{"id":32377,"date":"2016-04-28T14:55:46","date_gmt":"2016-04-28T18:55:46","guid":{"rendered":"http:\/\/www.bumc.bu.edu\/busm\/?p=32377"},"modified":"2016-04-28T14:55:46","modified_gmt":"2016-04-28T18:55:46","slug":"unraveling-alzheimers-disease-part-4-the-gene-hunter","status":"publish","type":"post","link":"https:\/\/www.bumc.bu.edu\/camed\/2016\/04\/28\/unraveling-alzheimers-disease-part-4-the-gene-hunter\/","title":{"rendered":"Unraveling Alzheimer\u2019s Disease \/\/ Part 4 The Gene Hunter"},"content":{"rendered":"

Searching for the disease\u2019s genetic roots<\/h4>\n
\"Farrer,
Lindsay Farrer, PhD, BU Distinguished Professor of Genetics, chief of biomedical genetics, and a BU Alzheimer\u2019s Disease Center faculty member. Photo by Cydney Scott.<\/figcaption><\/figure>\n

Alzheimer\u2019s disease is an epidemic. It attacks the brain\u2019s nerve cells, causing memory loss, behavioral changes, confusion, and deterioration of language skills. It affects more than 5 million Americans 65 and older, and that is expected to increase to 13.8 million by 2050 unless science finds a treatment. Alzheimer\u2019s and other forms of dementia are projected to cost the nation $236 billion this year and the figure could reach $1 trillion by 2050, according to the Alzheimer\u2019s Association<\/a>.<\/p>\n

At Boston University, dozens of researchers are looking for tests that could lead to early diagnosis and interventions to prevent or delay the disease, running clinical trials that may result in treatments and an eventual cure, working to understand genetic risk factors, and studying Alzheimer\u2019s impact on caregivers.<\/p>\n

The Boston University Alzheimer\u2019s Disease Center<\/a>, established in 1996, is one of 31 such centers nationwide funded by the National Institutes of Health<\/a> and dedicated to conducting research into the disease, enhancing clinical care, and providing education.<\/p>\n

In this special report, BU Today<\/em> examines the work of five BU researchers.<\/p>\n

I<\/span>n 1984, Lindsay Farrer was a young medical geneticist finishing his PhD at the Indiana University School of Medicine, studying families afflicted with Huntington\u2019s disease, a devastating inherited disorder that causes nerve cells in the brain to waste away, leading to uncontrolled movements, dementia, and eventually, death.<\/strong><\/p>\n

One day, he walked into his advisor\u2019s office and saw a huge family genealogy, or pedigree, spread across the desk. \u201cIs it a new Huntington\u2019s pedigree?\u201d he asked. \u201cNo,\u201d replied his advisor. \u201cIt\u2019s Alzheimer\u2019s disease.\u201d<\/p>\n

Farrer<\/a> had never heard of Alzheimer\u2019s, and his advisor had scarce information to share: \u201cI only know a little bit about it,\u201d he said, \u201cbut we\u2019re going to find out.\u201d<\/p>\n

Three decades later, Alzheimer\u2019s has moved from the ranks of obscure diseases to the forefront of the national conversation. And Farrer, BU Distinguished Professor of Genetics, chief of biomedical genetics, and a BU Alzheimer\u2019s Disease Center<\/a> faculty member, is a leader in studying the genetics of the disease. Today, he says, genetic research offers the best hope for understanding and treating Alzheimer\u2019s.<\/p>\n

\u201cAlready we\u2019re seeing, from the genetics alone, multiple biological pathways that are somehow involved with the disease,\u201d says Farrer,. \u201cI expect that reliable biomarkers for predicting Alzheimer\u2019s and effective treatment are going to emerge from some of these gene targets. They are going to yield fruit.\u201d<\/p>\n

All the blueprints for building our bodies, from belly button to brain stem, lie in our genes. A gene is a stretch of DNA that carries the instructions for making a single protein. For example, a gene called APP<\/em> spells out the code for amyloid beta precursor protein (also called APP), a key player in Alzheimer\u2019s disease. Many genes have variants\u2014sections of code that vary from person to person, giving one woman blue eyes, for instance, and another brown.<\/p>\n

\n

\u201c<\/span>Already we\u2019re seeing, from the genetics alone, multiple biological pathways that are somehow involved with the disease,\u201d says Farrer.<\/h4>\n<\/blockquote>\n

In the early days of medical genetics, back when Farrer was starting out, scientists targeted only the simplest genetic diseases, like Huntington\u2019s, caused by mutations in a single gene. They tackled these diseases by collecting detailed patient information, drawing extended family pedigrees, profiling family members for genetic variants, and statistically analyzing the data for clues as to what variants are linked to, or track with, the unknown disease gene. When scientists had a sense of where a gene might be, they painstakingly \u201cwalked\u201d the chromosome, starting at the linked genetic variant and tagging a tiny, known sequence with fluorescent dye, then decoding, bit by tiny bit, ever-longer stretches of DNA until they found something out of the ordinary.<\/p>\n

This method, called linkage analysis, although slow and labor-intensive, led scientists in the early 1990s to discover the genes for Huntington\u2019s disease, cystic fibrosis, and the BRCA1<\/em> form of breast cancer. Then Farrer and other scientists aimed for something tougher: the genes associated with early-onset Alzheimer\u2019s, a rare form of the disease passed from parent to child, which accounts for only about 0.1 percent of cases. People with this form of the disease usually develop symptoms in their 40s and 50s. In 1991, scientists in London were the first to find genetic variants associated with early-onset Alzheimer\u2019s\u2014mutations in the APP<\/em> gene that cause the body to dramatically increase production of beta-amyloid, the sticky protein fragments that form plaques in the brains of Alzheimer\u2019s patients. Soon afterward, Farrer and colleague Peter St. George-Hyslop<\/a> at the Cambridge Institute for Medical Research in England, discovered two genes, presenilin 1 and presenilin 2, which code for proteins involved in processing APP. Almost all cases of familial early-onset Alzheimer\u2019s are caused by variants of these two genes and a third, APP<\/em>.<\/p>\n

The discovery of these three genes emboldened researchers, including Farrer, to aim for something even tougher: late-onset Alzheimer\u2019s, the more common form of the disease, typically occurring in people after age 65. A team of Duke researchers led by Allen Roses scored an early victory in 1993, using linkage analysis to find that variants in a gene called APOE<\/em> substantially increase or decrease a person\u2019s risk of getting late-onset Alzheimer\u2019s.<\/p>\n

\u201cThat was such a revolutionary finding,\u201d says Farrer. \u201cAt the time, the known primary role of apolipoprotein E\u2014the protein encoded by APOE<\/em>\u2014was to transport cholesterol. Who would have imagined that Alzheimer\u2019s disease has anything to do with cholesterol? Moreover, this discovery goes beyond Alzheimer\u2019s disease. Geneticists thought, \u2018Well, gee, we can do this for diabetes. We can do this for cancer. We can do this for all kinds of things. It turns out, however, that was not the case.\u201d<\/p>\n

\n
\n
\n
\n

Genetics of Alzheimer\u2019s<\/h3>\n<\/div>\n

<\/p>\n<\/div>\n<\/div>\n