Teams of scientists will use support from the National Institutes of Health to conduct research into the genetic underpinnings of Alzheimer’s disease, analyzing how genome sequences—the order of chemical letters in a cell’s DNA—may contribute to increased risk or protect against the disease. The NIH awarded grants for using innovative new technologies and computational methods for the analysis. The scientists also will seek insights into why some people with known risks do not develop the disease.

Scientists hope new research will provide better understanding of Alzheimer’s disease.

The awards, expected to total $24 million over four years, go to eight academic medical centers that have been at the forefront of research in Alzheimer’s genetics: 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 University of Texas, Houston.

The investigators will analyze the genome sequencing data generated during the first phase of the Alzheimer’s Disease Sequencing Project (ADSP), an innovative collaboration that began in 2012 between the National Institute on Aging (NIA) and the National Human Genome Research Institute (NHGRI), both part of NIH. The first phase of the project determined the order of all 3 billion letters in the individual genomes of 580 participants. It also generated 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. Funds supporting the new analysis come from fiscal 2014 additions to the NIA budget directed at intensifying Alzheimer’s research.

“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 NIH Director Francis S. Collins, MD, PhD.

The effort is critical to accomplishing the genetic research goals outlined in the National Plan to Address Alzheimer’s Disease , first announced by the U.S. Department of Health and Human Services in May 2012 and 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 dementias. Its primary research goal is to prevent and effectively treat Alzheimer’s disease by 2025. The recommendation to conduct these specific types of studies came from the NIH-supported Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention, and applications were submitted in response to an NIH call for applications 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, MD.

With these awards, multiple research teams will use the ADSP data to identify rare genetic variants that protect against, or contribute to, Alzheimer’s disease, explore differences in data from different racial/ethnic groups, and examine how brain images and other biomarkers are associated with genome sequences.

The projects made possible by the new funding are:

The Consortium for Alzheimer’s Sequence Analysis (CASA). This five-university collaboration received a $12.6 million grant to analyze ADSP whole exome and whole genome sequence data generated from 6,000 volunteers with Alzheimer’s disease and 5,000 older participants free of the disorder. They also will study genomic data from 111 large families, a portion of which are of Caribbean Hispanic descent, that include multiple members with Alzheimer’s disease. The goal is to identify rare genetic variants that protect against or cause Alzheimer’s disease.

CASA principal 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 families affected with Alzheimer’s disease. Ellen Wijsman, Ph.D., University of Washington, Seattle, will receive grants expected to total $2.8 million over four years to work toward a more refined mapping of the Alzheimer’s genome in families. By identifying genomic regions that are likely to contain rare high-risk or protective Alzheimer’s variants in individual families or groups of families, this analysis of ADSP data may lead to the identification of gene variants that affect not only specific families, but that may be common to specific ethnic groups. (NIA grant U01AG049507)

Protective gene variants. Alison Goate, D.Phil., Washington University in St. Louis, will receive grants expected to total $1.7 million over four years to identify gene variants that protect against Alzheimer’s in people who are at greater risk for developing the disorder because they carry the APOE4 allele. She will examine ADSP and additional datasets to determine whether certain gene variants protect all who carry them, or only those who also carry specific genetic risk factors, and investigate whether these protective factors reduce risk in both Europeans and African-Americans. Her study will also explore how gene variants influence the age of onset of the disease. (NIA grant U01AG09508)

Risk and protective genes and the Alzheimer’s phenotype. Sudha Seshadri, M.D., Boston University, will receive grants expected to total $3 million over four years to detect genetic variants associated with increased risk of, or protection from, Alzheimer’s in ADSP data from 5,000 people who developed the disease despite being at relatively low risk due to age or APOE genotype, and 5,000 cognitively normal older participants who likely lack these risk gene variants. The study also involves over 10,000 additional persons from the Cohorts for Heart and Aging Research in Genomic Epidemiology   (CHARGE) Consortium. (NIA grant U01AG049505)

Identifying risk-raising and protective copy number variations. Eric Boerwinkle, Ph.D., University of Texas Health Sciences Center, Houston, will receive grants expected to total $3.8 million over four years to identify novel copy number variations (CNV) — or the number of copies of a particular gene or region of the genome that varies from one individual to the next — that are associated with risk for, or protection, from Alzheimer’s in ADSP and CHARGE consortium datasets. The investigators will use sophisticated bioinformatics and computational tools to explore the function of genes disrupted or overlapped by CNVs and their impact on disease risk in multiple ethnic and racial groups. To gain further insight, they will examine whether CNVs influence memory performance, brain images and other biomarkers of Alzheimer’s disease. (NIA grant U01AG049506)

To further the ADSP goals, the grantees will collaborate with the NHGRI Large-Scale Sequencing and Analysis Centersprogram, an NIH-supported consortium that generates and analyzes large genome sequence datasets 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.