The National Institutes of Health will support teams of scientists to conduct research into the genetic basis of Alzheimer’s disease, analyzing how genome sequences, which indicate the order of chemical letters in a cell’s DNA, may increase risk or protect against the disease. The NIH awarded grants to support researchers and institutions using innovative new technologies and computational methods for the analysis. The scientists will also try to understand why the disease does not develop in some people with known risks.
Expecting to total $24 million over a four-year span, the awards will be given to eight academic medical centers: University of Pennsylvania, Philadelphia; Case Western Reserve University, Cleveland; University of Miami; Columbia University, New York City; Boston University; University of Washington, Seattle; Washington University in St. Louis, and a UTHealth researcher, all of which have been at the forefront of research in Alzheimer’s genetics.
The research will study the genome sequencing data generated during the first phase of the Alzheimer’s Disease Sequencing Project (ADSP), an innovative collaboration between the National Institute on Aging (NIA) and the National Human Genome Research Institute (NHGRI), both of which were launched in 2012 and are part of the NIH. The order of all 3 billion letters in the individual genomes of 580 participants was decoded during the first phase of the project. Whole exome sequencing data (focused on the proteins influencing the disorder) of an additional 11,000 volunteers — 6,000 with Alzheimer’s compared to 5,000 controls — was also generated. Fiscal 2014 additions to the NIA budget directed at intensifying Alzheimer’s research will fund the new analysis.
“We are delighted to support the important research being accomplished under this broad-based, collaborative effort. This team effort is vital to advancing a deeper understanding of the genetic variants involved in this complex and devastating disease and to the shared goal of finding targets for effective interventions,” said Francis S. Collins, M.D., Ph.D., NIH Director.
The effort is of vital importance to accomplish the genetic research goals outlined in the National Plan to Address Alzheimer’s Disease, which were first announced by the U.S. Department of Health and Human Services in May 2012 and are updated annually. Developed under the National Alzheimer’s Project Act, the plan provides a framework for a coordinated and concentrated effort in research, care, and services for Alzheimer’s and related dementia. The primary research goal is to prevent and effectively treat Alzheimer’s disease by 2025. NIH-supported Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention recommended conducting these specific types of studies, and an NHS call for applications was issued in May 2012.
“Working closely with our NHGRI colleagues to build, store and make freely accessible to researchers the ADSP datasets, we have opened up new avenues for research. Building on that cache of data, we have moved quickly to this next stage of analyzing the data in new and innovative ways,” said NIA Director Richard J. Hodes, M.D.
A number of research teams will use the ADSP data in order to identify rare genetic variants that protect against or contribute to Alzheimer’s disease, in addition to exploring differences in data referring to racial/ethnic groups, and examining how brain images and other biomarkers are associated with genome sequences.
The following projects will receive the new funding:
The Consortium for Alzheimer’s Sequence Analysis (CASA). This is a five-university collaboration that received a $12.6 million grant to analyze the ADSP whole exome and whole genome sequence data generated from 6,000 volunteers with Alzheimer’s disease and 5,000 older participants who did not have the disorder. They also will study genomic data from 111 large families, some of which are of Caribbean Hispanic descent, including multiple members with Alzheimer’s disease. They aim at identifying rare genetic variants that can either protect against or cause Alzheimer’s disease. CASA leading investigators are: Lindsay Farrer, Ph.D., Boston University; Jonathan Haines, Ph.D., Case Western Reserve University, Cleveland; Richard Mayeux, M.D., Columbia University, New York City; Margaret A. Pericak-Vance, Ph.D., University of Miami; and Gerard D. Schellenberg, Ph.D., University of Pennsylvania, Philadelphia. (NIA grant UF1AG047133)
Genome mapping in Alzheimer’s disease-affected families. Ellen Wijsman, Ph.D., University of Washington, Seattle, will receive an expected total of $2.8 million in grants over four years in order to refine mapping of the Alzheimer’s genome in families. By identifying genomic regions likely to contain rare high-risk or protective Alzheimer’s variants in individual families or groups of families, this analysis of ADSP data may help identifying gene variants affecting not only specific families, but that could be common to specific ethnic groups.
Protective gene variants. Alison Goate, Ph.D., from Washington University in St. Louis, will receive grants expected to total $1.7 million over four years. Her work will be to identify gene variants that protect against Alzheimer’s in people who are at greater risk of developing the disorder because of being APOE4 allele-carriers. She will be examining ADSP as well as additional datasets in order to determine whether certain gene variants protect all carriers, or only those who also carry specific genetic risk factors. She will then investigate whether these protective factors reduce risk in Europeans and African-Americans alike. Her study will also address how gene variants influence the age at which preliminary symptoms of the disease are felt.
Risk and protective genes and the Alzheimer’s phenotype. Sudha Seshadri, M.D., from Boston University, will be granted an expected total of $3 million over four years to detect genetic variants linked to increased risk of, or defense from, Alzheimer’s in ADSP data collected from 5,000 people who developed the disease in spite of being at relatively low risk considering age or APOE genotype, as well as 5,000 cognitively normal older participants who apparently lack these risk gene variants. The study also features over 10,000 additional people from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
Identifying risk-raising and protective copy number variations. Eric Boerwinkle, Ph.D., from the University of Texas Health Sciences Center, in Houston, will receive grants expected to total $3.8 million over four years. He will be working to identify novel copy number variations (CNV), the number of copies of a particular gene or region of the genome that varies from one individual to the next. These are associated with risk for, or protection, from Alzheimer’s in ADSP and CHARGE consortium datasets. Sophisticated bioinformatics and computational tools will be used in order to explore the function of genes disrupted or overlapped by CNVs and their impact on disease risk in several ethnic and racial groups. Researchers will further their study by examining whether CNVs influence memory performance, brain images and other biomarkers of Alzheimer’s disease.
In order to further the ADSP goals, the grantees will collaborate with the NHGRI Large-Scale Sequencing and Analysis Centers program, a consortium supported by NIH that generates and analyzes large genome sequence datasets intended for biomedical research projects.
“The ADSP data generated over the last two years are now paving the way for cutting-edge investigations that may lead to new targets for drug development. The upcoming data analyses will be pivotal for realizing that vision,” said NHGRI Director Eric D. Green, M.D., Ph.D.
The National Human Genome Research Institute is one of the 27 Institutes and Centers within the National Institutes of Health. Its Extramural Research Program supports grants for research, as well as training and career development nationwide.
The National Institute on Aging leads the federal government effort by conducting and supporting research not only on aging but also on the health and well-being of older people. It provides information on age-related cognitive change as well as on neurodegenerative disease specifically at its Alzheimer’s Disease Education and Referral (ADEAR) Center.
Under the U.S. Department of Health and Human Services, NIH, the nation’s medical research agency, includes 27 Institutes and Centers. It is the primary federal agency that conducts and supports basic, clinical, and translational medical research. It is investigating the causes, treatments, and cures for common as well as rare diseases.