Progress in Alzheimer's Disease Research

Tell us about your experience.
After I finished medical school/neurology training, I started on faculty at Indiana University, School of Medicine in the neurology department. I ran a few clinical trials during my time there and became increasingly interested in clinical trial design. Beginning in 1998, I went to work at Eli Lilly and Co. where I focused on late phase work and worked primarily on Alzheimer’s. I started this consulting business about three years ago, and Cogstate was one of the first companies I started consulting with.

For our listeners who aren’t as familiar with Alzheimer’s disease, can you explain the specific diagnosis versus one of dementia or mild cognitive impairment?
Alzheimer’s is the most common of what we call neurodegenerative diseases; in other words, diseases where brain cells are slowly dying. Alzheimer’s is the most common cause of dementia, but isn’t the only kind of dementia. Recently, the development of biomarkers has allowed clinicians to evaluate if people have the classic pathology to diagnose Alzheimer’s without an autopsy. It turns out, for Alzheimer’s and neurodegenerative diseases you have pathology for many years before you have symptoms. For Alzheimer’s in particular, one of the most important pieces of pathology are amyloid plaques. These plaques are present in the brain for 15-20 years before the onset of any symptoms. After developing these plaques, people develop what’s called mild cognitive impairment which means they experience changes in cognition, but do not meet the strict criteria for dementia. Eventually, people move into mild, moderate, and severe dementia.

We know that 50 million people worldwide have dementia and as you state, Alzheimer’s contributes to about two-thirds of cases. Can you tell us a bit more about the current state of Alzheimer’s research?
Alzheimer's disease research began with Dr. Alzheimer in 1906, but drug treatment got started in 1990. The first drug approval for Alzheimer’s was a drug called Tacrine in 1993, but this was taken off the market due to causing liver problems. The last new drug approval for Alzheimer’s came in 2003. These medicines are really used to treat the symptoms of the disease. They don’t get at the underlying pathology of the disease. For the last several years, researchers have been more focused on what are typically called disease modifying drugs, which get at the underlying pathology of Alzheimer’s. 

99.6% of all Alzheimer's trials fail. Do you think the high failure rates of these trials scare sponsors and prevent them from wanting to invest?
That’s been a bit of a rollercoaster. At times, I think that has been the case. There’s a huge unmet need for Alzheimer's research as it is the sixth leading cause of death in the United States. Since we are an aging population, the population growth we will experience will cause the cost of Medicare in the United States to be a trillion dollars a year. Pharmaceutical companies will step up to the plate to try and meet the needs of our population. But then, as you pointed out, when we went through this period when there were so many drugs that were well studied, it just turned out they didn’t work, so there was a time when pharmaceutical companies were skittish about getting into something so risky. 

What has allowed us to identify these new discoveries and potential advancements in Alzheimer’s disease research?
There are a number of factors that come into play. A lot of it is hard work and a lot of it takes longer than one would like. Another aspect is: what do we know about the biology of Alzheimer’s disease and how are we refining the targets? The other advancement in the field is study design. People have learned from past experiences and learned the importance of demonstrating target engagement, meaning ensuring the drug gets into the brain and does what it is supposed to do.

It sounds like we may be on the verge of the first disease modifier for Alzheimer’s disease. If it gets approved in the next few months, how will that affect the perspectives on Alzheimer's disease at large?
My personal perspective is that it really doesn’t matter if certain drugs are approved or not. From a scientific standpoint, the field knows that the antibodies being researched are giving us a signal. Psychologically, I think it does make a difference for a lot of people, including some of the investors.

Are there any final thoughts you would like to share with our audience about Alzheimer's disease research?
Yeah, just to reiterate, I think it is a really exciting time for our field. I think we are really starting to get a foothold on treatment modalities, targets, and study designs that can start leading towards more rapid successes. The limiting step in Alzheimer's disease research is recruitment into clinical trials. The only thing I would mention is that if people are having symptoms or even just have a family history, there is a study going on that could be good for you. You shouldn’t go into a clinical trial thinking that the drug will make you better. You should go into a study because people who participate in a clinical trial do better overall than people who don’t. The reason being you get fantastic medical care, you get a lot of attention paid to you, both for Alzheimer’s as well as general medical problems that may come up, and you’re doing something good for society.