WashU, Pitt awarded $10.7 million for Alzheimer’s disease research – Washington University School of Medicine in St. Louis

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Study to find genetic pathways that lead to the formation of plaques and tangles

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Despite decades of research and investment, the genetic basis of Alzheimer’s disease is still largely unknown, hampering drug development and early detection efforts. To change that, a new grant will support the first comprehensive study to use whole genome sequencing to fill critical gaps in knowledge about the disease. The five-year project, valued at $ 10.7 million, is led by researchers from the Washington University School of Medicine at St. Louis and the Graduate School of Public Health at the University of Pittsburgh.

The research team, funded by the National Institutes of Health’s National Institute for Aging Research (NIH), plans to identify the genetic variants, genes, and pathways that lead to the formation of plaques and tangles, two specific signs of disease – called biomarkers – that begin to appear in the brain of people with Alzheimer’s disease 15 to 25 years before they show symptoms.

Cruchaga

“Genetic studies of measurable traits such as plaques and tangles offer advantages over other classic case-control studies because these traits appear earlier and are more closely related to the biology behind the disease,” said Dr. Carlos Cruchaga, co-principal investigator on the study and the Reuben Morriss III professor of neurology at Washington University School of Medicine. “In addition, studying these traits is more likely to identify drug targets along the genetic pathways that lead to disease. This genetic information can help us better predict disease risk at the individual patient level. “

Cruchaga, also a professor of psychiatry, works with co-principal investigator Ilyas Kamboh, PhD, professor of human genetics and epidemiology at Pitt Public Health. Together they plan to examine up to 5,000 participants at high risk of Alzheimer’s disease. Researchers will collect biomarker data to identify genetic variants that appear decades before the disease’s clinical symptoms.

“All of the clinical trials looking for a drug to fight Alzheimer’s disease have failed because they focused on patients who have already developed the disease so they already had high levels of plaques and entanglements,” said Kamboh. “Once you have the plaques and tangles, it seems like an irreversible process, so let’s focus on the preclinical stage of the disease.”

According to the World Health Organization, Alzheimer’s disease is the most common form of dementia, with around 50 million cases worldwide and 6 million new cases each year. It is a major cause of disability and addiction in the elderly.

The plaques and tangles in the brain associated with Alzheimer’s can be thought of as cholesterol in the arteries of the heart and linked to heart disease, Kamboh explained. Cholesterol can calmly build up on the walls of the coronary arteries for years without causing symptoms until it causes a heart attack and irreversibly damages the heart. Some genes cause people to accumulate more cholesterol and an understanding that can enable people to take medications and change their lifestyle to reduce their risk of heart disease. It can also lead drug companies to develop drugs that target the genetic pathways that lead to the formation of cholesterol deposits.

The new project will investigate the genetic basis of plaques and tangles known to define Alzheimer’s disease and those caused by abnormal accumulation of amyloid beta and tau proteins, respectively. Both can be detected early in the brain of people living by neuroimaging and cerebrospinal fluid testing.

“In the past, we could only identify these plaques and tangles after death through a brain autopsy,” said Kamboh. “Now we can identify them while people are alive.”

However, these imaging and fluid collection techniques are expensive and can be invasive.

“New methods are currently being developed to detect the presence of abnormal amyloid beta and tau proteins in lower-cost blood tests,” said Cruchaga. “We hope that with more information about the genes associated with plaques and tangles, we can uncover underlying pathways that lead to Alzheimer’s disease and discover potential drug targets.”

This study is supported by the National Institutes of Health (NIH) National Institute of Aging Research. License number R01 AG064877.

The 1,500 faculty physicians at Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching and patient care and is consistently one of the best medical schools in the country according to US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its connections with the Barnes-Jewish and St. Louis Children’s Hospitals.

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