The E4 variant of the APOE gene is the strongest genetic risk factor for Alzheimer’s disease that develops after age 65: a person carrying two copies has a lifetime risk of an Alzheimer’s diagnosis more than 10 times higher than someone carrying two copies of the E3 variant. On the other hand, the E2 variant reduces risk of Alzheimer’s, yet increases risk of cerebral amyloid angiopathy (CAA), a frequent comorbidity with AD. Substantial data inform us that APOE variants differentially affect amyloid plaque accumulation and clearance, tau tangle formation and neuroinflammation, non-AD hallmarks of aging and the porosity of the blood-brain barrier, yet the mechanisms by which these effects arise are not understood.
The Fleming APOE Consortium is bringing together experts across the various dimensions of AD affected by APOE to develop a better understanding of these mechanisms. The group is considering, among other questions, how different APOE variants affect microglial behavior; whether apoE produced in the body impacts the health of the brain; how genetic sex and APOE interact; and whether the structure of APOE particles in our blood might tell us about our risk and level of AD pathology in our brain. Expanding our understanding of the role of APOE will lead to new and more effective diagnostic tools, and therapeutics to slow, reverse or prevent Alzheimer’s disease.
FLEMING APOE CONSORTIUM: FUNDED RESEARCHERS
Randall Bateman, M.D., Washington University School of Medicine in St. Louis
Guojun Bu, Ph.D., Mayo Clinic Jacksonville
Oleg Butovsky, Ph.D., Brigham and Women’s Hospital
**Paul Greengard, Ph.D., Rockefeller University
*David Holtzman, M.D., Washington University School of Medicine in St. Louis
Jean-Pierre Roussarie, Ph.D., Boston University School of Medicine
Cheryl Wellington, Ph.D., University of British Columbia
**Deceased in 2019
The connection between the APOE gene and Alzheimer’s disease has received a great deal of interest, because having one of the variants of the gene-APOE4-can increase risk of developing the disease by a factor of 10x. Amyloid, which develops as abnormal protein bundles in the Alzheimer’s brain, builds up most readily in the presence of APOE4, but the reasons that this buildup occurs are not completely understood.
Once amyloid plaques form in the brain, a destructive process takes place and the disease begins to develop. Tau, a critical protein in the brain, begins to form abnormal tangles and the brain interprets this as a sign of infection. This triggers the brain’s natural immune system, microglia, to fight the infection, but the microglia over-respond and begin to spray damaging chemicals, such as cytokines and free radicals, into the brain, causing further damage to the tissue.
Evidence for APOE’s impact on other components of Alzheimer’s pathology, including tau, inflammation, and the surrounding cerebral vessels, is starting to emerge. David Holtzman, MD, Co-Chair of the Cure Alzheimer’s Fund Research Leadership Group, reported in the science journal, Nature, that mice expressing APOE4 show far more tau tangle growth and inflammation than mice expressing either of the other two APOE variants, APOE2, or APOE3. APOE clearly has an important role in Alzheimer’s disease.
Aside from the threat of amyloid, tau, and inflammation-the hallmarks of Alzheimer’s pathology-co-existing conditions, such as diabetes and hypertension, can compromise blood vessels further raising risk of developing Alzheimer’s disease. Among the brain’s blood vessel is the blood-brain barrier, a semi-permeable membrane that serves to protect the brain by blocking harmful invaders and pathogens from entering the brain, while allowing chemicals to exit. We already know that APOE4 weakens the blood-brain barrier thereby lowering the brain’s defense against unwanted visitors.