The International Genomics of Alzheimer's Project will bring together the four biggest Alzheimer's disease research consortia and create the largest database of cases and controls ever studied. David Holmes asks what took them so long...
Studies find possible new genetic risk factors for Alzheimer's disease
NIH-funded genome-wide association study is largest ever conducted in Alzheimer’s research
Scientists have confirmed one gene variant and have identified several others that may be risk factors for late-onset Alzheimer's disease, the most common form of the disorder. In the largest genome-wide association study, or GWAS, ever conducted in Alzheimer's research, investigators studied DNA samples from more than 56,000 study participants and analyzed shared data sets to detect gene variations that may have subtle effects on the risk for developing Alzheimer's. The National Institutes of Health funded the study appearing April 3, 2011 in the online issue of Nature Genetics.
"New technologies are allowing us to look at subtle genetic differences among large groups of study participants. By comparing people diagnosed with Alzheimer’s with people free of disease symptoms, researchers are now able to discern elusive genetic factors that may contribute to risk of developing this very devastating disease," said Richard J. Hodes, M.D., director of the National Institute on Aging (NIA). "We are entering an exciting period of discoveries in genetics that may provide new insights about novel disease pathways that can be explored for development of therapies."
The Alzheimer's Disease Genetics Consortium (ADGC), a collaborative body established and funded by the NIA, part of the NIH, coordinated the study. The research reported today involved investigators at universities and research centers across the country. Datasets were funded in part by the NIA, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Center for Research Resources, all part of the NIH. The Alzheimer’s Association, U.S. Department of Veterans Affairs, Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research also lent support. Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine, Philadelphia, directs the ADGC, which also received Recovery Act funds in 2009.
Until recently, only one gene variant, Apolipoprotein E-e4 (APOE-e4), had been confirmed as a significant risk factor gene for the common form of late-onset Alzheimer’s disease, which typically occurs after age 60. In 2009 and 2010, however, researchers confirmed additional gene variants of CR1, CLU and PICALM as possible risk factors for late-onset Alzheimer’s. This newest GWAS confirms that a fifth gene variant, BIN 1, affects development of late-onset Alzheimer’s. It also identified genetic variants significant for Alzheimer’s at EPHA 1, MS4A, CD2AP, and CD33. The genes identified by this study may implicate pathways involved in inflammation, movement of proteins within cells, and lipid transport as being important in the disease process.
In addition, a second paper appearing online in the journal presented GWAS findings for Alzheimer's by another scientific team. The United Kingdom-based group, led by Julie Williams, Ph.D., Cardiff University School of Medicine, Wales, found the same genes as risk factors and identified a gene variant ABCA7 as an additional gene of interest. Components of the NIH involved in or supporting the study included the NIA, the National Heart, Lung and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases. Some private support came through the independent Foundation for the National Institutes of Health.
"Researchers conducting GWAS are looking for genetic variations that may have a smaller effect but still play a role in the disease," said Schellenberg. "Our findings bring us one step closer to a fuller understanding of the genetic basis of this complex disease, although more study is needed to determine the role these genetic factors may play in the onset and progression of Alzheimer’s."
Schellenberg said the study was made possible by the research infrastructures established and funded by the NIA, including 29 Alzheimer's Disease Centers, the National Alzheimer's Coordinating Center, the Genetics of Alzheimer’s Disease Data Storage Site, the Late-onset Alzheimer's Disease Family Study, and the National Cell Repository for Alzheimer's Disease. They collect, store and make available to qualified researchers DNA samples, datasets containing biomedical and demographic information about participants, and genetic analysis data.
The NIA leads the federal government effort conducting and supporting research on aging and the health and well being of older people. For more on health and on aging generally, go to www.nia.nih.gov. The NIA provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer's Disease Education and Referral (ADEAR) Center at www.nia.nih.gov/alzheimers. To sign up for e-mail alerts about new findings or publications, please visit either website.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Naj, A.C., et al. Common variants of MS4A4/MS4A6E, CD2AP, CD33 and EPHA 1 are associated with late-onset Alzheimer's Disease. Nature Genetics. Epub April 3, 2011.
Hollingworth, P., et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA 1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genetics. Epub April 3, 2011.S
PHILADELPHIA - In the largest study of its kind, researchers from a consortium led by the University of Pennsylvania School of Medicine, the University of Miami, and the Boston University School of Medicine, identified four new genes linked to Alzheimer's disease. Each gene individually adds to the risk of having this common form of dementia later in life. These new genes offer a portal into what causes Alzheimer's disease and is a major advance in the field.
The study, conducted by the Alzheimer's Disease Genetics Consortium, reports genetic analysis of more than 11,000 people with Alzheimer's disease and a nearly equal number of elderly people who have no symptoms of dementia. Three other consortia contributed confirming data from additional people, bringing the total number of people analyzed to over 54,000. The consortium also contributed to the identification of a fifth gene reported by other groups of investigators from the United States, the United Kingdom, France, and other European countries. The findings appear in the current issue of Nature Genetics.
The study is the result of a large collaborative effort with investigators from 44 universities and research institutions in the United States, led by Gerard D. Schellenberg, PhD, at Penn, with primary analysis sites at Miami, led by Margaret A. Pericak-Vance, PhD, and Boston, led by Lindsay A. Farrer, PhD.
"This is the culmination of years of work on Alzheimer's disease by a large number of scientists, yet it is just the beginning in defining how genes influence memory and intellectual function as we age. We are all tremendously excited by our progress so far, but much remains to be done, both in understanding the genetics and in defining how these genes influence the disease process," Schellenberg said.
Until recently, only four genes associated with late-onset Alzheimer's have been confirmed, with the gene for apolipoprotein E-e4, APOE-e4, having the largest effect on risk. The Nature Genetics studies add another four -- MS4A, CD2AP, CD33, and EPHA1 - and contribute to identifying and confirming two other genes, BIN1 and ABCA7, thereby doubling the number of genes known to contribute Alzheimer's disease.
The researchers' ultimate aims are two fold. First, identification of new Alzheimer's disease genes will provide major clues as to its underlying cause. Genetic studies can provide new insights into the molecules at the center of the disease. Gaining this type of understanding is critical for drug discovery since the currently available treatments are only marginally effective.
Second, gene discovery of the type highlighted in the Nature Genetics article will contribute to predicting who will develop Alzheimer's disease, which will be important when preventive measures become available. Knowing these risk genes will also help identify the first disease-initiating steps that begin in the brain long before any symptoms of memory loss or intellectual decline are apparent. This knowledge will help researchers understand the events that lead to the destruction of large parts of the brain and eventually the complete loss of cognitive abilities.
Currently, Alzheimer's genetics researchers are coming together for an even larger, similar study. The Alzheimer's Association in the US and the Fondation Plan Alzheimer in France have funded the formation of the International Genomics of Alzheimer's Project, whose members met for the first time in November 2010 in Paris.
The research published in Nature Genetics was supported by the National Institute on Aging, part of the National Institutes of Health, which includes 29 Alzheimer's Disease Centers, the National Alzheimer's Coordinating Center, the NIA Genetics of Alzheimer's Disease Data Storage Site, the NIA Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease. These Centers collect, store and make available to qualified researchers DNA samples, datasets containing biomedical and demographic information about participants, and genetic analysis data.
ABOUT ALZHEIMER'S DISEASE
Alzheimer's disease is a progressive neurodegenerative disorder for which there are no prevention methods. Available drugs only marginally affect disease severity and progression, making Alzheimer's disease effectively untreatable. Alzheimer's disease invariably progresses to complete incapacitation and death over a period of several years. The risk for Alzheimer's disease increases exponentially with age with a prevalence of 3-5% for 65-69 years increasing to ~30-40% for 85-89 years. In the United State, 3-5 million people have Alzheimer's disease, costing $24.6 billion per year for health care and an additional $36.5 billion per year for lost productivity, worker absenteeism, and replacement. The cost in human suffering is incalculable. There are 35 million people with Alzheimer's disease world-wide. As the population ages, in the US, Alzheimer's disease cases will increase to 8-16 million by 2050, with 1 in 45 Americans affected. Alzheimer's disease will add enormously to future US health care costs. Identification of genes that contribute to Alzheimer's disease risk and that influence other characteristics of Alzheimer's disease will reveal basic pathogenic mechanisms, identify proteins and pathways for drug development, and provide genetic methods for determining people at greatest risk for when preventative measures become available.
PHILADELPHIA - The launch of the International Genomics of Alzheimer's Project (IGAP) - a collaboration formed to discover and map the genes that contribute to Alzheimer's disease – was announced today by a multi-national group of researchers. The collaborative effort, spanning universities from both Europe and the United States, will combine the knowledge, staff and resources of four consortia that conduct research on Alzheimer's disease genetics.
The four groups are:
The European Alzheimer's Disease Initiative (EADI) in France led by Philippe Amouyel, M.D., Ph.D., at the Institute Pasteur de Lille and Lille University.
The Alzheimer's Disease Genetics Consortium (ADGC) from the United States led by Gerard Schellenberg, Ph.D., at the University of Pennsylvania School of Medicine.
The Genetic and Environmental Risk in Alzheimer's Disease (GERAD) from the United Kingdom led by Julie Williams, Ph.D., at Cardiff University.
The neurology subgroup of the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) led by Sudha Seshadri, M.D., at Boston University.
“Identification of genes that contribute to Alzheimer's risk and that influence the progression of disease will help lead us to the cause of the disease, identify proteins and other new targets for drug development, and provide genetic methods for determining which people are at greatest risk for Alzheimer's disease when preventative measures become available,” said Dr. Schellenberg. “This is extremely important work in taking our ability to detect and treat Alzheimer's disease to the next level,” said Dr. Amouyel.
While each consortium alone is currently working with thousands of participants – including people with Alzheimer's and those free of dementia – scientists in the four groups recognize that only by working together can they amass a large enough collection of participants to accelerate gene discovery. Formation of IGAP creates a shared resource database that includes genetic data for the more than 40,000 individuals.
Drs. Amouyel, Schellenberg, Seshadri and Williams are enthused about the collaboration that brings together, for the first time, all of the large genetics groups in the world working on Alzheimer's disease. They share high expectations that the cooperative effort will greatly advance knowledge about Alzheimer's disease.
“Working together on this scale will bring us years closer to understanding this cruel disease, and to the development of new Alzheimer's treatments,” said Dr. Williams.
“We're pleased to fund this project that will bring together well-established and highly regarded research groups throughout the world to enable an unprecedented sharing and analysis of Alzheimer genetic data,” said William Thies, Ph.D., Alzheimer's Association Chief Medical and Scientific Officer, and Philippe Lagayette, President of the Fondation Plan Alzheimer in France.
Alzheimer's disease is a progressive, neurodegenerative disorder that is fatal, and has no prevention methods and no cure. Available drugs only marginally affect disease severity, making Alzheimer's disease effectively untreatable. Alzheimer's disease invariably progresses to complete incapacitation and death over a period of several years.
In the World Alzheimer Report 2010, Alzheimer's Disease International estimates that there are now 35.6 million people living with dementia worldwide, increasing to 65.7 million by 2030 and 115.4 million by 2050. According to the Report, the total estimated worldwide costs of dementia are US$604 billion in 2010.
“The skyrocketing prevalence and cost of Alzheimer's disease and related dementias will soon undermine the delivery of healthcare worldwide,” said Dr. Schellenberg. “That gives innovative collaborations like this new international genomics project added incentive to act quickly and boldly to make new discoveries.”
“Our first efforts will be to bring together all the data from the different groups so that they can be analyzed,” said Dr. Amouyel. “The next step will be to perform new analysis on subjects not yet in any genetics studies to further increase the number of people in our studies and to increase the ability to detect new genes.”
The International Genomics of Alzheimer's Project (IGAP)
The primary goal of IGAP is to completely understand the role inheritance plays in Alzheimer's disease. To achieve this goal, IGAP will work to identify all the genes that contribute to the risk of developing this disease. IGAP investigators will have access to combined genetic data from a large number of Alzheimer's disease subjects and compare it to genetic data from an equally large number of elderly people who do not have Alzheimer's. In the initial phase of the work, more than 20,000 people with Alzheimer's and about 20,000 healthy elderly subjects will be compared. As the study progresses, 10,000 additional people with Alzheimer's and the same number of healthy elderly subjects will be added to the study. The subjects for these studies come from different Alzheimer research project locations across Europe, the UK, the US, and Canada. Results from IGAP studies will be presented at scientific meetings and publications as the information is developed. IGAP expects to present its first findings at the Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD) in Paris, July 16-21, 2011.
The ADGC is supported by the National Institute on Aging/National Institutes of Health (NIH). The EADI is supported by the Fondation Plan Alzheimer, the Institut Pasteur de Lille and Inserm. GERAD is supported by the Medical Research Council (UK). CHARGE is supported by the NIH, Erasmus University and others.
The national effort to better understand, diagnose and treat Alzheimer's disease was recently advanced with millions of dollars in research funding by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH). The awards, funded under the American Recovery and Reinvestment Act, will enable scientists to pursue new and ongoing studies to identify additional risk factor genes associated with Alzheimer's, improve diagnostic tools, find bio markers, develop therapies, conduct clinical trials and explore preventive measures. The grants will focus on Alzheimer's disease and on age-related cognitive change --changes in thinking, learning, and memory that can come with growing older.
"We are delighted to announce the award of Recovery Act funds to many dedicated, hardworking scientists committed to advancing scientific discovery into Alzheimer's disease and cognitive impairment," said NIA Director Richard J. Hodes, M.D. "Over the next two years, the recipients will use this unprecedented boost in research funds to help reach our ultimate goal of understanding age-related cognitive decline and reducing the individual and societal burden of this devastating disease."
More than 100 Alzheimer's research grants were awarded under the Rec overy Act, which are listed at http://grants.nih.gov/recovery/ . The grants featured here highlight how these funds will expand research. Some of the funding will advance the work of existing NIA initiatives that benefit from large-scale collaborative, interdisciplinary research:
The AD Genetics Consortium and more -- Identifying genes affecting risk for late-onset Alzheimer's
A grant of more than $5.4 million will add 3,800 Alzheimer's patients and an equal number of people free of the disease to a previously funded study by the Alzheimer' Disease Genetics Consortium (ADGC). Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine in Philadelphia, leads the consortium, which aims to identify the additional risk factor genes for late-onset AD. All of these study participants are currently enrolled in the NIA-funded national network of 29 Alzheimer's Disease Centers (ADCs). When added to the samples from other sources, this will make available one of the largest collections of samples to perform genome-wide association studies (GWAS) in an effort to identify the susceptibility and protective genes influencing the onset and progression of late-onset disease. The large number of DNA samples brought together in this study may enable the researchers to detect genes whose individual effects in the disorder may be small but may still play a role.
The ADGC will use research infrastructures previously established by NIA: DNA samples will be stored at the National Cell Repository for Alzheimer's Disease for distribution to qualified researchers; the datasets, containing a wealth of information about participants, are stored at the centralized database for the ADCs run by the National Alzheimer Coordinating Center; genetic analysis data will be stored at the AD Genetics Data storage site at the University of Pennsylvania. The combined resources will allow scientists also to search for genes associated with a number of traits associated with Alzheimer's, as well as for genes related to cognitive decline.
"This funding will bring us closer to identifying the elusive genetic variations that contribute to overall risk and development of late-onset Alzheimer's disease," said Marcelle Morrison-Bogorad, Ph.D., director of the NIA Division of Neuroscience. "With this large sample size and the rapid DNA sample and data sharing, there are tremendous opportunities for defining new disease pathways that could lead to the development of new therapies."
NIA Awards $19.5 Million to AD Genetics Consortium for GWAS
The NIA recently awarded a 5-year, $19.5 million grant to the Alzheimer's Disease Genetics Consortium (ADGC) to conduct a genome-wide association study (GWAS) to identify the remaining genes associated with an increased risk of developing late-onset Alzheimer's disease (AD). Dr. Gerard D. Schellenberg of the University of Pennsylvania School of Medicine will lead the study.
GWASs require a large number of samples to be studied to detect significant differences in genetic associations between people who have AD and those who do not. The ADGC is a collaborative effort of AD geneticists who are collecting more than 10,000 cases and 10,000 controls for such a study. In this study, investigators will look for genes that may influence the age of AD onset, rate of progression, and AD-related biomarkers. They will also be able to look for genes associated with age-related cognitive decline.
Identifying the remaining risk-factor genes will provide insight into new pathways that result in late-onset AD, a first step in the development of drugs to combat development of AD. It will also help identify people at high risk of developing late-onset AD, who would be prime candidates for prevention therapies and clinical trials.