LEADS influences African American participation in clinical research and develops new investigations for patients and their families
While at a meeting of the National Council of Negro Women Indianapolis Section in 2019, LeChelle Mabry heard about a lack of African American participants in the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) at Indiana University School of Medicine.
Alzheimer’s disease disproportionately affects African Americans, and little is known why. Mabry joined LEADS as a non-cognitively impaired participant soon after that meeting, to improve the representation in the study and spread more awareness within the African American community.
The research of LEADS also resonated at home — Mabry’s mother had Alzheimer’s disease, and she later passed away from the disease in 2021, two years after Mabry joined the study.
“I was her primary caregiver, and I wanted to know all I could about the disease,” she said. “I love learning and investigating.”
Mabry, a retired accountant and graduate of IU, is one of the 100 cognitively normal participants in the 700-person study of people between the ages of 40 and 64 at 18 sites across the United States. The other 600 participants have some type of cognitive impairment, typically either early-onset Alzheimer’s disease or mild cognitive impairment due to Alzheimer’s disease.
“We can definitively state that LEADS is the most well characterized group of people with early-onset Alzheimer’s disease in the United States,” said Liana Apostolova, MD, an IU Distinguished Professor and the Barbara and Peer Baekgaard Professor of Alzheimer’s Disease Research in the Department of Neurology at IU School of Medicine.
LEADS, led by Apostolova and her co-principal investigators Gil Rabinovici, MD, University of California-San Francisco; Brad Dickerson, MD, Massachusetts General Hospital and Harvard Medical School; and Maria Carrillo, PhD, of the Alzheimer’s Association; has received $78 million in National Institute of Aging (NIA) funding.
The five-year study, which officially launched in 2018, was the largest National Institutes of Health grant at IU School of Medicine in 2023 at $13.9 million. IU School of Medicine, a national and international leader in Alzheimer’s disease research, is ranked No. 6 in NIA funding among all medical schools in the nation, with $71.8 million in 2023.
Alzheimer’s & Dementia, the journal of the Alzheimer’s Association, dedicated a special issue to LEADS in late 2023, reflecting on key findings from researchers over the past half-decade and how they plan to grow the study in the coming years.
The study is investigating sporadic early-onset Alzheimer’s disease in people between the ages of 40 and 64. Only about 5% of the more than 6.5 million Americans living with Alzheimer’s disease have this rare form of the disease, and many don’t have a family history of the disease.
These are people who might be in the height of their career or have children still living at home, but, since early-onset Alzheimer’s disease progresses much faster than the late-onset form of the disease, it quickly hampers a person’s ability to work or manage their home. The disease not only affects a person’s memory but also their language, logic and reasoning skills.
“Our goal is to understand why some people develop this as early as they do,” said Dustin Hammers, PhD, associate professor of neurology and a co-investigator for LEADS. “Because it’s such a rare condition, we didn’t have enough data in the field until LEADS was created.”
LEADS researchers use cutting-edge technologies to advance their understanding of the disease through neuroimaging, fluid biomarkers, genetics and cognitive and clinical assessments. All data collected in LEADS is openly shared with physicians and scientists.
“When you open research ideas to the U.S. and world, we’ll be able to answer a lot more questions and get really good use of the data that participants have provided,” Hammers said.
Better representation in research means better data
When LEADS began enrolling in 2018, the team quickly learned there was a need for better representation among participants based on who initially signed up for the study. To improve inclusion, Apostolova received a supplement from the Alzheimer’s Association to recruit more diverse participants.
“This is the biggest study of its kind, and we owe it to the NIA, the Alzheimer’s Association and everyone to have good representation,” Hammers said. “If we’re making interpretations about diagnoses and trends, we should be able to accurately represent our population.”
Mabry, a member of many historically Black organizations, such as Alpha Kappa Alpha Sorority, Blacks in Government, the NAACP and the National Council of Negro Women, said there needs to be more awareness about Alzheimer’s disease in underrepresented research populations.
“My specific interest in joining LEADS was the effect upon African Americans and the awareness, or lack thereof, in our community,” Mabry said.
African Americans and Hispanics are twice as likely to have late-onset Alzheimer’s disease than white people, according to the Alzheimer’s Association. It’s unclear why these health disparities exist. Some studies indicate a correlation between higher rates of vascular disease and Alzheimer’s as well as socioeconomic factors, like health insurance and access to medical care.
Increasing the diversity of participants in LEADS has helped researchers investigate specific risk factors for early-onset Alzheimer’s disease and see why specific groups of people are more likely to have the disease and if there are any potential genetic factors, Apostolova said.
Intervening with physical activity and cognitive activities
The success of the LEADS program over the last several years has led to the creation of new sub-studies furthering the investigation into early-onset Alzheimer’s disease.“No single study can have all the answers,” Hammers said.
Lifestyle Interventions for the Treatment of Early-Onset Alzheimer’s Disease Study (LITES), sponsored by the Alzheimer’s Association and the NIA, evaluates potential treatment options for people with early-onset Alzheimer’s disease. Hammers is the principal investigator of the study. The goal of LITES is investigating whether lifestyle interventions, such as physical exercise and cognitive training, improve a person’s thinking skills or their mood. The program started recruiting participants in January, Hammers said.
“We have learned that patients with early-onset Alzheimer’s disease and their families are highly motivated to take part in the study,” Hammers said. “We hope to understand if these types of interventions are capable of being used in patients with more severe cognitive difficulty.”
The study will examine whether a computerized cognitive training program and a remote-administered guided-movement exercise training program, followed consistently over 14 weeks, are able to improve short and long-term thinking skills, mood and daily functioning for people living with early-onset Alzheimer’s disease, Hammers said.
“There are currently no treatments – behavioral or pharmacological – approved for patients with early-onset Alzheimer’s disease,” Hammers said. “Our hope is that information learned from our study will inform treatment for both early-onset and traditional Alzheimer’s disease.”
Agitation, depression and anxiety impact patients and their families
Angelina Polsinelli, PhD, assistant professor of clinical neurology and a co-investigator for LEADS, has focused some of her work in the study on investigating neuropsychiatric symptoms in people with Alzheimer’s disease as well as the impact of the disease on care partners. Neuropsychiatric symptoms, which can include depression, anxiety, hallucinations and agitation, are common in people with Alzheimer’s disease and related dementias, Polsinelli said. She compared the severity of symptoms in early-onset to late-onset, as well as early-onset to early-onset forms of dementia not related to Alzheimer’s disease.
Through studying data in a national Alzheimer’s disease database, Polsinelli found that people with early-onset Alzheimer’s disease tended to have more neuropsychiatric symptoms overall compared to the late-onset form of the disease. Some of those higher rates of symptoms, she said, may have to do with people in midlife experiencing more anxiety and depression, but the neuropsychiatric symptoms are more severe and pronounced when the person has the disease.
Polsinelli next studied neuropsychiatric symptoms in LEADS, comparing people with early-onset Alzheimer's disease to people with early-onset cognitive impairment but not Alzheimer's disease.
The early-onset non-Alzheimer’s disease group had more neuropsychiatric symptoms than those with early-onset Alzheimer’s disease, especially higher apathy, disinhibition and irritability. Polsinelli said those findings could help a physician better diagnose someone who might not have Alzheimer’s disease with another type of dementia, such as frontotemporal dementia.
“A characterization of what these neuropsychiatric symptoms look like in early-onset patients can help differential diagnosis, medication management or behavioral management,” she said.
Additionally, Polsinelli said that neuropsychiatric symptoms are also a main driver of distress for care partners and their families, even more than memory and cognition difficulties.
Polsinelli received the Sarah Roush Memorial Fellowship in Alzheimer’s Disease Research for 2024. The fellowship was established by the Indiana Alzheimer’s Disease Research Center and is funded through a generous donation from James and Nancy Carpenter and a matching contribution from Stark Neurosciences Research Institute.
She aims to better understand the experience of care partners of people living with early-onset Alzheimer’s disease. Typically, they are spouses or partners, usually of a similar age, between 40 and 64 years old. Next common are adult female children or daughters-in-law. However, cultural and social norms, community resource availability and family structure all play a role in determining who provides care, Polsinelli said.
"This is the first step in getting information from people who are living this day to day." Polsinelli said. "What do they need? What would be helpful? We want to especially talk to care partners from historically underserved and underrepresented groups to ensure the information we're getting represents our whole community and their experiences."
Through focus groups and interviews, Polsinelli will develop a questionnaire about the day-to-day needs of care partners from medical providers and other community resources. She is ultimately interested in developing a series of skills-based programs for care partners as the disease changes and progresses in each stage, from mild to moderate to severe dementia.
