Silvia Fossati, director of the Alzheimer’s Center at Temple’s Lewis Katz School of Medicine, will lead a new clinical trial aimed at reducing vascular side effects associated with Alzheimer’s disease anti-amyloid treatments and improving memory and cognition.

More than 15 years after Silvia Fossati began studying the role of blood vessels in Alzheimer’s disease, her research is moving a step closer to patients with the launch of a new clinical trial. The trial builds on the hypothesis she first proposed over a decade ago: that FDA-approved carbonic anhydrase inhibitors could improve vascular cell heath in Alzheimer’s models.

“This is a dream come true for a scientist,” said Fossati, who serves as director of the Alzheimer’s Center at Temple. “To see something you start within the lab in a cell culture lead to a new clinical trial is extremely exciting because of the potential to help patients.”

Fossati, who recently celebrated her investiture as the Scott Richards North Star Foundation and Stop Alzheimer’s Now Chair in Alzheimer’s Research on Oct. 15, was awarded nearly $2 million from the Alzheimer’s Association Part the Cloud grants program. The goal of the trial is to reduce vascular side effects associated with anti-amyloid treatment while further improving memory and cognition in patients with mild cognitive impairment and early Alzheimer’s disease.

“I’m very grateful for the award,” she said. “I’m very hopeful that these drugs can be number one, safe for the patients, and number two, reduce their side effects and improve memory. After more than 10 years of research on these mechanisms, this is a pivotal moment for us to really see if our findings work in people. It is our responsibility to advance science responsibly and with integrity, so patient safety is a top priority with the final vision to really make a positive difference for people living with Alzheimer’s disease.”

Founded in 2012 by philanthropist Michaela “Mikey” Hoag, Part the Cloud is an Alzheimer’s Association initiative that funds promising early-stage research to accelerate the development of potential treatments. On Sept. 23, the organization announced nearly $7 million in new investments to advance investigational therapies into clinical trials with Fossati as one of five recipients from the United States and Canada.  

There is no cure for Alzheimer’s disease, but anti-amyloid therapies have been shown to help slow disease progression. However, these therapies are only effective at slowing the disease by about 30% and can cause side effects involving brain swelling or small hemorrhages.

Fossati’s combination trial, “Phase 1/2 Trial: Carbonic Anhydrase Inhibitors Plus Anti-Amyloid Therapy,” will test acetazolamide, a drug already approved for other conditions, alongside FDA-approved anti-amyloid antibody therapies. The goal is to decrease patients’ side effects and improve their memory and cognition.

“People using anti-amyloid therapy will still have symptoms and will eventually still develop severe Alzheimer’s disease,” added Fossati.  These combination therapies could delay the disease’s progression. At the same time, we want to reduce side effects and, secondly, improve memory and cognition. And with these drugs that we tested in the lab, we found that we can do both things in Alzheimer’s models.”

The trial expands Fossati’s research on the relationship between the brain’s blood vessels and neurodegeneration. When she began studying Alzheimer’s disease, the role of blood vessels in the disease’s progression was not widely recognized.

“We know patients lose neurons in Alzheimer’s, but when I started in this field, almost nobody believed that the blood vessels were important for that process,” she said.

Her lab focuses on understanding how dysfunction in the brain’s blood vessels and the deposition of amyloid on them, called cerebral amyloid angiopathy, contribute to Alzheimer’s disease, and other forms of cognitive impairment and dementia.

“My aim is to understand the mechanisms in the brain and challenge assumptions about Alzheimer’s,” she said. “We now know that blood vessels are really very important for Alzheimer’s disease and the dysfunction that happens. Everything that can hurt your heart can also hurt your brain. If your blood vessels are not functioning properly and if your heart isn’t functioning properly, then your brain will have damage as well.”

Building on this research, Fossati and her colleagues will now test whether this combination approach they identified can benefit people in the earlier stages of Alzheimer’s disease.

“These drugs don’t work in people who already have advanced Alzheimer’s disease,” Fossati said. “The earlier they come when they have mild cognitive impairment, the better it is for them to start therapies.”

By improving vascular health and inflammation in the brain, acetazolamide could facilitate removal of amyloid and improve memory, while reducing the risk of vascular problems associated with anti-amyloid antibodies.

“We already know that this drug is safe in human patients for long-term treatments, but this is the first time this medication has been given to Alzheimer’s or dementia patients, so it could be a true breakthrough,” she said.  

Fossati and her team plan to enroll 60 participants starting early next year and follow each person for 12 months. The overall study is expected to run for three years. Participants will be randomized to receive an FDA-approved anti-amyloid therapy either with or without acetazolamide, a carbonic anhydrase inhibitor. The researchers will assess patient safety; improvement of side effects related to anti-amyloid therapy; cognitive and neuropsychological test results; and blood biomarkers related to vascular function, inflammation and neurodegeneration.

The clinical trial brings together researchers and clinicians across Temple to move the work from the laboratory to patient care.

“We couldn’t do this without the teamwork of our Alzheimer’s Center, our Temple Neurology clinicians led by our Chair of Neurology Paul Katz, School of Pharmacy medicinal chemists such as Marc Ilies and biostatisticians such as Huaqing Zhao,” she said. “We started with the basic science but to then move on to the clinical level, we really need the clinicians and partners from across Temple to be involved.”

The trial also advances Fossati’s broader vision for the Alzheimer’s Center at Temple, which includes establishing a memory clinic that is starting to take shape as the new clinical trial begins.

“I wanted to do research that was not only basic, but translational, to move everything we are doing to the patients and move the field forward,” she said. “This is not the end point. This is the starting point for me.”