Dennis Selkoe

At last month’s World Medical Innovation Forum hosted by Partners HealthCare, a distinguished panel of leading experts in the field of neuroscience announced that they had selected “early diagnosis and treatment of Alzheimer’s disease” as the top emerging innovation with the potential to bring renewed optimism to both patients and physicians. Fittingly, it was Dennis Selkoe, MD, co-director of the Ann Romney Center for Neurologic Diseases in BWH’s Department of Neurology, who took the stage to describe the panel’s selection. Selkoe has been at the forefront of research into the causes of Alzheimer’s disease throughout his career at BWH. During that time, Selkoe helped uncover evidence about the disease’s basis that would, over time, gain traction and provide a foundation for new, promising therapies.

From the 1980s to the present day, Selkoe and his colleagues have amassed multiple lines of evidence to support the “amyloid hypothesis,” which proposes that Alzheimer’s disease is caused by the build-up of amyloid-beta peptide (Abeta) in the brain. Many pharmaceutical companies are now developing monoclonal antibodies that target Abeta. In a report in March, Biogen announced that its antibody drug had exceeded expectations in a small clinical trial, slowing the decline of mental function. Advancements in early detection and the launch of the Alzheimer’s disease (A4) Prevention Clinical Trial have also brought a sense of momentum to the field.

BWH Clinical & Research News caught up with Selkoe to hear more about the field’s progress and the deep contributions that researchers at BWH and elsewhere have made to the advancements seen today.

CRN: Can you put the results from Biogen and other companies into context for us? What does this mean not only for the field but also for patients?

DS: The new trial data from Biogen and other companies suggests that if you infuse antibodies that target Abeta into people, not only can you decrease amyloid plaques in the brain, but people also become clinically stabilized – that is, you see less cognitive decline. We don’t say they are cured – we don’t have evidence that their condition is reversed completely, but we do see less of a decline. These trials are in people who already have Alzheimer’s disease, but everyone is interested in seeing what will happen if we are able to intervene even earlier. Antibodies are only one therapeutic avenue to pursue, but this avenue seems to be working. It looks like it will be the first to cross the finish line.

CRN: Today’s trials build on work that you and your colleagues began back in the 1980s. Can you tell us more about what the field was like back then? What did the research community know about Alzheimer’s and what remained to be discovered?

DS: Let me show you a figure from a paper we published in 1991.

This image is taken from the brain of a patient whom I followed during his life. I knew this person – I took care of him for a number of years. He died of Alzheimer’s disease at age 69. In his brain, we see two typical plaques: the two round, brown structures you see are amyloid plaques. The squiggly black lines are degenerating axons and dendrites – the connections between nerve cells. The other lesions you see are dark-stained neurons – these are the tangles.

We talk about Alzheimer’s disease being characterized by plaques and tangles – plaques are the amyloid beta (Abeta) protein and tangles are tau. They are very different proteins that have nothing to do with each other in normal biology, but they both mount up in this condition. This is what the German psychiatrist Alois Alzheimer described – he saw these lesions in a picture just like this one taken in 1906. Some things never change.

I started out working on tangles. In 1986, my lab and three others discovered that these tangles are made up of the protein tau. But even before that, I had increasingly turned my attention to the Abeta plaques – I believed that these came before tangles. There’s good evidence now that this is true.

CRN: This was at a time when more people in the field were focused on tau. Why did you think amyloid beta plaques would be important, too?

DS: We based our hypothesis on good evidence – namely, what’s been documented in Down syndrome. People who have Down syndrome have an extra copy of chromosome 21. And 100 percent of people with Down syndrome get Alzheimer’s disease. We now know that this is because among some 2,000 genes on chromosome 21 is the gene for amyloid parent protein (APP) – that was a powerful clue.

The real pioneer in understanding amyloid was a physician named George Glenner. He was a friend of mine, and his ideas influenced me. He had worked on other amyloid diseases in the body – there are many other amyloids besides Abeta, and they are associated with other diseases. Glenner isolated the amyloid protein in 1984, and many in our field believe that was a critical starting point – an inroad to our understanding of Alzheimer’s.

CRN: How was the amyloid hypothesis initially received by the field?

DS: In the beginning, it was extremely unpopular. I wasn’t the only one who took it up, but there weren’t many of us. Around 1981, I began studying Abeta plaques in addition to tangles and thought these lesions could be a direct route to the cause of Alzheimer’s. Others disagreed, saying these were the “tombstones” of the process, appearing only at the end stage of the disease. But that turned out not be the case.

We did a lot of research, and, in 1992, we made a big breakthrough here at the Brigham. We found evidence that Abeta is made normally throughout life – that was a big surprise. We found that all neurons—even fetal neurons—cultured in the lab were capable of making this protein. Our study ended up on the cover of Nature.

CRN: How did these findings influence the field and change the perception of Alzheimer’s disease?

DS: This opened the door for new discoveries. Thousands of studies and papers followed by research groups around the world investigating how this protein gets made. And it put Alzheimer’s disease in the class of other chronic diseases, such as arterial sclerosis – “hardening of the arteries” – where just about everyone walking down the street knows that cholesterol is made normally, but that its build-up contributes to heart attacks. Now, there was an analogy to the amyloid protein in Alzheimer’s disease.

CRN: What other contributions did your team make to the field?

DS: We also investigated the ‘cutting’ process by which the amyloid parent protein (APP) is cut up into smaller pieces, some of which bind to each other to form Abeta plaques. The amyloid parent protein gets cut several times – we discovered the enzyme that makes the second cut. That enzyme is called persenillin.

CRN: You and your colleagues have made some landmark contributions to the field. What is it like to see new treatments – like the antibody drug – based on your findings begin to show promising results in clinical trials?

DS: It feels great. I’m delighted to be working at the Brigham, especially with the opening of the Ann Romney Center for Neurologic Diseases. In many ways, Alzheimer amyloid research began at the Brigham and just a few other places, and it’s inspiring to see where that research has led.