The focus of my research is the genetic epidemiology of complex aging traits, with a particular interest in Alzheimer's disease (AD). To determine how much influence any single genetic or environmental risk factor possesses and how these factors influence one another remains an extraordinarily complex, biological challenge. To meet this challenge, my general approach is to simplify this problem at three different levels of investigation: search for "natural experiments," when possible; measure intermediate endophenotypes; and apply analytical and theoretical modeling. Using this integrative approach, I have examined several key areas of research on AD and the biology of aging. Current projects in these areas include:

Genetic Epidemiology of Alzheimer's disease and Other Neurodegenerative Disorders (View Relevant Publications)
Since joining the Taub Institute and Sergievsky Center at Columbia University Medical Center in 1999, I have been working on familial AD. To better understand the genetics of AD, I have been focusing on the carriers of the G206A founder mutation of the PSEN1 gene from early-onset AD families as well as familial late-onset AD families of Caribbean Hispanic ancestry. In addition, I have been examining adults with Down syndrome. While these study participants with excess cerebral deposition of amyloid β peptides are at exceptionally high risk of developing AD, there is a wide variation in risk or age-at-onset of AD. Thus, all these cohorts are well-suited to identify distinct mechanisms by which genetic and environmental modifiers work.

Aging and the Genetics of Exceptional Survival (View Relevant Publications)
I was first introduced to the concept of accelerated biological aging as a graduate student while studying whether mothers who have children with Down syndrome at young age are more likely to develop AD because they are aging 'faster' than others. A decade later, I am applying genetic/genomic approaches to determine why some adults with Down syndrome who have 3 copies of the APP gene are protected from developing AD into their 70s, while others develop AD in their mid-40s. To quantify biological aging further, my colleagues in the Long Life Family Study and I have been investigating whether telomere repeat length, as a surrogate measure of cellular aging, is heritable and whether individuals with short telomere repeat length are at elevated risk of earlier death. The main goal of this multi-center project is to examine genetic and environmental contributions to exceptional healthy aging. To this end, we identified two genetic loci that were associated with longer telomere repeat length. This study of healthy aging can now be extended to see how these or other genetic loci are associated with other aging phenotypes, such as memory.

Natural experiments to understand the role of gene-environment interaction in common diseases (View Relevant Publications)
Once candidate genes are identified, it is important to understand how these genes behave under different conditions. For this purpose, we have identified natural experiments in unique, global populations to examine exceptionally high/low risk populations, minimizes bias common in observational studies, and simplify causal models. For example, to address the role of vascular contribution toward AD, I am working on a genetic epidemiologic study on a highly-inbred population of Native American Indians living in an impoverished, polluted, lakeside area in Venezuela. Despite the unfavorable environment, study participants appear to remain cognitively healthy, and we are now examining the role of vascular risk factors on brain health by examining their MRI data, while taking into account genomic factors. In Kazakhstan, we are currently conducting a study integrating genomics with metabolomics in urbanized Kazakhs to determine how aging and obesity influence levels of metabolites at the cellular level. Naturally, the early onset AD study of the founder PSEN1-G206A mutation and adults with Down syndrome are another forms of a natural experiment, where carriers are born with a high risk genetic factor.

To conduct these multidisciplinary studies, I have been working with many collaborators over the years in the Taub Institute and Columbia University Medical Center, as well as internationally. With Drs. Richard Mayeux and Yaakov Stern, I work on the genetics of AD and related neuropsychological traits. With Drs. Nicole Schupf and Wayne Silverman, I investigate high risk adults with Down syndrome to identify genetic factors that protect or elevate the risk of dementia. Once genes are identified, I have worked with Drs. Peter St. George-Hyslop, Benjamin Tycko, Carol Troy, and Asa Abeliovich to determine the functional role of these genetic variants. With Drs. Joseph Terwilliger and Kenneth Weiss, I have been working on the theoretical problems in genetic epidemiology, and with Dr. Gladys Maestre on the isolated inbred cohort in Venezuela.

Joseph H. Lee, DrPH
Associate Professor of Epidemiology (in the Gerturde H. Sergievsky Center and Taub Institute)
Jhl2@cumc.columbia.edu