A gene so powerful it nearly triples the risk of Alzheimer's disease has been discovered by an international team including researchers from Mayo Clinic. It is the most potent genetic risk factor for Alzheimer's identified in the past 20 years. The findings were reported Wednesday in the online edition of the New England Journal of Medicine.
The team included researchers from 44 institutions around the world, including 10 from Mayo Clinic's campuses in Florida and Minnesota. The study was led by John Hardy, Ph.D., a researcher at the Institute of Neurology at University College London and a former professor at Mayo Clinic in Florida.
The researchers used new sequencing techniques to home in on the TREM2 gene. Additional TREM2 sequencing was then performed, in part, by scientist Aleksandra Wojtas in the Mayo Clinic in Florida laboratory of Rosa Rademakers, Ph.D. These studies led to identification of a set of rare variants in TREM2 that occurred more often in 1,092 Alzheimer's disease patients than in a control group of 1,107 healthy people.
The most common variant, R47H, was then evaluated in follow-up studies of a large number of Alzheimer's disease patients and controls. Minerva Carrasquillo, Ph.D., a scientist in the Mayo Clinic in Florida laboratory of Steven Younkin, M.D., Ph.D., spearheaded the direct genotyping and analysis of R47H in DNA samples from 1,994 Alzheimer's disease patients and 4,062 "control" participants - individuals verified not to have Alzheimer's. The patients and control participants were evaluated by Mayo Clinic physicians, led by co-authors Dennis Dickson, M.D., Neill Graff-Radford, M.D., and Ronald Petersen, M.D., Ph.D. These follow-up studies showed unequivocally that the R47H variant of TREM2 substantially increases the risk of Alzheimer's disease.
"The TREM2 variant may be rare, but it is potent," Dr. Carrasquillo says. "In our series, it was present in 1.9 percent of the Alzheimer's patients and in only 0.37 percent of the controls. This strong effect rivals that of the well-established genetic variant known as APOE 4, and it was observed both in our study and in the independent study led by deCODE that was published with ours. R47H isn't fully penetrant - meaning that not all people who have the variant will develop Alzheimer's and in those who do, other genes and environmental factors will also play a role - but like APOE 4 it does substantially increase risk."