Co-chaired by three members of CAF’s Research Consortium—Drs. David Holtzman, Sam Sisodia and Rudy Tanzi—participants included all the other members of the Research Consortium (except Virginia Lee, who had a prior commitment) and several invited guests whose records of research include valuable insights into this relationship. The guests were Michael Brown, MD, and Joachim Herz, MD, Southwestern Medical School; Alan Tall, MD, Columbia University; Karl Weisgraber, Ph.D., Gladstone Institute, University of California, San Francisco; and Cheryl Wellington, Ph.D., University of British Columbia.
Co-Chair Holtzman, of Washington University at Saint Louis, provides this overview of the symposium’s purpose and outcome:
Other than age, the strongest risk factors for Alzheimer’s disease (AD) are genetic. In the most common form of AD, lateonset AD, cognitive decline and dementia typically begin after the age of 60. In this form of the disease, by far the strongest genetic risk factor for AD is one’s APOE genotype. Inheritance of the APOE4 form of APOE is associated with increased risk and the APOE2 form is associated with decreased risk. Despite knowing of this genetic link for 17 years, it still is not entirely clear why APOE genotype is linked with altered risk to develop AD.
At a CAF-sponsored meeting on this topic, the body of biological knowledge regarding how and why APOE likely is linked with AD was discussed in detail.
There is mounting evidence that one of the major reasons APOE is linked with AD is the ability of the APOE protein to influence when the amyloid-beta peptide begins to accumulate in the brain to instigate damage. The details of the relationship between APOE and amyloid-beta and the details of how APOE probably influences amyloidbeta metabolism were discussed as well as future experiments that can assist in nailing down the detailed mechanism of this effect.
APOE is a lipoprotein that influences cholesterol and lipid metabolism. What is known about how APOE functions in the blood and in the brain in regard to lipid metabolism were discussed. In addition,participants looked at what further studies might be useful to perform to enhance understanding of how modulating APOE’s function as a lipid carrier could be assessed, to determine whether this might be useful as a treatment strategy. There are a variety of different receptors on cells that have the potential to interact with APOE. Some of these receptors communicate signals to cells that promote electrical communication and survival. Experiments are under way to determine whether the interactions of these receptors with APOE are important in the process of AD as well as whether they also might serve as treatments. Finally, the detailed structure of the APOE molecule has not yet been completely solved. Detailed analysis continues along this front to better understand how drugs and proteins might be designed to interact with APOE to influence AD pathogenesis and ultimately treatment.
A number of ideas for collaborative research in this important area were developed during the symposium and now are being discussed among the participants.