: Theory, methods and applications. Crawford MH (Ed.), Cambridge: University of Cambridge Press, 2006, pp. 38-76.
Yan W, Li X, Wang Q, Huang Y, Cao F, Zhang W, Lee JH. Overweight, High Blood Pressure and Impaired Fasting Glucose in Uyghur, Han and Kazakh Chinese Children and Adolescents. Ethnicity and Health. (in press)
Luukkonen T, Poyhonen M, Palotie A, Ellonen P, Lagstrom S, Lee JH, Terwilliger JD, Salonen R, Varilo T. A balanced translocation truncates Neurotrimin in a family with intracranial and thoracic aortic aneurysm. Journal of Medical Genetics. 2012;49(10):621-9. doi: 10.1136/jmedgenet-2012-100977. PMID: 23054244