For decades, medical scientists struggled to find an effective treatment for Alzheimer's disease. Recently, new drugs have emerged that can slow the cognitive decline. Indiana University researchers have been at the forefront of this progress, providing hope to the more than 6.7 million Americans living with Alzheimer's disease or related dementias, and millions more worldwide.
When the first disease-modifying drug for Alzheimer's received full, traditional approval by the Food and Drug Administration in 2023, many experts in the field hailed it as the "end of the beginning." The long wait for a breakthrough was finally over.
Yet much remains to be discovered about the multifactorial causes of Alzheimer's and how to stop this devastating disease before it starts to impact a person's cognition. The IU School of Medicine has more than 100 faculty experts dedicated to researching dementia, with a collective $87 million in National Institutes of Health funding for Alzheimer's research in 2023.
Along with its clinical partner, IU Health, the IU School of Medicine was among the earliest institutions in the nation to offer patients treatment with lecanemab, marketed as Leqembi, which removes buildup of amyloid protein plaques in the brain - a hallmark of Alzheimer's. Next came donanemab, a similarly working drug marketed as Kisunla by Eli Lilly and Co., which received FDA approval in July 2024.
"Twenty-five years ago, we all hoped that a drug like this would be the cure," said Donna Wilcock, the Barbara and Larry Sharpf Professor of Alzheimer's Disease Research and director of the Center for Neurodegenerative Disorders in the IU School of Medicine-IU Health Neuroscience Institute. "That's not really the case, but it significantly slows a patient's decline when they are positive for amyloid in their brain and when we catch this early enough in the disease progression."
Now, IU's innovative work to develop a blood test for Alzheimer's disease, led by Wilcock and senior research professor of neurology Jeff Dage, is expected to make screening for eligibility easier.
"A blood test for Alzheimer's disease will make these new treatments even more accessible to patients and enable us to capture patients early in their disease when they will stand to benefit the most from the new treatments," Wilcock said.
IU's comprehensive approach to ending Alzheimer's
For nearly a decade, lecanemab has been tested in clinical trials at the IU School of Medicine, an effort led by Dr. Jared Brosch, associate professor of clinical neurology. While this drug does not stop the disease or lead to cognitive improvement, it does "freeze" a person in their current functional state, providing potentially several additional years of independence if the disease is caught early, Brosch said. More than 70% of those treated in the clinical trials were able to live independently and continued to do so after 1.5 years of treatment.
"These people are going to primary care clinics, they are in the community, and they are experiencing memory problems - but they might not be telling anyone about it," he said. "Those are the people that really benefit the most and who we need to get to."
The IU School of Medicine was also a clinical trial site for Lilly's donanemab. Dr. Liana Apostolova, associate dean of Alzheimer's disease research and the Barbara and Peer Baekgaard Professor of Alzheimer's Disease Research at the IU School of Medicine, presented findings from the drug's Phase 3 clinical trial at the 2023 Alzheimer's Association International Conference in Amsterdam in advance of the drug's full FDA approval.
At that conference - the world's largest annual gathering of Alzheimer's researchers - IU scientists played a key role. Cristian Lasagna-Reeves, an investigator with IU's Stark Neurosciences Research Institute, presented findings from what the Alzheimer's Association deemed the "most impactful study published in Alzheimer's research over the preceding two years." His discoveries about the significance of the Bassoon protein could lead to therapeutic strategies even more effective in impacting tau pathology and disease progression. He is collaborating with Brosch and researchers in the Target Enablement to Accelerate Therapy Development for Alzheimer's Disease program, known as TREAT-AD.
"They have a clear picture on how to move forward to clinical trials, and all of that can be done 100% at IU," Lasagna-Reeves said.
IU School of Medicine and Stark have recruited several scientists from Lilly to help with Alzheimer's drug development, including senior research professor of medicine Alan Palkowitz , who leads the TREAT-AD program, and senior research professor of medicine Timothy Richardson, who leads the program's medicinal chemistry core. These researchers are developing new Alzheimer's therapies targeting 13 different proteins in the brain.
"With local partners such as the Indiana Biosciences Research Institute and Purdue University, a growing international network and the strong pharma presence of Eli Lilly and Company, IU has the potential to be a major force in leading the field toward new disease solutions for decades to come," Palkowitz said.
IU's global impact also includes the National Centralized Repository for Alzheimer's Disease and Related Dementias, a central biobank that enables scientists from around the world to access critically important biological samples for new and ongoing research, an effort led by Tatiana Foroud, executive associate dean for research affairs at the IU School of Medicine and IU Distinguished Professor.
"We're like your Amazon of samples for Alzheimer's and for Parkinson's," Foroud said.
The Indiana Alzheimer's Disease Research Center, led by Andrew Saykin, has been at the forefront of dementia research for more than 30 years. And the MODEL-AD program - Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease - led by IU Distinguished Professor Bruce Lamb, provides Alzheimer's researchers with 40 different animal models used in pre-clinical research before human clinical trials begin.
Apostolova leads the Longitudinal Early-Onset Alzheimer's Disease Study. Known as LEADS, this landmark IU School of Medicine study that launched in 2018 is following more than 600 cognitively impaired adults ages 40 to 64 over their lifetimes. LEADS aims to unlock the mysteries of why Alzheimer's disease progresses nearly five times faster in this younger population than it does for people with late-onset disease.
"I believe our unique cohort will be of great interest to pharmaceutical companies," Apostolova said. "These individuals hold unknown facts and potential hints for finding cures for Alzheimer's."
This research is growing to include five international sites, adding to its 18 data collection sites in the U.S., through a $704,523 grant from the Alzheimer's Association Greater Indiana Chapter to fund International LEADS. The grant will support new sites in Buenos Aires, Argentina; Amsterdam, the Netherlands; Barcelona, Spain; London, England; and Malmö, Sweden.
"Although the U.S. is a really nice melting pot, we might see that populations within different countries present differently for early-onset Alzheimer's disease," Apostolova said. "Our goal is to seamlessly include the international data into one larger repository and study the disease globally across the world."
Mitigating side effects of new Alzheimer's drugs
While the recent breakthrough in Alzheimer's treatment is widely celebrated, Wilcock aims to make new therapies safer for all patients who could benefit from them. About a quarter of patients who take amyloid-targeting drugs experience brain bleeding or swelling.
Wilcock recently received a $3.36 million grant from the National Institute of Neurological Disorders and Stroke to study why these patients are developing amyloid-related imaging abnormalities, known as ARIA, which can be seen on MRI scans.
"There's a lot of evidence to suggest that ARIA is being driven by a neuroinflammatory event," said Wilcock, who is also a primary member of the Stark institute.
Wilcock hopes patients who are identified as high-risk for amyloid-related imaging abnormalities will one day be able to take a complementary therapy to reduce or eliminate that risk while still benefiting from the new class of Alzheimer's drugs now on the market. Symptoms may include headache, confusion, nausea and dizziness.
"This grant will aim to investigate the causes of these abnormalities and how to stop them from happening," she said.
Wilcock first began studying amyloid-related imaging abnormalities in mouse models more than two decades ago. Working with new imaging technologies and better models from MODEL-AD, her research team will evaluate the processes happening around blood vessels that might be driving these events in the brain. She's also studying the role of an enzyme that is significantly activated when given antibody immunotherapies like lecanemab and donanemab.
"If we had a means of saying to someone, 'You're at higher risk of ARIA, but we know if we give you an adjunct therapy of a drug that's already approved, it will reduce or eliminate your ARIA risk,' that would open the therapy to a much broader population," Wilcock said.
For those in the early stages of Alzheimer's who are at lower risk for these abnormalities, the new anti-amyloid drugs are proving to be helpful in slowing disease progression.
"That's a big deal," Brosch said. "That's time for a person to be living more independently and traveling and enjoying their grandchildren."
The emergence of these drugs is only the "end of the beginning" for discoveries in Alzheimer's treatment. IU researchers will continue to be at the forefront of this life-changing research.
"I think there's really going to be exponential growth from this point forward," Wilcock said.
Now, with almost 100 patients receiving the new lecanemab treatment at IU Health - and the program poised to increase this number significantly through 2024 and onward - Wilcock and Brosch are working with Dage, the blood biomarker specialist, and associate professor of radiology and imaging sciences Shannon Risacher, an MRI specialist, to collect blood samples, MRI images and other data from these patients. Studying biometric signatures will allow IU researchers to better identify people who are at risk of adverse events, as well as those who stand to benefit the most.
"We hope to identify pathways that can be targeted to prevent side effects in the first place, allowing more patients to be helped by these drug therapies," Wilcock said.
