June is Alzheimer’s and Brain Awareness Month, and to highlight innovative research to help prevent and treat cognitive diseases, we interviewed Dr. Daniel Murman, a neurologist at the University of Nebraska Medical Center (UNMC) in Omaha. Dr. Murman focuses on older adults who have cognitive impairment or dementia. He is the UNMC Director of Behavioral and Geriatric Neurology Program and Vice Chair of Clinical and Translational Research. With nearly 25 years of his career dedicated to Alzheimer’s, Dr. Murman is currently leading a clinical trial on preventing Alzheimer’s.
What positive developments are happening in the fight against Alzheimer’s and other types of dementia?
Over the past 10 to 15 years, new technology has helped identify early changes of Alzheimer’s disease in living people. Specifically, amyloid PET scans can now identify amyloids as part of the amyloid plaque of Alzheimer’s disease. Through these scans, it now appears that changes in the brains of people who eventually develop symptoms of Alzheimer’s disease begin 15 to 20 years before they get those symptoms. So we now have a prevention window, a time that we might be able to intervene with somebody who seems to be on the path to develop Alzheimer’s. It is probably a larger window of time than a lot of us anticipated where there might be changes occurring long before people have symptoms.
One of the targets in our research is a brain protein called beta amyloid, or sometimes called amyloid beta. Beta amyloid is a fragment of a larger protein that seems to be toxic to nerve cells. Beta amyloid aggregates into small collections, then fibrils, and eventually plaques. Exactly which development stage and which species of this beta amyloid is most toxic are still areas of research, but the thinking is if you accumulate too many of these fragments, that is a very early step in the Alzheimer’s degenerative process.
What is the Alzheimer’s Prevention Initiative Generation Study?
The focus has been on finding ways to try to either prevent the production of the beta amyloid protein or remove it. So the Generations program was created to try to find people who are at increased risk of getting Alzheimer’s disease because they carry two copies of a gene called apolipoprotein E4, or APOE4. We all carry the apolipoprotein E gene, which comes in three forms: E2, E3 and E4. But people who carry the E4 copy of the gene are at a little higher risk of getting Alzheimer’s, and those with two copies of E4 have some additional risk.
We are testing an oral medication that is an enzyme inhibitor designed to dramatically decrease the production of beta amyloid fragments we think are harmful. We are selecting a group of the population with a genetic predisposition to increased amyloid accumulation. Developing Alzheimer’s is a combination of aging, lifestyle and the E4 gene and likely other genes all coming together to determine if and when someone might get early signs of the disease.
There are two Generation studies. The Generation 1 study is focused on people who have two copies of the APOE E4 risk gene and that’s rare—probably about 3% of the population. For the Generation 2 study, patients have only one copy of E4 but also need to have some signs of increased amyloid. The first study assumes most patients would have some amyloid accumulation. This is a prevention trial so the subjects we’re looking for are ages 60 to 75, but they function normally from a memory and thinking standpoint, have no trouble with the activities of daily living, and don’t have a lot of other serious medical problems. The participants will receive either a placebo/inactive medicine or the experimental medicine during the course of the study to see if the investigational medication can delay the onset of symptoms of Alzheimer’s disease. The nationwide Generation study is taking place at numerous sites and is sponsored by Novartis Pharmaceutical and headed up by Banner Alzheimer’s Institute in Phoenix.
How are the studies progressing?
We’ve been recruiting at our Omaha site for about a year and a half. In the U.S., each Generation study is trying to get over 500 subjects enrolled. This is a lengthy study that will continue for five to eight years because only a small percentage of people are going to develop memory loss in this window of observation. We’re trying to see whether people receiving the medication are less likely to develop memory loss than the people on the placebo—memory loss will begin to progress and indicate problems. Current estimates are that by the end of 2019, both studies will be full with enough subjects. We’re in the beginning stages, but so far the medication appears to be well tolerated. If people are interested in being a study candidate for this or other Alzheimer’s trials, they can go to GenerationProgram.com, UNMC Clinical Trials or the Alzheimer’s Association at alz.org.
How can the Generation studies help with preventing Alzheimer’s?
When we think about prevention, there may be this long period of time where people may be developing the disease process in the brain but have no symptoms. The hope for prevention is that if we could delay symptom onset, by three to five years for example, there’ve been estimates that the number of people who are actually suffering from Alzheimer’s could be cut in half. So prevention could have a dramatic impact if we were successful.
The hope is to delay memory-loss symptoms and change in function by years, and ideally, three to five years would be a magnitude of change that could have a big impact. The challenge is that these trials take such a long time—eight to 10 years to find a result. If it’s not successful, then you go back and do another study. It can be a long process to find out if you had the right medicine and the right group. At the earliest, it will be five or six years from now before everything will be finished and the results published.
About the Author
An award-winning journalist who has documented stories in nearly 20 countries, Beth Lueders is an author, writer and speaker who frequently reports on diverse topics, including aging and health issues for both U.S. and international corporations.