Alzheimer Disease Research: What’s New and What’s Next?

James Leverenz, MD

A year in which Alzheimer disease (AD) research saw continued positive momentum, a palpable buzz rang within the community, including for one James Leverenz, MD. In 2020 alone, there were data on flu vaccinations as a potential AD risk reducer, multiple biomarker studies that explored the diagnostic advantages of the p-tau181 and p-tau218 tracers, and a new drug application submission for aducanumab, which could become the first FDA-approved disease modifying therapy (DMT) for patients with AD.

Leverenz, the director of the Lou Ruvo Center for Brain Health at Cleveland Clinic, expressed that the collective effort of the field has led to this increased momentum swing. He also noted that the increased knowledge about the disease and its diagnosis, as well as those of other dementias and cognitive impairments, has been a drastic improvement over the years.

While challenges in diagnosing AD remain, the risk factors that are associated with the disease have been well documented, which has led to a heightened awareness among the general population. Leverenz sat down with NeurologyLive to give an update on the state of AD, where research has made strides, and what is on the forthcoming agenda. He also discussed the importance of diversifying research populations to account for different genetic backgrounds that could ultimately impact AD data.

NeurologyLive: Can you talk a little bit about the importance of World Alzheimer's Day and raising awareness towards this disease?

James Leverenz, MD: I would say the awareness level is gone up substantially. I like to equate it to where cancer was in the 60s and 70s. Cancer was this single term that everyone was scared of, and appropriately so. Alzheimer disease, and more generally, dementia, is an area where were starting to see the subtypes, and it is not as simple as a single disease. We’re seeing that the public is being very supportive of the research and care that we’re providing. It’s been a very exciting time, because for those of us who have been hitting our heads against the wall for a while, to get the funding to move this field forwards really cements the movement that’s going on.

Among all the notable research released in the past year, has there been anything that has been particularly striking for you?

Those of us who’ve been at this for a while now have seen these things coming along. What gets me excited is that we’re developing a lot of tools that are going to allow us to take a precision medicine approach to cognitive impairment in the elderly. We know that for most older individuals, memory loss is not just in AD, Lewy body disease, or stroke, but it’s often mixed pathology—that even in AD, there are subtypes, too. Getting back to my original analogy of cancer, there was originally just lung cancer. Now, it turns out there’s many different types of lung cancer, and each type requires a precision approach that is influenced by the age, gender, and other factors as well. I see dementia going in that direction, and that’s what we’ll really start to see some important findings.

Things such as the tau markers in the blood are important. Is that the single answer? No, but when you think about the amyloid imaging, spinal fluid testing, blood testing, these become the foundation building blocks that we really need to take a precision approach to treating dementia. Even aducanumab was a little bit of a lesson. We’re still waiting to get an understanding of the full impact of what that will be, but at the same time, it’s important to recognize that there’s a subgroup that they were looking at were particularly responsive. That’s what I expect to see. Some people may carry a certain risk gene, certain age, certain gender, certain characteristics to their dementia, AD, or Lewy bodies that are going to respond in particular ways to particular medications, just like you see in cancer. We’re going to chip away at these things. I’m old enough now to remember when childhood leukemia was 1 of those early things where once we defined it well, there were some groups that responded extremely well to therapy, which was something you never expect to see. I’m certainly keeping my fingers crossed with dementia and AD headed that same way.

Can you detail the challenges in diagnosing Alzheimer disease?

Clinically, what we run into is a lot of people who are worried. There is some normal age-related changes that happen. Usually what we see is that people struggle pulling things such as words, or names. But with hints, things come back to them. It’s not like they never were able to learn these things, which is what we typically see in AD. We’re still seeing patients come in like that. Diagnostically, what we’re trying to identify people with the disease, before they develop a lot of symptoms, maybe even presymptomatically. We saw that with colon cancer where you can catch these things before, they get out of hand. We’re hoping that we can do something similar in the dementia area. With AD biomarkers, can we identify people who are at the very earliest stages of the disease who don’t have any symptoms yet. And then when people do develop symptoms, it’ll be increasingly important to be able to be precise about what exactly is causing the problem. Is this just AD? Is this frontal dementia? We see some crossover with the symptoms, but with different underlying biologies and pathways. When I’m talking to patients and families, I’ll often say “a syndrome is like you have a headache, and a headache can be anywhere from a tension to a brain tumor. We all worry about a brain tumor, that doesn’t go away. But you treat a brain tumor differently than you treat a tension headache. We’re going to have to approach memory loss in elders very precisely and understand what is biologically causing this problem.

In terms of risk awareness, what progress has the AD community made over the past few years?

We know that there are risk factors for AD. The 1 thing we’ve realized, which is not a surprise when you think about biology, is that people who are more resilient and able to tolerate some of the early changes of AD in the brain are people who are healthy in a general way. They exercise, they have the right diet, etc. Now, is that because its affecting AD or some of the other cofactors? We don’t really know. When you look at the effect of what disease modifying therapies, are they the equivalent to the effects people get by just exercising regularly and watching their diet? Obviously, you’d like to combine the 2, but both are important aspects. Now with the increased funding we’re seeing in this research area, we can start to parcel out those specific effects.

One of my colleagues, Stephen Rao, MD, has been looking at why exercise and physical activity seem to have differential effects on preventing cognitive decline in people who carry and APOE allele versus those who don’t. Those are the kind of precision medicine approaches that we need to take. That’s the sort of step that research wasn’t taking 10 to 20 years ago.

What is the importance of equal representation of genomic populations in AD research?

That’s an important issue. It is important that we get a broader range of populations participating in research. That is something that the National Institutes of Health (NIH) have really focused on. They have tried to get more involvement from these underrepresented communities whether it be African America, Hispanic, Latino. These are all very important issues because they bring in different genetic backgrounds that we know play a role. We just touched on the APOE allele, who knows if maybe there’s a difference in how physical activity has on carriers versus non-carriers. Additionally, is a disease modifying therapy going to work the same for someone with an African American background versus northern European? Because we don’t have those answers. We are focusing on getting these populations involved at our own Alzheimer center at the Cleveland Clinic. Our minority advisory board has really tried to connect with the community better to increase participation in research.

Transcript was edited for clarity.