Donna Wilcock, Ph.D., of the University of Kentucky’s Sanders-Brown Center on Aging (SBCoA) was awarded a $1.7 million National Institutes of Health grant for her lab’s exploration of adverse effects of two new Alzheimer’s disease drugs — aducanumab and lecanemab —​ which have been shown to slow the progression of cognitive decline.

Aducanumab received FDA approval in June 2021 and the makers of lecanemab recently released promising results from clinical trials. FDA approval for lecanemab is pending.

The positive topline data reported on the CLARITY AD Phase 3 clinical trial of lecanemab was both welcomed news and  encouraging news for those living with Alzheimer’s disease and their families, as well as for those who dedicate their life’s work to seeing an end to the disease. Many of those researchers are here at UK, which was a clinical trial site for lecanemab.

While both aducanumab and lecanemab are providing some hope —​ as with pretty much any medication —​ there are some potential side effects. Immunotherapies like these two drugs have been associated with an adverse event called amyloid related imaging abnormalities (ARIA).

“What ARIA is in real terms is that on MRIs after treatment with these antibodies a subset of patients develop either vasogenic edema, which is fluid going from the blood vessels into the brain that shouldn’t be there, or microhemorrhages, very small bleeds in the brain,” said Wilcock.

Clinical trials showed that as many as 25-30% of people who took aducanumab develop ARIA, however, not all are symptomatic. While clinical trials of lecanemab show as many as 15% encounter ARIA with a portion experiencing no symptoms. Once ARIA is detected, patients must stop the treatment, even those who aren’t experiencing symptoms.

“The goal ultimately is to show data that will hopefully support a potential adjunct therapy that could be used with these antibodies, that would make them safer for more of the population,” said Wilcock.

Researchers have known about ARIA for many years. Wilcock published one of the first papers describing it while working with animal models back in 2003. She is now expanding upon that work, considering the data from the two recent drugs. “There is an urgent need to understand a couple of things: how does ARIA occur in response to these antibodies and is there anything we can do to prevent ARIA from occurring?” she said.

For the past decade, Wilcock and her team have been studying microhemorrhages in cases of small vessel disease and vascular cognitive impairment.

“We have taken everything we have learned over the past 10 years and that model, as well as some of the early data about how the immunotherapies work, and we have developed a hypothesis that ARIA is caused by the inflammatory response to the antibody —​ treatments like aducanumab and lecanemab —​ and that inflammation causes the activation of a protein known as MMP-9,” said Wilcock. “We believe the activation of MMP-9 is what causes ARIA to occur.”

Wilcock is joined on this grant by a few of her colleagues affiliated with UK’s Sanders-Brown Center on Aging: David Fardo, Ph.D., and Yuriko Katsumata, Ph.D., both from the College of Public Health; and Joseph Morganti, Ph.D., from the College of Medicine.

The grant will be used for two things: first, to test that hypothesis, using a similar study design to what Wilcock did in 2003, but utilizing today’s technology in an effort to fully understand what exactly the immunotherapy is doing to various pathways.

Second, Wilcock’s research team will look at different drugs, already on the market for other diseases, that are known to either inhibit inflammation or inhibit MMP-9. The team will examine if administering any of those drugs at the same time as these immunotherapies prevents ARIA from occurring, while still maintaining the efficacy of the treatment for Alzheimer’s disease.

There currently is no cure for Alzheimer’s disease. Wilcock says drugs like aducanumab and lecanemab that slow disease progression are critically important as they help to provide some hope for those living with dementia and their families.

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number RF1NS130834. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.