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Research at Boston University

All in the Genes

By Maggie Bucholt
Age & the Mind

More than five million senior citizens across the United States suffer from Alzheimer’s disease, and as more and more baby boomers turn 65, that number is expected to increase significantly. The staggering costs of caring for memory-impaired seniors who need assistance with daily living can strain the personal resources of families as well as the publicly financed Medicare system. Preventing, slowing, or stopping late-onset Alzheimer’s disease, estimated to affect one in three elderly Americans, has become a priority, prompting President Obama to boost research funding as part of a historic and ambitious plan, the National Alzheimer’s Project. Through observations of genes, proteins, and gum disease, these three Boston University researchers are at the forefront of efforts aimed at identifying risk factors and developing new pathways to therapeutic targets.

Photo courtesy of Lindsay A. Farrer

The discovery of five new genes linked to Alzheimer’s disease (AD) by geneticist Lindsay A. Farrer and his colleagues has effectively doubled the number of clues available to researchers determined to discover why certain individuals are at risk for the cruel disease that depletes memory and intellectual function.

"My research is the jumping-off point,” says Farrer. “What pathway in the body does this invoke, and how do we test it?”

Farrer is one of five primary investigators at the Alzheimer’s Disease Genetics Consortium (ADGC), which published their findings in Nature Genetics in 2011. Researchers from five universities and medical schools, including BU’s School of Medicine, lead the ADGC, which is funded by a five-year, $18.3 million grant from the National Institute on Aging (NIA). Its goal is to identify genes associated with an increased risk of developing late-onset AD, which is more common and complicated than early-onset AD.

Alzheimer’s is not fully understood; researchers have linked it to the formation of beta-amyloid, which is created when AAP, a protein on nerve cells, fails to break down. Accumulation of amyloid plaques in the brain causes neurons to die and is associated with the onset of AD symptoms.

It is believed that genetic, environmental, and lifestyle factors contribute to late-onset AD, which typically occurs after age 65. The first genetic risk factor to be discovered for this form of the disease was the apolipoprotein E (APOE) gene, and in the last few years, researchers have discovered several others. The five new genes are connected to AD through inflammatory processes, metabolism of lipids, degradation of tau protein resulting in the formation of neurofibrillary tangles in the brain (another hallmark pathological feature of AD), and the movement of molecules within cells, also known as “protein trafficking.” The watershed moment occurred in 2007, when Farrer and his colleagues identified the link between the sorting receptor protein SORL1, one of many proteins that influence the trafficking of the amyloid precursor protein (APP), and Alzheimer’s disease.

“SORL1 behaves as a traffic cop directing the processing of AAP,” he says, “either APP goes one way and is harmlessly routed out of the cell, or to another station in the cell where it becomes beta-amyloid, which in large quantities is toxic.”

In what Farrer refers to as a “frontal assault” on the disease, the Obama administration announced an $80 million increase in AD research funding last year. Farrer was one of approximately 15 researchers invited by the National Institutes of Health/NIA to design a study using “next generation sequencing” technology on an unprecedented scale. Farrer and his colleagues have submitted an NIA grant application proposing to analyze data containing entire genome or exome (the portion of the genome that encodes genes) sequences already being generated for more than 11,500 people. The project will be a massive undertaking that he estimates will take several years, if approved.

“The primary goal is to find the genetic clues that implicate biological pathways, and then find the best way to a therapeutic approach,” he says.

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