Building on Momentum: Overviewing Ongoing Efforts from the Alzheimer’s Association

Heather Synder, PhD

The 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, was a massive success, with a full house of over 2250 international leaders to discuss the future of Alzheimer disease (AD) clinical research. Over the past year, the field has experienced another significant leap of growth, powered by advances in translational research and capped off by the approval of lecanemab (Leqembi; Eisai), the first traditionally approved therapy in nearly 2 decades.

At the meeting, there was a slew of presentations dedicated towards agents in the pipeline, each with various mechanisms of action. While lecanemab represented another step towards treating the disease, clinicians understand AD will be successfully treated with a combination of approaches that target different pathologies of the disease.

The Alzheimer’s Association, the world’s largest nonprofit funder of AD research, has been committed to accelerating the global effort to provide effective therapies for patients with AD and other dementias. Following the conclusion of CTAD, NeurologyLive® sat down with Heather Synder, PhD, vice president of medical and scientific operations at the Alzheimer’s Association, to discuss some of the major progress stemming from the meeting and how the organization is continuing to help. Synder discussed research efforts that are gaining more ground, including the origins behind the heterogeneity of AD and why certain patients are more at risk than others.

NeurologyLive®: What were some of the most positive takeaways from the recently concluded meeting?

Heather Synder, PhD: I think within the space of Alzheimer's and all dementia research, when we're at these meetings, like CTAD, the energy in the room is one of the things I walk away with clearly in terms of where we are in the momentum and the progress that's being made. Throughout CTAD, we saw a number of early-stage reports of trials reporting out in terms of some of the safety and tolerability and dosage. We saw some additional data being reported out from the dental anatomy lab studies. We're continuing to see reports from the AHEAD trial, which is testing lecanemab in a population of individuals that have lower levels of beta-amyloid in their brains as confirmed by blood initially, and then PET but not cognitive demonstrations. They shared some of the results that they're seeing in testing these blood tests as part of that recruitment pipeline and then going on to imaging as well.

Where are the Alzheimer’s Association’s efforts currently being dedicated toward?

When we look at the pipeline, it's really been the last decade that we've where we've seen that transition and the diversity in what's being funded, starting with some of the mechanistic discovery science, looking at the pathophysiology and some of the biological mechanisms, expanding into metabolism, looking at the bioenergetics, the vasculature, vasculature functions, immune and inflammation mechanisms that are in the brain. And the intersection of all of these is just some of those examples. And we're now seeing that understanding in the biology translating over into both diagnostics, as well as therapeutics that are translating into those early phase one, phase two, and phase three [trials]. In fact, one of the presentations at CTAD was by Dr. Jeffrey Cummings, MD, PhD, who presented his database that he's been publishing on an annual basis in one of the Alzheimer's Association's journals of what's in the pipeline in Alzheimer clinical trials. We've continued to then see that transition both of the increase in trials year over year, but also that incredible diversity of the mechanism of action that's being targeted in these clinical trials. At CTAD, we saw trials that were looking at some of the metabolism components, with one group looking at targeting that underlying biology with gamma and delta phosphor ester acid. We saw reports out in other mechanisms that were in the immune system and targeting specific biology there. I think we also saw a report out from Dr. Michael Rafii, MD, PhD, at the University of Southern California, who talked about where that transition [occurs] in the Down Syndrome population and looking at trials that were targeting important biology for individuals with Down Syndrome and to build out that clinical trials research on the network as well.

What aspects of Alzheimer research do you feel need more attention?

The Alzheimer's Association when we look at our portfolio, we are the world's largest funder of Alzheimer's and dementia science. And in fact, in 2023, we just announced that we had a milestone year with research investments exceeding $100 million of new investment just in an annual year. Its exciting to see, again, that continued momentum. Now in looking at the diversity of what we're seeing, about 50% of the funding that we give is in discovery science. We've seen an incredible emphasis on things around under lysosome and lysosomal biology and some of those pathways and how they may be playing a role. I think also the mixed biology or mixed dementia. We know many individuals with Alzheimer disease have other brain changes that are associated or other pathologies that are associated with Lewy body dementia or Lewy Body diseases or frontal temporal diseases or vascular diseases. And understanding that intersection has been a big focus as well, in the biological space, in translating that to some of the aspects around care. There's been a lot of attention in trying to understand how real-world data can generate the evidence that's necessary so we can establish care guidelines for all individuals. How do we think about ensuring access and understanding health disparities and building out how health equity in our communities more broadly? Across all of that, as we think about really addressing health disparities and building that health equity, how do we ensure that all communities have access to the clinical trials that are ongoing, the diagnostic tools, and ultimately the therapies that come out of those trials as well?

On a global stage, what are we doing to better understand sex, gender, and ethnic differences in Alzheimer's vulnerability?

When we look at the numbers, and I'll start with just even the numbers that we know. Here in the United States, we know there's over 6.7 million Americans that are living with Alzheimer dementia, two-thirds of those are women. We don't completely know why. And it was actually about just under 10 years ago, about eight years ago, the Alzheimer's Association brought together a group of individuals to say what does the science tell us? Is there a reason for this difference? Or is it that women live longer, and in fact, it's much more complicated than that. Certainly, women do live longer, but some of the contributions to risks throughout life are also different between men and women.

Things like some of the mechanisms that we've already been talking about, our immune systems are different, they respond differently. Our metabolism, and I don't mean our metabolism of our diet and nutrition, although there is there are differences there between males and females, but how our brain processes energy in the bioenergetic pathways, there are differences there. The contributions of hormonal changes and hormonal pathways, whether you're talking about menstruation to childbearing, all the way through menopause, obviously, are quite different between males and females throughout life. All of that plays a role in our brain’s overall health and perhaps contributing to making our brain more vulnerable or not to some of the changes associated with Alzheimer and other diseases. As we understand more and more about this disparity, it becomes important to think about the diagnosis and to think about treatment as well.

The early warning signs in a male may be different from the early warning signs in a female and we don't completely understand that. Some of the work led by Dr. Pauline Mackay that was presented a couple of years ago at the Alzheimer's Association's International Conference suggested that regardless of the level of beta-amyloid pathology or tau pathology that individuals have, females still outperformed on some of the verbal recall testing, than males within the same assessment. When you're using verbal recall as part of your diagnostic process, what may that mean? In terms of when you may detect those earliest cognitive changes. This, again, moves us to looking at biomarkers and things like blood tests and imaging and cerebral spinal fluid as leveling out that playing field and saying, what are the biological changes? When are they changing? And when do we say that somebody is trending towards disease changes.

Transcript was edited for clarity. For more coverage of CTAD 2023, click here.