How are biomarkers shaping Alzheimer’s disease, and what’s next?

Tony: Thank you. It’s nice to be here.

Nicky: Oh, it’s a pleasure to have you. So today, we’re talking all about biomarkers and Alzheimer’s disease. But before we do, I’d love to learn a bit more about you and your journey into the area.

Tony: Yeah, absolutely. So my background is in both medicine and science. I was part of the MD-PhD program at the University of Chicago many years ago, where my PhD was in neuroscience.
After medical school, I went on to start a company that, as many young companies are, was overambitious and underfunded—and we ended up failing. However, it introduced me to the business of biotech, and I’ve spent my entire career in the field.

I spent about 17 years at a company called Acorda Therapeutics, where we were developing drugs primarily for neurodegenerative conditions, although we also had a heart failure program.
Since then, I’ve been with several small companies, most notably Cognition Therapeutics, where I’m now the Chief Medical Officer. We’ve been focused on dementia—particularly Alzheimer’s disease and Lewy body dementia—but we also had a program in dry AMD, looking at how our drug might impact geographic atrophy in that condition.

Nicky: Ah, interesting.
So today, we’re talking about Alzheimer’s disease and dementia, and I looked up a few stats before we joined our podcast from the Alzheimer’s Association. They estimate that 6.9 million Americans over the age of 65 are living with Alzheimer’s disease in 2024. So this is impacting a lot of people—and obviously, their families.
It must feel like a really meaningful and important area to be helping progress.

Tony: Oh, definitely.
I mean, one of the reasons I’m in the field is that, you know, when you get up every day—well, obviously, we all want to go to work, have a job, and put food on the table—it’s really nice when you have the feeling that, with success, you’ll make things a little better.

And as you mentioned, particularly in Alzheimer’s disease, the burden in the United States and throughout the world is really becoming overwhelming—especially in the years to come as population growth slows and the proportion of individuals who are older and suffering from Alzheimer’s becomes disproportionate.
So any therapies that can reduce that burden on people, families, and communities—and the cost of care—would be a great contribution to the field.

Nicky: Absolutely.
So thinking about biomarkers—let’s just go back to the beginning briefly. When did we realize the value of biomarkers in Alzheimer’s disease?

Tony: Yeah, so the biomarker work in Alzheimer’s has a long history—certainly long before I started in the field. I think of biomarkers in a few different categories or buckets, although people may categorize them differently. Generally, there are: biomarkers that assess risk for developing Alzheimer’s, diagnostic biomarkers, and those that track progression.

Then there are exploratory or research biomarkers that help us understand the basic pathophysiology of the disease.

From the beginning, Alzheimer’s was defined around the presence of amyloid. That became the first biomarker—looking at amyloid via PET imaging using a radioactive tag and positron emission tomography to measure plaque in the brain.
We also measure soluble components of amyloid, particularly monomer ratios, either in cerebrospinal fluid or blood.

Over the years, we’ve learned a lot more about the disease. The field has grown substantially. We now look at genetic risk markers like APOE4, presenilin mutations, certain forms of the amyloid precursor protein, and more recently, TREM2, which is linked to microglia and inflammation.

The standard biomarker workup often includes PET imaging for both amyloid and tau. Amyloid forms plaques, and tau—a microtubule-associated protein—forms tangles and contributes to axonal breakdown.
We also assess these via fluid biomarkers from CSF or blood. When you combine monomeric amyloid with tau species—especially phosphorylated tau relative to total tau—you get a diagnostic readout that’s nearly as accurate as PET imaging.

We also track brain volume, especially the hippocampus, via MRI, as it shrinks more rapidly in Alzheimer’s.
There are also imaging biomarkers associated with synapses, like SV2A, and other useful but less-discussed techniques like EEG, where slow-wave activity increases with neurodegeneration.

FDG-PET assesses brain metabolism and is typically abnormal in neurodegeneration.
In fluids like CSF and plasma, we look at synaptic breakdown proteins—neurogranin, synaptotagmin, SNAP-25—and neurofilament light chain (NfL), which reflects ongoing neurodegeneration.

Another key marker is GFAP, a glial activation marker indicating neuroinflammation.
And finally, phospho-tau 217 is used both diagnostically and to track ongoing degeneration.

Nicky: Yeah, there’s been so much development.
The idea of biomarkers has massively impacted clinical practice and how patients are diagnosed and monitored. But do all Alzheimer’s patients present the same way in terms of biomarker patterns—or is there a lot of variation?

Tony: There is definitely a lot of variation. We all have unique brains, disease states, and comorbidities.

However, there are consistent features in people with Alzheimer’s: Elevated amyloid, detectable via PET or fluid biomarkers, and Tau tangles, which are disease-defining

If someone has amyloid above a certain level, they will almost certainly progress to cognitive impairment and eventually Alzheimer’s.

There’s variability, especially as the disease progresses. Some of it may be due to genetics like APOE patterns, or even individual synaptic density before disease onset.
Interestingly, in later stages of disease, tau levels may actually decrease in PET imaging—perhaps because there’s less to release—but the biology behind that is still being investigated.

Other markers like neurodegeneration and neuroinflammation can vary from person to person.
Now, one thing we’ve learned from companies like Lilly and Eisai is that tau levels—whether from PET or fluid biomarkers—can predict who responds best to amyloid-targeting therapies.

Our drug, CT-1812 (or zervimesine), doesn’t remove amyloid, but prevents soluble amyloid species from interacting with their receptors.
We analyzed tau levels in our phase II study and found, like others, that those with lower tau responded better to our drug across clinical measures.

Nicky: As someone who works in—or leads—a company developing drugs, what do biomarkers mean to you? They obviously play a role in clinical trials, but not necessarily in measuring the primary endpoints. Can you tell us more?

Tony: Sure. One big advantage of biomarkers is that they can sometimes be more objective and easier to measure—though not always.
For example, early in Alzheimer’s research, we tracked PET imaging changes, and Biogen even secured approval for aducanumab based on reduced amyloid PET signal.

But what we’ve learned from Lilly and Eisai is that clinical outcomes—real patient impacts—can be measured in Alzheimer’s trials, and that’s now the focus.

That said, pharmacodynamic biomarkers—those that change in response to a drug—are very valuable in early studies for dose finding and understanding exposure. For anti-amyloid antibodies, tracking PET imaging of amyloid is key to determining effective exposure.

Multiple sclerosis is a great example where inflammatory MRI biomarkers like T2 lesions correlated almost perfectly with clinical relapse reduction—leading to the approval of many MS drugs.

Outside the antibody space, we use a range of biomarkers to understand biological activity. In our phase II trial, we saw a trend toward reduced neurofilament light chain (NfL) in CSF, which tracks with reduced neurodegeneration.
In a pre-planned analysis of low-tau patients, we saw even stronger clinical signals and biomarker changes—like reduced GFAP, p-tau217, and NfL—which support the drug’s effect.

Nicky: Yeah, I guess it complements and reflects what you see from the clinical results.

Tony: Yep, absolutely. And over time, the utility of biomarkers will only improve.
We’re really just at the beginning of drug development in this space. After acetylcholinesterase inhibitors and memantine, it wasn’t until recently that disease-modifying therapies—like antibodies—were approved.

Now, as we understand what changes with effective treatment, the predictive value of biomarkers will improve. They’ll also help identify the best early signals and refine diagnosis and monitoring.

Nicky: Absolutely. Do you think that’ll reflect in clinical practice as well as in trials?

Tony: I think so. One major barrier now is the practicality of PET imaging to assess amyloid—it’s not scalable worldwide. Even in the U.S., it’s challenging.

But fluid biomarkers—like the amyloid monomer ratio combined with the p-tau/total tau ratio—are promising.
These will likely enter practice.

And now that we have drugs like lecanemab and donanemab, there’s much more motivation to confirm diagnosis with biomarkers.
If we also find that lifestyle or other interventions impact biomarkers, we’ll use them more to assess risk and progression, even outside of drug trials.

But again, we’re in the early stages of linking biomarkers to both therapeutics and everyday clinical practice.

Nicky: Yeah. It’s exciting to think where we’ll be in, say, ten years’ time. So just to go back to Cognition and the work you’re doing—what are your next steps in terms of Alzheimer’s research?

Tony: We completed a phase II study called SHINE in people with mild to moderate Alzheimer’s disease. We enrolled 153 individuals, split across two treatment arms and one placebo group. They were treated with CT-1812 for six months, and we tracked their progression.

It was primarily a safety and tolerability study, but we also looked at clinical outcomes. As mentioned, those with lower tau levels showed a stronger signal for slowed progression.

Next steps are to design registrational trials, meet with the FDA, agree on enrollment criteria, endpoints, safety database, and manufacturing.
We’re doing something similar in dementia with Lewy bodies (DLB), where our phase II results were also encouraging. So we’re developing protocols and preparing to meet with the FDA to align on registrational plans there too.

Nicky: Excellent. Oh, sounds like exciting times ahead.

Thank you, Tony, for your excellent insights, and thank you to our listeners for joining.
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Until next time—goodbye.