Temple Research Suggests FDA-Approved Drugs Might Prevent Alzheimer’s
By Mark Terry
May 3, 2023
The FDA approved Biogen’s Aduhelm (aducanumab) to treat early Alzheimer’s in June of 2021. Then, in 2022, the agency approved Eisai and Biogen’s Leqembi (lecanemab) to treat the disease. Neither is exactly dazzlingly in their effectiveness. Both are expensive and come with a host of potential side effects, including amyloid-related imaging abnormalities (ARIA), which can be fatal if unchecked.
Both drugs are antibodies that target beta-amyloid, one of the abnormal proteins that accumulate in the brains of Alzheimer’s patients.
Recently, researchers at The Lewis Katz School of Medicine at Temple University, led by Silvia Fossati, associate professor of neural sciences and cardiovascular sciences, published data in laboratory animals that looked at the effectiveness of two FDA-approved drugs that fall under the category of carbonic anhydrase inhibitors (CAIs). This class of drugs is used to treat glaucoma and high-altitude sickness, idiopathic intracranial hypertension, congestive heart failure, and other indications.
In the research, the drugs, which are taken orally with food, reduced neuro-inflammation, restored cell function and prevented cognitive impairment.
“We had previously studied the effect of these drugs, CAIs, on models of amyloid toxicity in vitro, on cells of the neurovascular unit, as well as neuronal and glial cells. And these drugs successfully inhibited mitochondrial dysfunction mechanisms and cell death in the cells in culture,” Fossati told BioBuzz.
Alzheimer’s disease is complex. Much of the focus in the last several decades has been on beta-amyloid, with attempts to treat the disease by clearing the abnormal protein failing repeatedly until aducanumab and lecanemab showed some efficacy. However, the mechanisms behind why the abnormal protein accumulates and another abnormal protein, Tau, accumulates, weren’t completely clear.
It did appear that neuroinflammation was a major result of amyloid accumulation, which further damaged brain cells. And it did seem that in Alzheimer’s brains, astrocytes and glial cells, brain cells that provide physical and chemical support to neurons and help clear out accumulated trash — such as amyloid and tau — weren’t functioning properly. And some of that appeared related to mitochondrial dysfunction.
Fossati and her team, working in a mouse model with cerebrovascular alterations mimicking cerebral amyloid angiopathy (CAA) and Alzheimer’s disease, tested two CAIs, acetazolamide and methazolamide.
“We were very successful not only at inhibiting cell death but also were able to clear amyloid from the brain, in particular in the areas that are more susceptible to Alzheimer’s disease,” Fossati said. The research was published in the journal Alzheimer’s & Dementia.
Elisa Canepa, associate scientist with the Alzheimer’s Center at Temple University, Lewis Katz School of Medicine, who was the first author on the study, told BioBuzz, “Astrocytes and microglia are the major cells in the brain involved in the inflammatory response, including clearing toxic substances in the brain, including amyloid-beta. Since we were preventing cell death mechanisms in these cells, this translated into glial cells and microglia functioning better, degrading waste material in the brain. We demonstrated that astrocytes together with microglia function better at digesting amyloid in the brain.”
One axiom about Alzheimer’s disease has also been that whatever is good for the body’s cardiovascular system is helpful in preventing Alzheimer’s. The Alzheimer’s Association notes that “many factors that damage the heart or blood vessels also damage the brain” and that some studies of autopsies found as many as 80% of Alzheimer’s patients had cardiovascular disease.
“Something that is sometimes forgotten in Alzheimer’s disease is the importance of the vasculature in the brain. The blood vessels in the brain do a great job of removing amyloid and tau, which accumulate in the Alzheimer’s brain. But the vasculature is one of the first things that is hit by the disease, and it doesn’t work anymore very early, even before amyloid accumulation,” Fossati said.
She went on to say that CAIs stimulate vascular cells to work better and to improve cerebral blood flow.
“It seems we can not only cure the disease but prevent the onset of the disease because then the amyloid accumulation will not happen. And that means that tau will also not aggregate. So this approach is acting very early in the pathogenesis of Alzheimer’s disease by targeting the vasculature,” Fossati said.
The researchers’ next step is to continue preclinical work with CAIs on tau and work toward clinical trials.
“In parallel with the cerebrovascular dysfunction, there is also a huge part of the disease made by inflammation. That’s why we’re working in parallel. From one side, cerebrovascular; on the other side, brain cells that function as waste clearance in the brain,” Canepa said. “To me, that’s one of the main effects we see made by CAIs. The vessels are working better, are larger in diameter, and therefore are better at clearing brain waste. On the other side, astrocytes and microglia are preventing cell death mechanisms in a positive way. So we also want to see how this affects Tau aggregate formation.”
They are also working to get funding for clinical trials and pull together an Investigational New Drug (IND) application to run a Phase I/II study. The drugs have been on the market for some time, so their safety is well-established.
When asked if any epidemiological studies of medical data had been performed to see if people on these drugs had a lower incidence of Alzheimer’s, Fossati pointed out that for their primary uses, such as high-altitude sickness, they were not usually used very long. And in the case of glaucoma, they were originally used systemically until they determined they could be used in eye drops.
“It’s complex because these drugs do a lot of different things. They are diuretics. They work well for high-altitude disease. They decrease cerebral edema, they improve cerebral blood flow. All of these mechanisms could participate in Alzheimer’s treatment, although the diuretic part is specific to the kidney,” Fossati said. “But the fact that they improve cerebral blood flow definitely could help clear amyloid. But our previous studies show the mechanism of action within the mitochondria improve mitochondrial health.”
The drugs also release reactive oxygen species from the mitochondria, such as hydrogen peroxide. “So at the cellular level, when the cells are healthier, the mitochondria are healthier, they can function better and remove amyloid better,” Fossati said.
Their work will continue, and working with Marc Iles, professor in the department of pharmaceutical sciences at the Temple School of Pharmacy, they are working on building the data and financial support for clinical trials, as well as preclinical studies that focus on the drugs’ role in benefiting mitochondria.
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
