The state of Alzheimer’s research at Penn

What do we know now about Alzheimer’s disease that we didn’t five years ago?

We’ve made a lot of progress in the past five years. As a field, Alzheimer’s disease has been an area of interest for a long time. We can now detect the pathology of Alzheimer’s in living individuals. Amyloid imaging is a way to look for this amyloid protein. It’s a little more than five years old, in clinical practice. Research amyloid imaging has been around since the early 2000s, but FDA approval of these compounds for clinical use was in the early 2010s. We now have a way to look for the amyloid proteins in individuals without any sort of significantly invasive procedure. Just getting a scan allows us to do that. And what we’ve found is more complicated than we anticipated. Even five years ago, the thought was that if an individual has an elevated deposition of amyloid, then that would be diagnostic itself for Alzheimer’s disease. Now that we have amyloid imaging as a tool, we know there’s a long timeline between amyloid deposition and clinically symptoms. People likely develop elevated amyloid levels 10 to 15 years before they have significant memory symptoms. So, we now have a group of individuals that we can identify who have elevated brain amyloid deposition but who are still cognitively normal. 

From a research perspective, tau, the other protein found in Alzheimer’s disease, is much more closely related temporally to clinical symptoms. That’s another tool we’ve gained in the past few years. And these imaging tools allow us to identify individuals we never would have identified before, people who are likely at a higher risk for the future development of Alzheimer’s.

Do most people know if they have these markers?

That’s an interesting question, because typically we wouldn’t tell cognitively normal people whether they have these proteins or not. Actually, we are doing a research study specifically about that. There’s a study called the REVEAL scan study here at Penn; we have people who have a family history of Alzheimer’s disease who are interested in learning their amyloid status, and as part of this research study, they are told their amyloid status by a clinician. 

It’s really in the research setting that we’re doing these disclosures still, in a really controlled manner [and not in clinical settings].

What is Penn’s history with Alzheimer’s research? How long have we been involved with this?

For the past 30 years, since 1991, we have been funded by the NIH as an Alzheimer’s Disease Core Center. The Center for Neurodegenerative Disease Research (of which the ADCC is part) is an encompassing center that includes researchers and clinicians both from the Penn Memory Center, the Penn FTD Center, Udall Parkinson’s Disease Center, and researchers from pathology, neuroscience, and psychiatry, among other areas.

The Penn Neurodegeneration Genomics Center (PNGC) is leading many NIH funded initiatives to better understand the genetic basis of neurodegenerative diseases. They have already discovered new genetic variants associated with Alzheimer’s disease that may be targets for future drug development.

It really is an amalgamation of people who work together for Alzheimer’s disease research. We have a strong group on the clinical side, but also include numerous researchers on the preclinical and basic pathology side to help us better understand neurodegenerative diseases.

And Penn got a grant from the Alzheimer’s Association recently, right?

We got a number of grants, actually. The researchers who got funding from them had a ceremony last week. We’ve had good success over the years getting grants around Alzheimer’s disease. The Alzheimer’s Association, in addition to NIH and clinical trials, research studies, we have a long history working on the field.

Is there an interdisciplinary element to the research happening here?

Absolutely. The Alzheimer’s Disease Core Center is headed by neuropathologists, working with neurologists, and very serious and basic science researchers. So it is, by definition, meant to be an interdisciplinary group. 

Do you look at other diseases like Parkinson’s to help inform research into Alzheimer’s?

We collaborate very closely as part of the Center for Neurodegenerative Disease (CNDR). There’s a lot of overlap with Parkinson’s disease research and we actually have a research platform across the CNDR, so that research data across the Penn Memory Center and the Parkinson’s Disease and Movement Disorders Center are collecting similar and complementary data that we can utilize as a resource as we move forward and continue to have collaborations across centers.

How does Alzheimer’s here in the U.S. compare to other places in the world? It seems we have an outsized number of people who have the disease?

Alzheimer’s disease is increasing globally as the population is getting older and living longer. The differences in incidence of Alzheimer’s disease globally is partially driven by genetic risk factors, though previously part of it has been related to not diagnosing or classifying the disease accurately in the past. But as diagnostic tools improve, I think there’s less discrepancy than we thought. Alzheimer’s is really a worldwide epidemic, not just a U.S. one. There’s some variation, but grossly there aren’t any areas of the world where you don’t have Alzheimer’s disease.

Anything that’s surprised you in the progress made in the past few years?

One of the unfortunate things we’ve learned in the last few years is the approach that we have been taking in terms of clinical trials—trying to use medications to try to get rid of the amyloid protein in symptomatic people—have been unsuccessful. These are trials that have gone on for over 20 years by now, the most recent being the aducanumab clinical trial that stopped early, earlier this year. 

Our thought was that the amyloid deposition is an essential part of Alzheimer’s disease, so you need the amyloid in order to get the disease; if you get rid of it, you get rid of the disease. That worked well in preclinical and animal models. But in clinical trials to date, it just has not worked. We have some pretty potent anti-amyloid antibodies that can get rid of the amyloid protein, make the person move from being elevated amyloid to not elevated, but it doesn’t change the [outcome]. That’s been surprising. That’s caused us to do somewhat of a reassess, to see if the problem was that we are not targeting it early enough. There are ongoing trials using approaches to remove the amyloid, anti-amyloid antibodies, or another compound called BACE inhibitors, to try to target people earlier in the process of the disease; meaning either earlier before they have dementia, or in the mild cognitive impairment stage, or these preclinical individuals who are normal but have risk factors like amyloid that can result in a higher risk of Alzheimer’s later. It’s surprising this approach didn’t pan out the way we thought it would. And it has called us to kind of extend our approach, find people earlier and use similar medications and approaches, or try something different rather than simply targeting amyloid.

What was your reaction to Pfizer holding back info?

A lot of people have asked me about that. The data that we are talking about was an internal study in which a comparison was made between people who were taking etancercept and people not taking the medication. They compared 127,000 people with an Alzheimer’s diagnosis to a group of 127,000 people who did not have the diagnosis. When they looked at this data, more individuals (302) in the non-Alzheimer’s group had taken etanercept than the group who had Alzheimer’s (110). I think the actual effect size that we would be talking about is very small and I think it’s unlikely that Pfizer had any ulterior motives. This was not a randomized controlled trial to look for an effect of etanercept—when we look at such large data sets, it is common to find small associations like this, but there is no reason to think this medication effect would be large enough to warrant significant further investigation. I think the likelihood of it being a medicine that will be effective for Alzheimer’s disease is really low.

Where will Alzheimer’s research be in another five years?

In another five years—I said this a few years ago, I’m hopeful we will have a disease-modifying agent. Meaning, we have a lot of understanding of the disease process, and every clinical trial has resulted in increased knowledge about the disease. We’ve had failure upon failure in Alzheimer’s disease research of the past few years, but each failure has given us more information about what we should be targeting and where. I’m hopeful that in five years we’ll have medicine that we can use to target the disease process, whether it’s amyloid or likely something else. I’m hopeful we’ll have something. More than the medications we have, which are limited right now. I wouldn’t go as far as saying we’ll cure Alzheimer’s in five years; I think that’s unlikely. But I think something that has an impact on day-to-day function is possible in the next few years.