WASHINGTON D.C.—Targeted toward finding a cure for Alzheimer’s disease by 2025, the U.S. National Institutes of Health (NIH) has given researchers the green light to freely access the first batch of genome sequence data from the Alzheimer’s Disease Sequencing Project (ADSP), launched under an intensified national program to treat the irreversible, progressive brain disease.
Published research studies estimate at least 5.1 million Americans may have Alzheimer’s disease. And as more baby boomers turn 65, by 2020 as many as 5.8 million could be affected—by 2030, 8.4 million could have Alzheimer’s disease.
Dr. Marilyn M. Miller, program director of the Genetics of Alzheimer’s Disease, Tau and Hormone Research Division of Neuroscience at the National Institute on Aging (NIA), who heads the NIA’s extramural Alzheimer’s disease genetics program, said the large scope of the study is the key to success in identifying new genes and potential targets for more effective interventions.
“Because Alzheimer’s is so complex, this broad-based collaborative effort, involving so many participants, will enable us to find potential solutions to tackle the disease,” Miller stated in a news release about the data.
The first data release in this project includes whole-genome sequence (WGS) data from 410 individuals in 89 families, according to the NIH. By December, researchers had deposited completed WGS data on 61 families and had deposited WGS data on parts of the remaining 28 families, with that last set of people expected to be completed soon thereafter. Researchers can access the sequence data at the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site.
While genetics plays a key role in predicting Alzheimer’s, age is the best known risk for disease, Miller said.
“Most people with Alzheimer’s do not start showing symptoms until age 65 or older,” Miller tells DDNews. “However, in rare cases, people develop Alzheimer’s disease much earlier, between the ages of 30 and 60. This ‘early-onset’ form of Alzheimer’s always runs in families. It is caused by a mutation in one of three genes inherited from a parent that cause abnormal proteins to be formed.”
The more common “late-onset” form of the disease typically occurs after age 65, she says, adding, “While no single gene mutation is known to cause this form of Alzheimer’s, evidence of a hereditary component is mounting.”
“The U.S. reached a significant milepost in 2011 when the oldest ‘baby boomers’ turned 65,” according to Miller. “The U.S. Census Bureau estimates that the 65-and-older population will double to about 72 million during the next 20 years. This population aging is accompanied by a sobering reality: The number of people with Alzheimer’s doubles for every five-year interval past age 65, studies show. And the ranks of the very elderly—those 85 years and older and at the highest risk for Alzheimer’s—are expected to triple by 2050.”
The apolipoprotein E (APOE) gene is the strongest genetic risk factor identified to date for late-onset Alzheimer’s, Miller notes. This gene, found on chromosome 19, comes in three different forms, or alleles: ε2, ε3 and ε4. The APOE ε2 allele is the least common form, found in 5 percent to 10 percent of people, and appears to reduce risk.
The APOE ε3 allele, the most common form, is found in 70 percent to 80 percent of the population and appears to play a neutral role in the disease, Miller adds.
The APOE ε4 allele, found in 10 percent to 15 percent of the population, increases risk for Alzheimer’s disease by three- to eightfold, depending on whether a person has one or two copies of the allele, she says. The APOE ε4 allele is also associated with an earlier age of disease onset.
APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease, Miller said. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s.
“Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer’s do not have the APOE ε4 allele,” Miller said in an official statement. “Researchers are working hard to identify many other genes that may influence risk for late-onset Alzheimer’s. Those doing genome-wide association studies (GWAS) have identified a number of genes in addition to APOE ε4 that may increase a person’s risk for late-onset Alzheimer’s.”
Using high-throughput analytical approaches and a large number of DNA samples, researchers have identified 23 genes in genome-wide association studies, she continued, adding, “Using the next-generation whole-genome sequencing method, the Alzheimer’s Disease Sequencing Project is studying the DNA of families with multiple members affected by the disease. This study will help us to understand the genetic components of Alzheimer’s.”
NIH Director Dr. Francis S. Collins announced the start of the genome program in February 2012.
“Providing raw DNA sequence data to a wide range of researchers proves a powerful crowd-sourced way to find genomic changes that put us at increased risk for this devastating disease,” Collins stated in a news release. “The ADSP is designed to identify genetic risks for late-onset of Alzheimer’s disease, but it could also discover versions of genes that protect us. These insights could lead to a new era in prevention and treatment.”
The National Alzheimer’s Project Act became law in 2011 in recognition of the need to do more to combat the disease. The law called for upgrading research efforts by the public and private sectors, as well as expanding access to and improving clinical and long term care.
One of the first actions taken by NIH under the Alzheimer’s Act was the allocation of additional funding in fiscal 2012 for a series of studies, including this genome sequencing effort.
Genome sequencing is considered a key strategy to identifying new clues to the fundamental cause of Alzheimer’s disease and the development of new diagnostics and treatments. The clues come from differences in the order of DNA letters in Alzheimer’s patients compared to control groups.
The National Human Genome Research Institute (NHGRI) has devoted $25 million in sequencing capacity at its three flagship centers: The Genome Institute at Washington University in St. Louis, the Human Genome Sequencing Center at the Baylor College of Medicine in Houston and the Broad Institute of Harvard and MIT in Cambridge, Mass.
“NHGRI’s expertise in managing large sequencing initiatives is a hugely important addition to the search for the genetic roots of late-onset Alzheimer’s disease,” said NIA Director Dr. Richard J. Hodes. “Partnerships between NIH institutes, like this one between NIA and NHGRI, have proved a powerful strategy for focusing research resources on critical public health problems.”
The current deposit of genomic data includes phenotypes, such as the Alzheimer’s symptoms of affected individuals, as well as family pedigrees and other demographic information.
“These studies have been designed to have enough statistical power to discover both risk alleles and protective alleles,” said Dr. Adam Felsenfeld, director of the NHGRI Genome Sequencing Program. “The analysis of this genomic data is just getting started, and we are looking forward to what we might learn.”
While the first goal of the National Alzheimer’s Project Act is to prevent and effectively treat Alzheimer’s disease by 2025, the organization USAgainstAlzheimer’s believes the NIH goal falls short by five years. Rather than endorse the NIH plans, this Washington, D.C.-based organization is connecting networks of organizations and individuals to take action to end Alzheimer’s by 2020.
“While we support the national plan and its goals, we believe, as most every family touched by Alzheimer’s disease believes, that preventing and effectively treating Alzheimer’s by 2025 is simply too long a wait for concrete progress,” the organization’s website states. “There are promising avenues of drug discovery and development that will, if successful, deliver a means of slowing or deferring Alzheimer’s symptoms by 2020. By voicing the urgency felt by so many families, we will pressure researchers and industry to do all in their power to make that happen.”