NIH consortium to investigate vascular involvement in Alzheimer's disease

The National Institutes of Health (NIH) has launched the Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease (M²OVE-AD) Consortium, which aims to understand the complex molecular mechanisms by which vascular risk factors influence Alzheimer’s disease and also to identify new targets for treatment and prevention.

“We have known for many years that Alzheimer’s disease patients—in addition to carrying lesions such as amyloid plaques and tangles—very frequently harbor cerebral vascular lesions. We also have evidence suggesting that maintaining vascular health can positively impact or delay the onset of a number of neurodegenerative diseases,” explained Suzana Petanceska, PhD, Senior Advisor for Strategic Development and Partnerships in the National Institute on Aging’s (NIA) Division of Neuroscience.

“That's where M²OVE-AD comes in,” she said. “We're trying to actually understand the molecular networks that tie the many factors of genetic and environmental vascular risks to processes known to initiate and propagate Alzheimer's disease.”

“A growing body of research suggests vascular damage often contributes to Alzheimer’s disease,” said Roderick Corriveau, PhD, Program Director of the National Institute of Neurological Disorders and Stroke (NINDS). “This focused collaborative effort may push our understanding of Alzheimer’s disease over a tipping point and facilitate the development of better treatments for those who are suffering.”

Developed by the NIA and NINDS, the 5-year, $30-million initiative gathers more than a dozen research teams to work on five complementary projects. M²OVE-AD is combining the open-science approach with the power of new molecular technologies and big data analytics to make biological datasets available to the wider research community, NIH stated.

The teams will generate several layers of molecular data from brain tissue donated by deceased Alzheimer’s research participants and from blood cells and plasma donated by living study participants with various types of vascular risk.

“Once the data are collected, they will apply cutting-edge analytical methods to generate mathematical projections related to how the molecular networks associated with various types of vascular risks are connected to various disease traits—whether it be neuroimaging pathologic traits or cognitive traits,” Dr. Petanceska said. “So, these predictions will then be tested in a variety of animal models where various aspects of vascular physiology or AD pathogenesis can be explored at a very detailed mechanistic level.”

Projects supported by M²OVE-AD include:

• Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia: Guojun Bu, PhD, and Nilufer Ertekin-Taner, MD, PhD, Mayo Clinic in Jacksonville, FL; in collaboration with researchers at Mayo Clinic in Rochester, MN; and the Icahn Institute for Genomics and Multiscale Biology in New York, NY, will investigate how molecular networks influence vascular risk in aging, Alzheimer’s disease, and other dementias.
• Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular Disease, and Alzheimer’s Disease: José A. Luchsinger, MD, and Adam Brickman, PhD, of Columbia University in New York, and Herman Moreno, MD, of SUNY Downstate Medical Center in Brooklyn, NY, will integrate studies in humans and in animal models to examine the interplay between diabetes, Alzheimer’s, and cerebrovascular disease.
• The Role of Renin Angiotensin-Endothelial Pathway in Alzheimer’s Disease: Ihab Hajjar MD, and Arshed Quyyumi, MD, of Emory University in Atlanta, GA, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.
• Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias: A research team led by Rima Kaddurah-Daouk, PhD, of Duke University in Durham, NC, North Carolina, and Mitch Kling, MD, of the University of Pennsylvania in Philadelphia, PA, will identify and define lipidomic signatures in plasma that are associated with cardiovascular disease and cognitive changes.
• Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation: The research team led by Steven Greenberg, MD, PhD, and Brian Bacskai, PhD, at Massachusetts General Hospital in Boston, MA, will investigate the molecular mechanisms underlying cerebral amyloid angiopathy (a common but poorly understood cerebrovascular lesion) and its impact on Alzheimer’s disease.

“The ultimate goal of M²OVE-AD is threefold,” Dr. Petanceska said. The first goal is to contribute to the development of a much better predictive model of Alzheimer’s disease that reflects its heterogeneity and multifactorial etiology, she explained.

The second goal is to discover and characterize new therapeutic targets that could be tractable for disease prevention, whether it be through pharmacologic or non-pharmacologic means.

The third goal is to identify molecular signatures that can be collected non-invasively measured in peripheral fluids and can be used to stratify patients for their entry into clinical trials testing various novel therapeutics.

“This is critical if we want to attain the goal of precision medicine for Alzheimer’s disease which is to treat the right patient with the right drug at the right stage of the disease,” Dr. Petanceska said.