Vascular pathologies and Alzheimer's disease: Probing genetic pathways

Mayo Clinic is investigating genetic pathways that may contribute to both vascular pathologies and Alzheimer's disease. Funded by the National Institutes of Health (NIH), the research involves analysis of changes at the cellular level as well as whole-brain tissue, in an effort to discover biomarkers and potential therapies for Alzheimer's disease.

"We've known for some time that the risk factors that lead to cerebrovascular disease — such as hypertension, high cholesterol and diabetes — also increase the risk of dementias, particularly Alzheimer's disease. We need to identify the pathways that may be influencing both before we can generate new therapies for Alzheimer's," says Nilufer Taner, M.D., Ph.D., a neurologist and neurogeneticist at Mayo Clinic in Jacksonville, Florida.

Mayo's research, funded by two grants totaling about $9.3 million, is part of a major NIH venture known as the Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease (M2OVE-AD) Consortium. The multicenter effort seeks to build a nuanced model of Alzheimer's disease that more accurately reflects its many causes and pathways.

Far-reaching impact

Mayo Clinic's M2OVE-AD research takes a novel approach, with parallel work occurring in patients and in laboratory models.

Under the initial grant, Mayo's Genetics of Alzheimer's Disease and Endophenotypes Laboratory, led by Dr. Taner, is analyzing brain tissue and blood samples from living patients with Alzheimer's disease and varying levels of cerebrovascular pathology. The information about gene expression obtained from the patient samples is used to build mathematical models of the diseases. The mathematical models are then tested in laboratory animal and cell models developed in Mayo's Neurobiology of Alzheimer's Disease Laboratory, led by Guojun Bu, Ph.D., who with Dr. Taner is a co-principal investigator on the NIH grants.

The Mayo researchers received an additional NIH grant in 2017 to investigate gene expression at the single-cell level. "We are generating a lot of data from whole-brain tissue. But in a disease as complex as Alzheimer's, it's critical for us also to understand the cell-specific changes," Dr. Taner says. "We hope to identify the specific cell base changes in the brain that play a role in the vascular risk factors and also contribute to Alzheimer's disease. We expect that looking at single cells will also allow us to capture an even larger number of changes than we see with whole-brain tissue."

The single cells will be derived from fresh brain tissue from patients who have neurosurgery performed by Alfredo Quinones-Hinojosa, M.D., chair of Neurosurgery at Mayo's campus in Florida and a co-investigator on this second NIH grant. With patient approval, Mayo Clinic collects for research the tissue that otherwise would be discarded after neurosurgery.

"This research is very important for developing biomarkers that can allow us to design new therapies for a devastating disease," Dr. Quinones-Hinojosa says. "This is the strength of Mayo Clinic — we partner with patients to take care of them and to find cures for their diseases so we can share our knowledge with the world."

Working in parallel with the patient-samples research, Dr. Bu will perform single-cell data analysis in mouse models. "To our knowledge, this single-cell work is unprecedented," Dr. Taner says. "Identifying specific cell-based expression changes is a major question not just in Alzheimer's disease but also in other neurological conditions. Our data will inform the field in general, with impact far beyond our own project."

Mayo Clinic's breadth of expertise allows for its participation in major initiatives such as M2OVE-AD. "Team science can only happen where there are multidisciplinary teams, each of which is at the top of its game," Dr. Taner says. "Our patients trust that we are going to be able to make a difference for these diseases — if not for them, then for the community. All of our work is laser focused on moving the field forward."

For more information

M2OVE-AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease. National Institutes of Health.