Alzheimer’s-in-a-Dish™: Developing Drugs for Disease Prevention and Treatment

Being grounded in medicinal chemistry and drug development laid the foundation for me to pursue a career in therapeutics. By happenstance, I was brought into a drug discovery program focused on AD after graduate school, which was deeply personal to me. I’ve experienced AD myself, like so many others, and seen the burden it places on families.

When I had the opportunity to work on a project developing GSMs as a postdoc at the University of California, San Diego, I jumped at it. The project was well-matured, and I had the opportunity to move it from the benchtop to the clinic.

Prevention was built into the project from the beginning. Dr. Rudy Tanzi and Dr. Steven L. Wagner developed the GSM portfolio, and what stood out to me when Wager brought me into the project was the paradigm shift that this approach represented. Historically, AD therapies focused on treating symptoms following disease progression, whereas GSMs created an opportunity to treat and prevent disease. I was very fortunate to work with Wagner to optimize these compounds over several years and now continue the work following his passing.

I was drawn to investigating GSMs because they represent a new class of AD therapeutics with a dual purpose: to treat and to prevent disease. Early treatments for AD focused on managing symptoms, and even newer antibody therapies that remove amyloid-beta plaques after they’ve formed do not prevent disease. As AD takes over 20 years to manifest from the initial deposition of amyloid plaques to symptoms of cognitive impairment, there is a large window of opportunity for prevention.

As background, a healthy brain naturally produces Aβ and clears any excess that accumulates as people age. However, the brain’s ability to maintain this healthy balance can deteriorate, creating the preconditions for disease. When this occurs, longer forms of Aβ, predominantly Aβ42, can accumulate and aggregate. This plays a central role in the initiation, progression, and pathogenesis of AD.

From previous work, we understood that gamma-secretase inhibition could result in detrimental side effects. Modulators are incredibly distinct from this; they don’t stop the enzyme from doing its job, they just change how it does it. The modulation ensures that the enzyme is in a more open state, so additional cleavages occur instead of a single cleavage producing Aβ42.

One of our compounds, GSM-779690, is designed to reduce Aβ42 while boosting the neuroprotective effects of Aβ37 or Aβ38. In this way, GSMs have a dual purpose: get rid of the bad and augment the good. This positions GSMs not only as disease-modifying treatments but as part of a future in which we intervene earlier and prevent development.

We envision using GSMs like “statins for the brain.” They allow us to address the earliest biochemical hallmark of disease, amyloid plaque formation, just as statins lower bad cholesterol and help prevent coronary heart disease. 

Rynearson explains how he envisages GSMs being used in a similar way to statins. Credit: Technology Networks.

When I first started working on these modulators, we had a series of very potent compounds, but they had major limitations. One of the biggest issues was solubility. The compounds were what we call “brick dust,” meaning they didn’t dissolve well, which is a real problem when developing an orally available drug.

We followed a design strategy in which we gradually made the molecules more polar—increasing their water solubility while improving their potency and ability to interact with the target. This required synthesizing a few hundred compounds, and we ended up with over 100 compounds that were both highly potent and had drug-like properties. That provided us with a strong set of candidates and ultimately allowed us to identify and advance our lead compound, GSM-779690, into development and clinical trials.

“Alzheimer’s-in-a-Dish” represents a real paradigm shift in how we study and screen therapeutics. Tanzi, scientific founder at Acta Pharmaceuticals, co-developed the human brain organoid model, which recreates key features of AD pathology in vitro, allowing us to observe Aβ accumulation, neuroinflammation, and neuronal changes in a controlled system.

The platform is faster and less expensive than traditional animal models, meaning researchers can test hundreds of compounds in weeks rather than years. That makes drug discovery much faster and allows us to identify “on-target” therapies much earlier in the development process.

One of the biggest advantages of “Alzheimer’s-in-a-Dish” is its adaptability. It’s only limited by your creativity.

Rynearson explains the benefits of a utilizing a brain organoid model in drug development. Credit: Technology Networks.

The system allows us to observe changes in a broader, more phenotypic way. When we see an effect, we can ask why it is occurring, develop a hypothesis, and follow up with experiments to tease out potential pathways.

Notably, this platform has already enabled large-scale screening of thousands of compounds and has informed innovations. For example, Tanzi screened 4,000 approved drugs and natural products using Alzheimers-in-a-Dish, and identified four natural products with the synergistic effect of helping the brain clear beta-amyloid and protect against neuroinflammation. These findings contributed to the subsequent development of CogniSHIELD.

However, the model doesn’t fully capture the complexity of the human brain, so it still needs to be used alongside other approaches. Although, as a discovery and screening tool, it gives us a very efficient and insightful way to understand how potential therapies are working.

For the first time, all the pieces needed for prevention are coming together. We have blood-based biomarkers and imaging that can detect early pathology long before symptoms appear, creating a window for intervention that didn’t exist before. We can stratify patients into groups that could benefit from various interventions. We’re seeing progress in new therapies alongside growing evidence that lifestyle interventions—sleep, stress management, social engagement, exercise, lifelong learning, and diet—can directly impact brain health.

When I was in academia, many companies were exiting AD therapeutic development. The cost of drug development, coupled with the industry’s long history of failures, was a tremendous threat to the development of new treatments. When the industry walked away, we didn’t. We never gave up on GSMs, so our work, coupled with recent advancements, positions us for success.

The recent advent of biomarkers for AD and the ability to stratify patients into pools changes everything and has attracted a lot of interest from industry. That's very encouraging, because without those partners, therapies won’t move forward.

We're on the precipice of putting a compound that Wagner conceived into people and understanding the benefit it could provide.

Data shows that close to 50 million people may already have early Alzheimer’s pathology developing. Reaching them early is the next frontier, and I believe it’s very achievable.