Research Scholars Program – BIRCWH Mentors
Lindsay Farrer, PhD
Dr. Lindsay Farrer’s research focuses on elucidating genetic risk factors for familial neurodegenerative and common adult-onset diseases. In recent years, his laboratory has localized disease loci for Alzheimer disease (AD), Wilson disease, Machado-Joseph disease, orthostatic hypotension, essential hypertension, osteoarthritis Waardenburg syndrome, keratosis, congenital cataract, and sensorineural deafness using genetic linkage methods. In collaboration with other laboratories, these efforts lead to the identification of novel genes including the presenilins which encode transmembrane proteins responsible for protein trafficking and can cause early-onset AD when defective. Dr. Farrer’s team is developing genetic mapping methods for locating genetic modifiers for disorders whose primary defects are already known, but account for only a small portion of the phenotypic variation. Such modifier genes will probably be more amenable than the primary structural genes to strategies for delaying or modulating expression. A Genetic Epidemiology Center was established at Boston University under Dr. Farrer’s direction. The Center, in partnership with Glaxo Smith Kline, Inc., is orchestrating efforts to map genes for metabolic syndrome (a.k.a. Syndrome X). Dr. Farrer’s laboratory is responsible for the design, data base management and statistical analysis for several NIH funded gene mapping projects including: (1) Boston University’s Hypertension SCOR Program; (2) a project within Boston University’s Sickle Cell Center to identify genes which modulate expression of sickle cell disease including thrombo-embolytic stroke and acute chest pains; and (3) two multi center projects to map genes for cocaine and opioid dependence.
Dr. Farrer directs several funded genetics projects in Alzheimer disease. He is the principal investigator of a large multi center AD project called MIRAGE whose goal is to determine the role of genetic and non-genetic factors in the disease through studies of patients and their relatives. Since 1991, the MIRAGE Study has collected clinical and risk factor information and DNA specimens from more than 2,500 rigorously evaluated AD patients and their family members, becoming the largest family-based epidemiological study of AD in the world. Among the many contributions of this unprecedented study is the finding that genetic factors have a major role in the development of AD in both Caucasians and African Americans. Dr. Farrer and his colleagues demonstrated that the ?4 variant of apolipoprotein E, the strongest AD risk factor identified thus far, is more weakly associated with disease in men and persons older than 75 years but, contrary to earlier evidence based on much smaller samples, is a strong risk factor in African Americans. A recent analysis of more than 2,500 MIRAGE participants revealed that use of statin medications lower the odds of AD 4-5 fold. This remarkable association is the most convincing evidence to date that statins may be protective in persons who would otherwise develop AD. These data have added enthusiasm to the planning of a statin trial by the NIA-funded Alzheimer Disease Cooperative Study consortium, and provides some of the strongest evidence yet to stimulate the examination of links between cholesterol and the pathophysiology of AD. Another recent analysis confirmed findings reported in other studies of a lower risk of AD among postmenopausal women using estrogen replacement therapy. However, this study using the very large MIRAGE cohort showed for the first time that the benefit is age-dependent and attenuated among women lacking the APOE 4 allele.
Dr. Farrer’s other AD studies target specific hypotheses by utilizing unique populations. For example, Farrer and collaborators are searching for genes which determine age at onset of AD in kindred from a remote rural area of Colombia comprised of several thousand individuals whose affected members share the same presenilin 1 mutation. Together with other members of the BU Alzheimer Disease Center, Dr. Farrer’s team is investigating several candidate genes for AD and their interaction with environmental factors in a large case-control population recruited from the Bedford VA Medical Center. Dr. Farrer’s laboratory is also working with scientists at the Mental Health Research Center in Moscow to investigate the molecular and epidemiological aspects of AD in Russians. Dr. Farrer and colleagues at Case Western Reserve University and Tel Aviv University are evaluating the genetic basis of AD in an inbred Arab community in northern Israel which has the highest known prevalence of AD in the world. They have already evaluated nearly all members ages 60 years and older, and identified via a complete genome scan several chromosomal regions likely harboring AD susceptibility genes.
Dr. Farrer is also interested in healthy aging. Last year, he teamed with Dr. Thomas Perls, Director of the New England Centenarian Study who recently re-located to Boston University, to investigate the genetic basis of exceptional longevity in a large cohort of centenarians and their offspring. Detailed health history and biochemical information collected from study participants will be compared with profiles of many genes selected on the basis of their presumed role in the aging process or location in chromosomal regions identified previously through a genome scan for exceptional longevity. His research collaborators include a number of BIRCWH mentors, including Dr. Robert Green and Dr. Mark Moss.