Dr Alvaro Pascual-Leone Discusses Disparities in Alzheimer Disease Research

Alvaro Pascual-Leone, MD, PhD

In the second installment of this 2-part interview for Alzheimer Disease Awareness Month, Alvaro Pascual-Leone, MD, PhD, spoke with The American Journal of Managed Care^® (AJMC^®), delving into the racial and ethnic disparities observed in Alzheimer and dementia research. He explores the potential factors driving these disparities and offers insights into the actions clinicians can take to alleviate these discrepancies.

Pascual-Leone is neurology professor at Harvard Medical School, serves as the medical director of the Wolk Center for Memory Health at Hebrew SeniorLife Rehab Center, and is a cofounder and chief medical officer of Linus Health.

AJMC: The disparity in beta-amyloid is leading researchers to explore whether Alzheimer disease or dementia manifests differently in diverse populations, which calls for a better understanding of how the disease manifests in different groups, especially underrepresented groups. How do you think this should be addressed, and what is the concrete next step?

Pascual-Leone: I think the concrete next step is to keep emphasizing the essential importance of actually having studies in those different racial groups and populations and to highlight, rather than minimize, the differences seen so that then one can build on that and explore it further. For example, the lecanemab study, that phase 3 study that has led to the FDA approval of this medication, I think it's a very nice, very well-conducted trial. But there is a curious finding in that setting, which is that women as a group did not respond to the efficacy level that males responded. In fact, the overall group effect appears to be driven by male response rather than by female response. We don't know why. The study was not designed to look at that as a primary outcome. So we don't even know for sure if that will hold true. But my point is, that's an important finding because it should lead to looking into it in depth.

I can give you a similar example with African Americans and the number of participants in this study being relatively low, and perhaps it being particularly important to highlight that, to be able to look at this medication and others, specifically in that racial group. I think that we need not only to design studies that look at these different populations, in a very explicit targeted way, but also in the studies we conduct, we need to be very proactive in highlighting potential findings that may warrant further exploration and examination.

AJMC: The gene variant APOE4 may play a role in the difference in amyloid thresholds among racial and ethnic groups. Can you provide more insight into the significance of this gene variant in Alzheimer disease and dementia research?

Pascual-Leone: What we know is that in Alzheimer disease, there is a small number of cases, maybe 4%, that are genetic in the way that most people think about it. There is one gene that if you got, you're going to have the disease. That's very rare, and it manifests quite early. We also know now, thanks to wonderful work from colleagues here at Harvard, that there are possibly other genes that counter that gene and make some people have the gene and resistant gene. But the vast majority of us, if we're going to have Alzheimer disease it's because of an alignment of many genes.

One of the genes that we know about and was identified early, in fact, leading in part to the amyloid hypothesis is APOE. To be clear, it doesn't mean that if you got the gene, you get the disease; it just means that if you have a certain form of the gene, which we call APOE4, if you have 2 copies of that form, then you have an increased risk of developing Alzheimer disease. And to your point, if you have Alzheimer disease, you have an increased risk of having dementia. If you have a different form of the gene APOE2, then if you have Alzheimer's, you have a reduced risk of developing dementia.

It turns out that different racial groups have different likelihoodd of having APOE4 or 2. And so, therefore, in part, it is linked to that. But it's also important now to recognize the relevance of that gene for the potential risk of some of the treatments we have. It turns out that for lecanemab that we talked about a disease-modifying treatment, one of the risk factors is having inflammation in the brain with potential risk for bleeds in the brain. Individuals with APOE4 have an increased risk of those complications. So it's a complicated story, where the significance of these genes is not what oftentimes people think about—if I have it, I'm going to have the disease—but rather it plays a role in potential risk of treatments and potential likelihood of disability. And so therefore, it is helpful information to have when one is trying to advise patients on what to expect, or what may come, or what to treat the disease with.

One point that might be related a little bit to your point of the last question, I think one thing that is important to realize is that what has changed in dementia and in Alzheimer disease with the new developments, regardless of your racial group, is the importance of early diagnosis so that it enables early intervention. We shouldn't wait until we have a great cognitive impairment and the entire family is convinced that you're not functioning properly. We should be identifying people much earlier before symptoms develop. This requires primary care physicians, not specialists like myself, and the patients themselves, to be empowered with the appropriate tools to detect the problems very early so that they can empower the individuals to make decisions as to what they want to do: lifestyles or medications or ideally the combination of both.