Expert: The Definition of Alzheimer Disease is Shifting From Clinical to Biological

During the 2024 Alzheimer Association International Conference (AAIC), Pharmacy Times interviewed Edward B. Lee, MD, PhD, neuropathologist at the University of Pennsylvania, who highlights that that understanding Alzheimer disease (AD) requires the integration of various fields such as genetics, pathology, epidemiology, pharmacology, and physiology. He notes that successful collaborations across these disciplines can lead to significant advancements in developing treatments for AD. He also emphasizes the evolving understanding of AD, noting a shift from defining the disease based on clinical symptoms to focusing on underlying biological markers such as amyloid plaques and tau proteins.

Pharmacy Times: Can you introduce yourself?

Edward B. Lee: My name is Eddie Lee, I'm a neuropathologist here at the University of Pennsylvania, and I do research on Alzheimer's disease (AD).

Pharmacy Times: What are some key challenges and benefits of integrating neuropathology with other disciplines in AD research?

Lee: So, AD is complicated. Part of what I try to emphasize is that we need the input of many different disciplines to really understand this disease, so, not just pathology, not just genetics, we need to understand epidemiology, pharmacology, and physiology, so all of those together to get a better understanding of this disease.

Pharmacy Times: How might successful multidisciplinary collaborations lead to advancements in AD research?

Lee: There are a couple examples. [In] my lab, we concentrate on finding rare genetic variants that cause rare disease, and when you make that connection, it's kind of like cause and effect. We have the genetic cause, and we look at the pathology, that's the downstream effect, and we're able to understand the mechanism in between. Based on that, we're now trying to develop drugs that target these pathways. So again, those are discoveries that aren't based on just 1 discipline, it's many disciplines together.

Pharmacy Times: What role do pharmacists play in multidisciplinary teams? How might they contribute to the understanding and management of neuropathological findings related to AD?

Lee: So, it turns out that the emerging therapies for AD are actually a little complicated. So, pharmacists need to understand that they're targeting specific pathologies in the brain, but also, there are other things that you have to pay attention to. Somebody's APOE genotype, for example, might put them at risk for certain side effects, some other neuroimaging characteristics also. So, you really need the input of multiple disciplines to understand whether or not somebody is eligible for certain medications and also for monitoring for their side effects.

Pharmacy Times: Can you describe what you will discuss at your plenary session during AAIC?

Lee: So, I took the liberty to talk a little bit about the history of Philadelphia, how we were founded based on, you know, inclusion, diversity, religious freedom, and some of the old history of neuropathology here in Philadelphia. Some of the great discoveries, for example, that tau makes up neurofibrillary tangles, or TDP-43 makes certain aggregates were made here in Philadelphia. But [I] also highlight how neuropathology integrates with other disciplines, so I talked about genetics, epidemiology...so presented how air pollution can lead to increased AD pathology in the brain, and all the other disciplines that kind of interface with neuropathology.

Pharmacy Times: How is clinicians’ understanding of neuropathology evolving in AD?

Lee: So it's interesting, if you look at the history of what we call AD, it has been changing. In the past, it was a lot more about what clinical syndrome, what phenotype you have, so do you have some memory problems? Do you have behavioral problems? What is your phenotype? It's switching now to focus more on the biology or the underlying pathology, so we're switching to thinking of AD as when you develop amyloid and when you have tau, that defines AD. And most of those people have memory problems, but some may have more behavioral problems or other things. So we're slowly shifting towards a more biological definition, and that helps in terms of how we think about targeting these things, because we're targeting actually underlying biological processes and not just the symptoms.

Pharmacy Times: Donanemab is the first therapy targeting amyloid plaque, and lecanemab is the first amyloid beta-directed antibody. How are therapeutic options increasingly focused on the underlying neuropathology of AD?

Lee: I think the most promising therapies are targeting the actual pathologies, and so those are the first ones targeting amyloid-beta. At this conference, you could see people targeting tau or alpha-synuclein, these other aggregates are developing in the brain. And so again, I think that coincides with the shift of defining the disease based on the biology and less [focus on] the symptoms. In the past, many of the drugs were, you know, affected the cholinergic system, which can affect global memory, but it isn't really specifically addressing the disease, whereas these new therapies are.

Pharmacy Times: How is neuropathology directing the future of research for treatments of AD?

Lee: I actually think neuropathology has been doing this the whole time. So, the very first description of what was called presenile, dementia, was by Alois Alzheimer, and he had a patient but also did the neuropathology and said, "There are amyloid plaques and neurofibrillary tangles, perhaps this is what's going on."

I think now people are just more comfortable integrating different disciplines including neuropathology into how we think about this disease.