$10.7M Grant Will Support Study of Genomic Data in Alzheimer’s

May 05, 2021 - The University of Pittsburgh Graduate School of Public Health and Washington University School of Medicine in St. Louis will lead a five-year, $10.7 million project that will explore the role of genomic data in Alzheimer’s development.

The project will be the first comprehensive study using whole genome sequencing to address a critical gap in knowledge about the disease. Funding from the National Institute on Aging will allow the research team to identify the genetic variants, genes, and pathways that lead to the formation of plaques and tangles.

These two specific biomarkers begin accumulating in the brains of people with Alzheimer’s 15 to 25 years before they show symptoms.

“All of the clinical trials to find a drug to stop Alzheimer’s disease have failed because they’ve focused on patients who have already developed the disease, so they already had high levels of plaques and tangles,” said Ilyas Kamboh, PhD, professor of human genetics and epidemiology at Pitt Public Health.

“Once you have the plaques and tangles, it seems to be an irreversible process, so we’re focused on the preclinical stage of the disease.” 

Researchers plan to work on as many as 5,000 participants derived from the Pitt and Knight Alzheimer’s Disease Research Centers with a high risk of Alzheimer’s and the associated biomarker data to identify genetic variants that manifest decades before clinical symptoms of the disease.

The WHO states that Alzheimer’s is the most common form of dementia, with about 50 million cases worldwide and six million new cases each year. It’s one of the top causes of disability and dependency among older people.

The plaques and tangles in the brain associated with Alzheimer’s can be thought of like cholesterol in the arteries of the heart that is associated with heart disease, researchers said. Cholesterol can quietly accumulate over years along the coronary arteries without any clinical symptoms, until it causes a heart attack, causing irreversible damage to the heart.

Some genes predispose people to accumulating more cholesterol. Knowing this can allow those people to take medication and make lifestyle changes that reduce their risk of heart disease. This can also prompt pharmaceutical companies to develop drugs that target the genetic pathways that lead to cholesterol formation.

The project will look for the genetic underpinnings of plaques and tangles known to define Alzheimer’s disease and formed due to abnormal accumulation of amyloid-beta and tau proteins. Both can be found early in the brains of living people through neuroimaging and testing of the cerebrospinal fluid.

“Genetic studies of plaques and tangles provide several advantages over other classic case-control studies. Plaques and tangles can be used as quantitative traits, which is a more powerful approach to identify genes implicated in disease than case-control study design,” said Carlos Cruchaga, PhD, professor of psychiatry at Washington University the Reuben Morriss III Professor of Neurology at Washington University School of Medicine.

“In addition, as these phenotypes are closer to the biology it is more likely that this study will translate the genetic findings to specific pathways leading to the identification of druggable targets. We plan to use the genetic information to create individual-level predictions to determine the risk of someone developing Alzheimer’s disease pathology." 

The researchers expect that the project will help shed light on the underlying causes of Alzheimer’s disease.

“Previously, we could see these plaques and tangles only after death, through a brain autopsy,” Kamboh said.

“Now we can identify them while people are living, but that is done through expensive imaging and invasive testing. New methods also are being developed to detect the presence of abnormal amyloid-beta and tau proteins in less expensive blood tests. Hopefully, by learning more about the genes associated with the plaques and tangles, we can uncover underlying mechanisms of Alzheimer’s disease and discover potential drug targets.”