Revolutionizing Dementia Research With Synuclein Biomarker Tests

Russell Lebovitz, MD, PhD

The SYNTap biomarker test (Amprion), first in its class qualitative laboratory developed test, is the only seed amplification assay that is available for helping to diagnosis synucleinopathies including Parkinson disease (PD), Lewy Body dementia (DLB), and Alzheimer disease (AD). Recently, Amprion was contracted by the National Institutes of Health (NIH) Intramural Research Program's Center for Alzheimer's and Related Dementias (CARD) to investigate the levels of misfolded alpha-synuclein proteins in patients with AD using data gathered from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).¹

In clinical setting, Amprion’s biomarker test has shown that approximately one-third of patients with AD have a second parallel disease that is driven by the misfolded alpha-synuclein. The detected patients with misfolded alpha-synuclein were reported to have more rapidly progressive symptoms, and may respond to treatment differently than patients with just AD.

Recently, Russell Lebovitz, MD, PhD, the chief executive officer and cofounder of Amprion, sat down with NeurologyLive® to discuss how the collaboration between Amprion, ADNI, and the NIH’s Center for Alzheimer's Research will aim to redefine dementia research. He also talked about how the study adds a novel dimension to dementia research, and how it will enhance the understanding of the disease progression. Additionally, Lebovitz explained how the discovery of synuclein biomarkers might influence the effectiveness of existing AD drugs, and what implications it might have for personalized medicine.

NeurologyLive: Can you provide more information about the collaboration between Amprion, ADNI, and the NIH Center for Alzheimer's Research, focusing on dementia research?

Russell Lebovitz, MD, PhD:This is a very exciting 3-way collaboration between Amprion and ADNI, the oldest and longest standing cohort of patients with dementia, and the NIH’s Center for Alzheimer's Research, which does a lot of great work particularly in the genetics area. The idea here is to look at the ADNI database and analyze it for misfolded synuclein using Amprion’s proprietary technology. This now seems to play an important role, much bigger than anyone ever guessed in Alzheimer and other dementias. When we find things that seem to correlate between different groups, either at autopsy, other biomarkers or clinical signs, we can go back without any extra work, and the group at NIH can do genetic analysis. The hope is to identify new targets that could be used for new therapies, better understanding, and better biomarkers. It's because ADNI has been around since the mid 80s and it's also NIH-funded. This is a very exciting opportunity, and we feel very fortunate at Amprion to be at the center of this and work with these extraordinary collaborators.

Could you elaborate on the plan and process that your company and other organizations are undertaking in this research project?

Historically, the markers for what is believed to be AD, which is the most prevalent dementia related to what we'll call ATN. The A is for amyloid beta, T is for tau, and N is for neuro degeneration. The neurodegeneration originally was PET imaging and that's how ADNI started as neuro imaging initiative. That's now moved to other biomarkers that approximate what you see with PET imaging. So, you have this amazing database, where some people progress fast and some people progress slowly. It's very hetero, dispersed in terms of the symptoms, however, everyone has very deep data. Now, Amprion and collaborators have come up with this whole other dimension of misfolded synuclein in neurodegenerative diseases. This was really identified originally as a major cause of PD but as we and others explore this, we see that it plays a very substantial role in all dementias and motor disorders. It's probably the most promiscuous of all of the misfolded proteins, leading to neurodegenerative disease.

We now have this whole extra dimension, and it becomes very exciting. There's now strong data that suggests patients who are diagnosed with AD who have a positive synuclein test with Amprion’s technology tend to progress much faster from the time of diagnosis than those without. It's a very important subset. the question is, why, how, and can we identify patients early on who have this synuclein biomarker? Can we validate in the ADNI dataset that they are progressing faster? If so, what is it about these patients? Can we find new targets for how synuclein interacts in an AD setting to be able to make the drugs that are on the market now better? Or to develop new drugs?

As an example, we know there are 2 drugs that have been approved in the past year and a half for AD,both of which target amyloid beta, and there's a third that's going to be approved very shortly. The data is very interesting, but it's not overwhelming. You have a drug that gets rid of amyloid beta in the form of plaque very efficiently,but these drugs have had a surprisingly low effect on clinical progression. Now, we can add a new dimension here.If the data holds out that a quarter to a third of these patients also have a synuclein marker and may progress 2 to 3 times faster, wecould go back and say if we eliminated patients with AD who also have synuclein, it is possible, maybe even likely, that these drugs may work 2 to 3 times better. By eliminating a population in which they are unlikely to work, we may benefit the people who don't have that marker.

I think this is the most exciting immediate benefit of this study. We can take drugs that we thought were so-so and show that by stratifying patients, they may work excellently in the right subset. There are other things we may discover along the way, but we're really interested both in helping people short term as well as long term by identifying new markers. If this holds up, for patients with Amprion’s SYNTap biomarker who progress faster and don't respond, we would eliminate them from single modality treatments. But as synuclein drugs are developed, those patients will be managed much more effectively with a combination of an existing amyloid beta drug and new synuclein drugs. I think all of this circles back to things that we've talked about before, which is neurodegenerative diseases in general. First, are all mixed, whether they're they have a primary cognitive or a primary motor symptom symptomatology. They are all very similar.What we can do is do personalized medicine by teasing out all of the different markers that indicate different pathways and mixed pathways.

What do you think is important for a successful research project and what are you most excited about discovering?

Well, the secret to any success is putting together teams of people who are extraordinarily talented and thoughtful. We are building that at Amprion, but [we’re fortunate] to be able to work with the people at ADNI who represent some of the major research universities in the world and working with NIH CARD group and particularly those with genetics expertise. Most of the ADNI patients already have whole genomic sequencing. That’s a giant project in itself that's already done. This is why just adding one more dimension of synuclein and SYNTap looking at misfolded synuclein, we can immediately see if there are genetic determinants of people who respond better or worse and those whose synuclein disease is progressing faster or slower.That needs large study and by the time we're done, we will have looked at probably 2200 or 2400 samples representing probably 1500 people followed in aggregate for over 35 years. This justifies the people who had the foresight literally in the 1980s, when we knew nothing about these diseases, to end for patients who were willing to give samples and participate and have scans. People give so much and it just takes time for technology to catch up but what they did in the 80s is about to benefit everyone now.

But even so, if you are part of something now, it may take 20 or 30 years for it to benefit people in general and that's really the message. It's having the foresight and the willingness to participate in something early before we know how it will be useful. The magic is that data stays and samples have freezers. It is amazing that these sample tests we run on are 35 or more years old sitting in a freezer, and it seems to work as well as it would have on day 1. All of these technologies come together, and I cannot thank the patients who participated enough and had the foresight to say, “I may not be able to help myself right now, but I'm going to help my children or grandchildren and others in their generation.” It's that incredible generosity that makes such a difference.

Transcript edited for clarity.

REFERENCES
1. Amprion Announces Collaboration with NIH Researchers on Dementia Hallmark Study. News Release. Published August 23, 2023. Accessed August 29, 2023. https://www.biospace.com/article/releases/amprion-announces-collaboration-with-nih-researchers-on-dementia-hallmark-study/