Timothy J. Hohman

Timothy Hohman

Vanderbilt University Medical Center has been awarded a five-year, $31.7 million grant from the National Institute of Aging to aggregate data and research on Alzheimer’s disease and related dementias. Dr. Timothy Hohman, Vanderbilt associate professor of neurology and one of three principal investigators for the project shared a more in-depth view of the effort with the Post.

How many different data sets/sites will this project aggregate? 

The Alzheimer’s Disease Sequencing Project includes more than 60 cohort studies and has already released processed genetic sequencing data for more than 20,000 individuals. The study is projected to expand to 100,000 participants across even more cohort studies by 2024. For this grant, we are establishing the ADSP Phenotype Harmonization Consortium and proposed to begin by harmonizing data for 31 of the cohort studies. As a few examples, we will be harmonizing data from the National Alzheimer’s Coordinating Center dataset that pools data across the NIA-funded AD Research Center network. Other datasets include the Alzheimer’s Disease Neuroimaging Initiative dataset, the Washington Heights Inwood Columbia Aging Project dataset from New York City, the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study all out of Rush University Medical Center in Chicago, and a number of cohort studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium just as a sample.

Across these cohort studies, we will be harmonizing a number of different data types including:

  • Cognitive data (like an individual’s memory ability)
  • Magnetic resonance imaging data that are used to quantify changes in the structure of the brain. This includes the size of parts of the brain like the hippocampus that is important for memory, or the white matter tracts in the brain that are important for transmission of signals from one region of the brain to another.
  • Positron emission tomography data that are used to measure the build-up of damaging proteins in the brain of living patients. We are focusing on amyloid plaques that are hallmarks of AD, but hope to expand to the emerging PET measures of tau tangles in the future.
  • Fluid biomarkers, like measures of those same proteins (amyloid and tau) in the cerebrospinal fluid that can be evaluated in living patients and are robust markers of protein changes in the brain.
  • Vascular risk factors (like smoking status, diabetes, or heart disease) and direct measures of vascular disease with MRI. This will help us incorporate important measures of vascular health that are known to co-occur with Alzheimer’s disease and contribute to the clinical progression of the disease.
  • Autopsy measures of neuropathology. A large number of the studies included in the ADSP include optional brain donation, so we will have the opportunity to harmonize direct measures of amyloid and tau pathology from postmortem brain tissue to better understand the genetic contributors to these important hallmarks of the disease.

How many patients’ data will be used?

We estimate that we will have harmonized brain imaging data from more than 20,000 individuals, harmonized autopsy data from 10,000 individuals, and harmonized cognitive data from more than 60,000 individuals by the end of the five-year grant period.

From a diversity perspective, how does this study compare to other Alzheimer’s studies?

The ADSP has intentionally focused on enriching for cohort studies that include under-represented minority populations to ensure the genetic analyses completed in the ADSP are applicable to the entire population. In particular, many of the cohort studies included are enriched for African American and Latinx participants. In fact, some of the earliest work from our cognitive harmonization team in the first year of the award will focus on tackling data harmonization across languages (for cohorts in which the testing is performed in both English and Spanish) due to the large number of Spanish speaking cohorts included in the ADSP.

How many VUMC students and staff will be working on this project?

We will have at least 20 members of our team at Vanderbilt working on this project, and of course many large teams working with us from around the country.

Who will be able to use the data that is collected?

Data will be available to qualified investigators around the world. This means that researchers who have received approval from an Institutional Review Board (for the safety of participant data) can request and access these genomic and phenotypic data from the ADSP. The data portal can be accessed here: https://www.niagads.org/

Explain how this project will make connections between genes

While this project sets the stage for some very important genomic analyses, the focus is just on harmonizing the phenotype data (e.g., outcomes) and making it available to the research community. That said, the project is one component of the much larger Alzheimer’s Disease Sequencing Project family of studies. This includes large teams focused on genomic processing and annotation (preparing the genomic data like we are preparing the phenotype data), analytics including machine learning and artificial intelligence (discover novel genetic effects), specialized genomic analysis to identify protective genetic variants and assess genetic contributions across ancestral backgrounds, and even functional genomics workgroups that focus on how we move from a discovered genetic association to a mechanism and therapeutic target. So our team is just one part of a much larger effort, all of us working together to try and solve this terrible disease!

What other institutions and organizations are involved in this effort?

The project includes 12 institutions outside of VUMC and Vanderbilt University including the University of Miami, the University of Southern California, Boston University Medical Center, Columbia University Medical Center, Indiana University School of Medicine, Stanford University, University of Pennsylvania, University of California Davis, University of California San Francisco, the University of Texas Health San Antonio, the University of Washington in Seattle, and Washington University in St. Louis.

Will the data be used primarily to help doctors diagnose patients or to develop drugs?

These are both important goals of the ADSP. Genomics data are incredibly valuable for identifying causal pathways of disease that can be leveraged to develop novel therapeutics, and that is certainly a major goal of many of the ADSP initiatives. Additionally, genomic data can be leveraged with the deep measures we are harmonizing here for precision diagnostics; these data can be leveraged to help identify the right patient for the right treatment at the right time, or even to identify future patients before they begin to experience symptoms to help initiate preventative measures.