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Researchers at Indiana University School of Medicine are co-leading a 5-year, $41 million study to better understand the biological pathways underlying Alzheimer’s disease and ultimately create more personalized patient care.

IU neuroscientists lead new study laying groundwork for Alzheimer’s disease precision medicine

Andrew J. Saykin, MS, PsyD

Andrew J. Saykin, MS, PsyD

Team will utilize single cell analysis of human brain tissue as well as longitudinal brain imaging and blood-based biomarker research

INDIANAPOLIS—Researchers at Indiana University School of Medicine are co-leading a 5-year, $41 million study to better understand the biological pathways underlying Alzheimer’s disease and ultimately create more personalized patient care through the development of a blood test for multiple pathways implicated in the disease – enabling earlier and less-invasive diagnosis.

This study, titled Centrally-linked Longitudinal Peripheral Biomarkers of AD, or CLEAR-AD, is a jointly-led effort of IU School of Medicine and Mayo Clinic in Florida that will connect more than 40 experts and 13 institutions across the country and abroad to collaborate and advance Alzheimer’s disease research in a number of new directions. Funded by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), CLEAR-AD will connect advanced single-cell analysis of human brain tissue with neuroimaging and blood-based biomarker research. Through this new large-scale data, researchers hope to advance precision medicine for patients.

“While we currently have very powerful and informative measures for Alzheimer’s diagnosis, most are slightly invasive and focused on amyloid plaques and tau tangles,” said Andrew Saykin, PsyD, director of the Indiana Alzheimer’s Disease Research Center and the IU Center for Neuroimaging and one of the four principal investigators on the study. “CLEAR-AD will use a systems biology approach to better understand those factors that drive these pathological hallmarks in the first place. There has been great recent progress with the development of blood tests, but assessing multiple biological pathways earlier and noninvasively could make diagnosis more accessible and treatment plans more individually tailored for each patient.”

Through collaboration with Mayo Clinic’s principal investigators, Nilufer Ertekin-Taner, MD, PhD and Minerva Carrasquillo, PhD, CLEAR-AD will include three closely related projects that together will help researchers better formulate unique ways to understand and diagnose a disease that has impacted millions of lives and that disproportionately impacts African American and Hispanic communities. The resulting data will be rapidly shared with the scientific community to accelerate collaborative progress.

Brain tissue

The first project, led by Ertekin-Taner, will focus on studying brain tissue from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with state-of-the-science single cell and single nucleus sequencing to understand the differences in gene expression across different types of brain cells from up to seven brain regions. An unprecedented database of molecular signatures connecting brain and blood will be produced for the research community to further analyze.

Kwangsik Nho, PhD

Endophenotypes in relation to blood

The second project, led by Saykin and Kwangsik Nho, PhD, associate professor of radiology and imaging sciences at IU School of Medicine and another principal investigator of CLEAR-AD, will focus on longitudinal analysis of endophenotypes, measurable biological traits related to Alzheimer’s disease, that can be studied with MRI and PET brain imaging, fluid biomarkers and clinical tests including cognitive performance. Alzheimer’s disease hallmarks, including cognitive decline, loss of cortical thickness and hippocampal volume on MRI, and accumulation of amyloid plaque and tau tangles on brain PET scans, will be related to molecular signatures from brain cells in project one. These efforts are expected to yield new insights into mechanisms of stage-specific disease evolution and indicate potential therapeutic targets.

Multi-ethnic analysis

The third project, led by Carrasquillo, seeks to bridge current knowledge gaps in Alzheimer’s research among multi-ethnic populations and will connect molecular signatures and endophenotypes from projects one and two with patterns observed among African American and Hispanic participants from several Alzheimer’s Disease Research Centers (ADRCs) including the Indiana Alzheimer’s Disease Research Center. This is important because African American and Hispanic people are more likely to develop the disease but less likely to be diagnosed. Past research has predominately included data from white participants of European ancestry, leading to a gap in knowledge of how the disease impacts African American and Hispanic populations. Of note, the KBASE2 study by the IU School of Medicine team and partners in Seoul, Korea is focusing on an Asian population, addressing another less well-studied group. CLEAR-AD helps to address the need to develop and validate advanced diagnostic tools that can support diverse populations in accessible ways. CLEAR-AD will utilize its connection with local communities across the country, including Indianapolis, to uncover the differences in Alzheimer’s disease genes and endophenotypes, including imaging, cognition and blood biomarkers, among African American and Hispanic populations compared to their white counterparts.

“CLEAR-AD will allow us to connect what we see in peripheral blood and on imaging to what we see in brain tissue, which will be paramount in the opportunity to create the next generation of blood tests to diagnose individuals with Alzheimer’s disease even earlier when the disease is most treatable,” said Nho.

What they’re saying:

Tatiana Foroud, PhD, executive associate dean for research affairs at IU School of Medicine, said CLEAR-AD fits nicely in the broad ecosystem of Alzheimer’s disease research at the school, where physician-scientists are taking a comprehensive approach to tackling the disease.

“From basic neuroscience to clinical trials, CLEAR-AD is an intersection of the wealth of Alzheimer’s disease research taking place at IU School of Medicine,” Foroud said. ”The school is also home to other large NIA initiatives focused on Alzheimer’s disease, including the Indiana Alzheimer’s Disease Research Center, the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS), the Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) and Model Organism Development & Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD)– all of which seek to better understand Alzheimer’s disease and develop improved treatments for this devasting disorder.”

“With the availability of imaging and fluid biomarkers of Alzheimer’s disease, it is now possible to track the disease process in living individuals in research settings and in some clinical practice environments,” said Nandini Arunkumar, PhD, a program director at NIA. “The aim of CLEAR-AD is to use these biomarkers to map the progression of the disease across diverse populations and generate rich molecular data that will be the basis for the next generation of biomarkers.”

In addition to IU and Mayo Clinic, teams from the following institutions will collaborate in this research: Baker Heart & Diabetes Institute (Melbourne, Australia), Duke University, Emory University, Helmholtz Zentrum München (Munich, Germany), One Florida ADRC, Sage Bionetworks (Seattle), University of Michigan ADRC, University of Pennsylvania, University of Washington (Seattle), Washington University (St. Louis) and Weill Medical College of Cornell University.

Research described in this announcement will be supported by the National Institute on Aging of the National Institutes of Health under Award Number


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About IU School of Medicine

IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.