Considerations Amid the Ever-Changing Field of Alzheimer Disease

Alvaro Pascual-Leone, MD, PhD

It is an estimated that 55 million people have dementia worldwide and, by 2050, this number may increase to 139 million because of population aging. Despite the struggle to find effective therapies, the field has seen immense growth in recent years, with a pipeline that is filled with dozens of different agents with various mechanisms of action. This has been fueled by years of research that has uncovered more about the pathophysiology of the disease and the impacts of amyloid-ß peptide.

The 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, was filled with the latest advances in antiamyloid treatments, emergence of diagnostic blood-based biomarkers, and results from phase 1 to phase 3 AD clinical trials. Above all, the scientific gathering was a testament to the progress made within the field, across all levels of research and drug development. While Eisai’s antiamyloid therapy lecanemab (Leqembi) received FDA approval earlier this year, there are still several questions about the integration of these new therapies and ensuring the proper patients receive them.

To get a better understanding of how clinicians are adapting to the ever-changing care and diagnosis of AD, NeurologyLive® sat down with Alvaro Pascual-Leone, MD, PhD, professor of neurology and director of the Berenson-Allen Center for Noninvasive Brain Stimulation at Beth Israel Deaconess Medical Center and Harvard Medical School. Pascual-Leone provided commentary on the advances over the years, the role of blood-based biomarkers, and the realistic goals behind antiamyloid treatments. Additionally, he discussed the keys to continued success, the frequency of misinformation, and the importance of flexibility and adaptiveness for clinicians.

NeurologyLive^®: What excites you about this year’s CTAD conference?

Alvaro Pascual-Leone, MD, PhD: It's great to be here. I think it's a very exciting time in dementia care and Alzheimer's disease care, specifically. I believe that the reality of having disease-modifying medications in the market, soon more to come, really transforms the field. It's not a question of whether this is the silver bullet; we're all hoping for an audit. It is not, but it is the opening of literally a new era, where there is a real opportunity to enable patients to live a fulfilling life even if they have the disease, to have a real impact, to add value to other things we've known make a difference but difficult to do, like lifestyle modification. I think you can sense the enthusiasm of the fact that there is a real change coming, and it's a timely and needed change because it's a devastating illness. For many years, we've had very little to offer. I think that is exciting.

With the oncoming integration of new assays and blood tests, is there a combination of these approaches that you feel is going to be best to screen patients?

What is clear from the evidence of the effect of therapeutic interventions, be it lifestyle or medications, is that they shouldn't be thought of as separate but synergistic. What is clear from both of them is that early intervention is paramount, and we need to start thinking about prevention and early detection. We know that right now, we're detecting patients way too late. That requires tools in the hands of the right providers. Blood biomarkers are one such type of tool that will allow us to identify a certain cascade of pathology. If we can say somebody has Alzheimer's disease eventually or at the very least has a high likelihood and deserves additional tests. If it seems clear that one single biomarker is not going to be the answer, then we probably need to combine different things. But I think at the same time, it's important to realize that they are only going to capture the underlying biology, not whether somebody is likely to have cognitive impact, whether somebody has cognitive problems or functional problems. We're not going to be able to just use the biomarkers; we're going to need to have biomarkers and a cognitive assessment.

Think of it as behavioral biomarkers rather than plasma biomarkers. The combination of tools that are very sensitive in detecting changes in individual cognitive trajectories, along with tests that, with a blood drop, allow us to detect whether somebody has a certain abnormal protein potentially depositing in the brain is going to change the field because it's going to allow us to very early empower individuals to find out whether or not they have something, which is what we've come to live with cancer and has changed cancer care or diabetes or hypertension before any downstream pathology develops and consequences with this ability. That's the big promise of Alzheimer disease, but it requires the development of those biomarkers in the hands of primary care physicians. Again, it's not just plasma. That's important. But I don't think it's sufficient; it's necessary, but not sufficient. We need also behavioral biomarkers that leveraging technologies we can provide.

As the AD field continues to see several large advances and change, how are clinicians ensuring they are providing the most optimal care possible?

The speed of developments and the speed of information have exponentially grown, and that's exciting because it increases the probability of finding the right thing. At the same time, it is a threat because it opens up the opportunity for people to get stuck with noise that are not real findings. It emphasizes the need for a real scientific careful approach so that people are not sold on promises that are not sufficiently supported by data. It emphasizes the importance of honesty and appropriate quality control. We need to learn there a little bit; there is a little bit too much marketing sometimes because of the need that people feel of doing something. How do we strike the balance of broad information sharing while at the same time appropriate expectation setting? I think it requires a lot of education. For example, to make a point that is sort of obvious, we've known for a long time that what is true in open-label trials, be it in animal models or not, may not pan out in controlled trials and may not really pan out in real-world evidence.

The awareness of that step of really weighing evidence appropriately is important, is paramount. The second aspect related to it is that what is true even at a population level may or may not apply to a person, for an individual. How do we get to that personalized precision medicine approach that we all need and want? I think it requires starting with tempering the expectations so that people are realistic as to what we have now. We have a lot; it can make a difference. It is important to take proactive action. But it's not. We're not there yet, and there's still ways to go.

I think we should not give any false promises. We need to realize that everybody is capable, appropriately educated, to be empowered to make the right decisions for themselves. And it requires effort and dedication; we shouldn't try to minimize it or make it overly simplistic. I think people can get it, and it's on the medical community to make sure that we empower individuals to make the right decisions for themselves. At the same time, it is also critical to realize that while doing that, we need to change the system, the medical system so that we can actually deliver on the potential of those promises.

You had mentioned lecanemab and other medications coming on the market. They require infusions and monitoring and early detection and support of the patient, but they also require enabling the patient to anticipate what the downstream implications of starting this medication are. What will I and will I not be able to do? What potential treatments am I choosing not to be eligible for if I have a stroke and am on this medication? Then the TPA may be too risky. What does it mean for me? There is a whole lesson we need to learn from palliative care and Advanced Directives to enable patients to make these decisions becomes a different way of addressing these disorders if we want to truly make them chronic disorders that people can have a fulfilling life with. There's a lot of potential and promise with this exciting, but we need to address the various aspects that are part of that challenge.

What are the keys to continued success in this field?

The awareness of the value of continued monitoring of how individuals are doing to be able to develop individual trajectories so that the earliest deviations can be detected will be an insurance of making sure that the earliest possible time points are detected. For that, I think we need to empower clinicians at the point of care, our primary care physicians, to have the tools they need to be able to do a vital sign of the brain, as it were, in the same way that we do for the heart or for screening. It's a mindset of prevention that I was mentioning earlier briefly, and that we need to adopt. But with that comes the addition of empowering individuals to monitor themselves so that they can detect, in their daily life, the early signs and trigger a visit to the clinician so that it's not waiting until next year, but rather, if.

Click here for more coverage of CTAD 2023.