Scientists' picture of how a gene strongly linked to Alzheimer's disease harms the brain may have to be revised, researchers at Washington University School of Medicine in St. Louis have found.
People with harmful forms of the APOE gene have up to 12 times the risk of developing Alzheimer's disease compared with those who have other variations of the gene.
Many researchers believe that the memory loss and cognitive problems of Alzheimer's result from the buildup over many years of brain amyloid plaques. The plaques are made mostly of a sticky substance called amyloid beta.
For years, researchers have thought that the APOE gene increases Alzheimer's risk by producing a protein that binds to amyloid beta. Scientists thought that this bond could make it easier for plaques to form.
But in a new study now available online in the Proceedings of the National Academy of Sciences, Washington University researchers show that APOE and amyloid beta don't bind together in cerebrospinal fluid and in fluids present outside cells grown in dishes. This means they are unlikely to bind together in the fluids circulating in the brain. The cerebrospinal fluid was taken from people who were cognitively normal but have forms of APOE that increase the risk of Alzheimer's.
"This is the first time we've looked at naturally produced APOE and amyloid beta to see if and how much they bind together, and we found that they have very little interaction in the fluids bathing the brain," said David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of neurology. "This suggests that we may need to rethink any therapeutic strategies that target APOE to slow amyloid plaque accumulation and Alzheimer's."
According to Holtzman, leading Alzheimer's researchers recently agreed that targeting APOE is a promising approach both for improving treatments for Alzheimer's. But to do that, scientists must first fully understand how the harmful forms of APOE increase risk of the disease.
"APOE is a major player in Alzheimer's, there's no question about that," said Philip Verghese, PhD, a postdoctoral research associate. "We did some additional studies in mice and cell cultures that suggested the APOE protein may be blocking a pathway that normally helps degrade amyloid beta."
APOE is involved in the metabolism of fats, cholesterol and vitamins throughout the body. Scientists have identified three different forms of the gene that each make a slightly different version of the protein.