Determining how and where Alzheimer’s disease spreads in the brain are objectives Indiana University School of Medicine researcher Meichen Yu, PhD, has been exploring for more than five years.
Now, he and his team will be the first to map and comprehensively analyze how the disease spreads and damages neural networks and pathology based on a collection of longitudinal brain imaging, genetics and brain chemistry. They will use validated biomarkers, predictive tools and computational models to accelerate biomarker discovery and therapeutic target identification, to advance precision medicine in Alzheimer's disease.
The project is part of a five-year, $1.7 million grant from the National Institute on Aging, which Yu will lead on behalf of the Medical Imaging Research Institute’s Center for Neuroimaging.
Alzheimer’s disease biomarkers offer decades of notice
Currently, more than 7 million Americans live with Alzheimer's disease symptoms, and that number is expected to double by 2060. While cases are trending substantially upwards, researchers and clinicians can now identify biomarkers, such as amyloid-beta plaques and tau accumulating in the brain as early as 20 years before dementia symptoms occur through a blood test, imaging and a clinical evaluation.
Amyloid-beta (Aβ) plaques are a distinguishable hallmark of the disease, and emerge as sticky, abnormal protein fragments that pool between nerve cells. Under normal brain function, tau helps maintain cellular structure and transports signals and nutrients to the brain. But when they become toxic from a chemical overload, tau begins to tangle and disrupt cellular function.
“We believe amyloid-beta and tau spread according to the brain network topology,” said Yu, a MIRI investigator and an assistant professor of Radiology and Imaging Sciences at IU School of Medicine, who is an investigator for both the Center for Neuroimaging and the Indiana Alzheimer’s Disease Research Center. “We study these proteins by building a brain network as well as tracking and predicting their pathway.”
Yu explained dementia symptoms, such as memory loss, begin to materialize when beta and tau begin to spread in the brain. The question he would like to answer is why these proteins accumulate in certain brain regions and then spread across a certain path.
“We don’t know whether these two proteins are collaborative or competitive in contributing to Alzheimer’s disease,” Yu said.
Researchers will work with three independent cohorts to facilitate the project, including the Indiana Memory and Aging Study (IMAS), the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). These cohorts provide national and international longitudinal datasets and validation across large, multi-ethnic populations that could later support clinical trial development.
Yu’s collaborator and mentor, Olaf Sporns, PhD, the Robert H. Shaffer Chair of the Department of Psychological and Brain Sciences at IU, is a renowned pioneer in network neuroscience, who helped shift how scientists view brain function — based on a comprehensive network and mapping of the brain which he coined “connectome.”
As part of the project, the researchers will:
- Identify multilayer connectome mechanisms that link network disruption, Aβ/tau burden and domain-specific cognitive dysfunction using data from the Indiana Memory and Aging Study, a multi-year clinical research program at the IU School of Medicine
- Develop novel connectome-based epidemic spreading models that integrate multilayer connectivity, gene expression profiles and neurotransmitter signaling to simulate spatial dynamics of Aβ/tau spread, brain atrophy and intervention effects
- Build personalized prediction models by integrating connectome data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to predict individualized Aβ/tau accumulations and cognitive decline
Yu said brain networks work much like airport hubs. “If tau and amyloid-beta target a busy hub, it will damage the entire network,” he explained. “But if they only target a small region with fewer connections, it may not have a strong effect on the entire network.”
The entorhinal region or the medial temporal lobe is the brain region where memory processing occurs, and it’s also one of the earliest areas that can collect the most tau, Yu said. As the disease progresses, it spreads to the posterior brain regions, he explained.
Imaging to help chart how tau and amyloid-beta moves
Based on data from the cohorts, the research team will construct brain networks using functional MRI or diffusion MRI and check after two years and then four years whether tau and Aβ had spread through a particular pathway. Diffusion MRI illustrates how water molecules move at the cellular level.
“There is extensive research on brain connectivity disruption in Alzheimer’s disease, but it has not made its way into the clinical, said IU MIRI Investigator Evgeny J. Chumin, PhD, assistant research professor of Radiology and Imaging Sciences and a collaborator on the project. “I think advanced MRI methods like resting state functional MRI have the potential to be a useful tool for predicting disease risk and progression. Meichen’s research under this grant will help move the field in that direction by giving us a better understanding of how brain connectivity differences among people may impact their disease course.”
Researchers hypothesize changes in multilayer brain networks could serve as reliable means in linking Alzheimer’s disease progression. By integrating complex connectivity with biological profiles, the team theorizes that they could more accurately model and predict Aβ/tau spread and neurodegeneration across a variety of populations, which could ultimately provide a strong framework for delivering more targeted interventions in treating and tracking Alzheimer's disease progression.
“The Center for Neuroimaging at IU MIRI has become a major hub for network science approaches to the brain and genomics, especially as applied to Alzheimer’s disease,” said collaborator Andrew J. Saykin, PsyD, director of the Center for Neuroimaging and the Indiana Alzheimer’s Disease Research Center (ADRC), who was among the co-authors of the 2021 Nature Reviews article, which links Alzheimer's disease to amyloid-beta and tau protein accumulation. “I am delighted that Dr. Meichen Yu was awarded a new NIH grant including advanced network analytics.”
Saykin also credited the CfN investigator, Sporns, for introducing the concept of connectome that became internationally recognized, as well as access to strong data sets offered by the Indiana ADRC, ADNI and KBASE.
“There is great synergy with new NIA-funded AI initiatives for Alzheimer's disease that will help advance analysis of structural and functional brain networks,” Saykin said.
Along with Sporns, Saykin, Chumin and Yu, the project will be supported by Sujuan Gao, PhD, professor of biostatistics & health data science at the IU School of Medicine and a new post doctoral researcher.
