A key component of the Federal research program for Alzheimer’s disease is to create and sustain an infrastructure that supports and enhances scientific discovery and translation of those discoveries into the prevention and treatment of Alzheimer’s disease. NIA’s coordinating mechanisms and key initiatives are central to this effort. Specifically, important advances are being made by supporting high-quality research, from which data can be pooled and shared widely and efficiently through a well-established Alzheimer’s disease research infrastructure.
This infrastructure and initiatives described in this report seek to bring together researchers and Alzheimer’s interests by:
- Convening and collaborating in workshops in new scientific areas
- Working across NIH to vigorously discuss new science and opportunities for new investment
- Partnering with other Federal agencies, not-for-profit groups, and industry in the shared goal of improved treatments, new prevention strategies, and better programs for people with Alzheimer’s and their caregivers.
The current research infrastructure supported by NIH includes:
NIA Intramural Research Program  (IRP). In addition to funding a broad portfolio of aging-related and Alzheimer’s research at institutions across the country, NIA supports its own laboratory and clinical research program, based in Baltimore and Bethesda, MD. The NIA IRP focuses on understanding age-related changes in physiology and behavior, the ability to adapt to biological and environmental stresses, and the pathophysiology of age-related diseases such as Alzheimer’s.
This image, developed from brain scans of people with Alzheimer’s disease, depicts the average loss of brain cells in different brain areas over 2 years. It shows how the disease (in red and gray) gradually spreads through areas of the brain important to learning and memory. Courtesy of Paul M. Thompson, PhD, and Arthur W. Toga, PhD, Laboratory of Neuro Imaging, UCLA.
Laboratory research ranges from studies in basic biology, such as neurogenetics and cellular and molecular neurosciences, to examinations of personality and cognition. The IRP also conducts clinical trials to test possible new interventions for cognitive decline and Alzheimer’s disease. The IRP leads the Baltimore Longitudinal Study of Aging (BLSA), America’s longest-running scientific study of human aging, begun in 1958, which has provided valuable insights into cognitive change with age.
The IRP’s Laboratory of Behavioral Neuroscience is identifying changes that take place in the brain that may predict age-related declines in memory or other cognitive functions. Using brain imaging techniques, such as magnetic resonance imaging (MRI) that measures structural changes and positron emission tomography (PET) scans that measure functional changes, IRP researchers are tracking memory and cognitive performance over time to help identify both risk and protective factors for dementia. For example, an IRP study involving more than 500 BLSA participants uses brain imaging, biomarkers, and cognitive assessments to track over time changes in cognitive function in people who do not develop Alzheimer’s and in those who develop cognitive impairment and dementia.
Additionally, IRP researchers help identify potential drug targets for Alzheimer’s disease. They screen candidate drugs for efficacy in cell culture or animal models. The most effective compounds are moved through preclinical studies to clinical trials. IRP researchers also collaborate with academia and industry to develop agents that show promise as an Alzheimer’s intervention. Industry has licensed patents covering a variety of novel compounds from NIA for preclinical and clinical development.
Alzheimer’s Disease Centers  (ADCs). NIA’s ADCs form the backbone of the national Alzheimer’s disease research effort. These multidisciplinary centers, located at 27 institutions nationwide, promote research, training and education, and technology transfer. Thanks to the participation of people in their communities, the Centers conduct longitudinal, multicenter, collaborative studies of Alzheimer’s disease diagnosis and treatment, age-related neurodegenerative diseases, and predictors of change in people without dementia that may indicate the initial stages of disease development.
The ADCs also conduct complementary studies, such as imaging studies and autopsy evaluations. All participants enrolled in the Centers receive a standard annual evaluation. Data from these evaluations are collected and stored by the National Alzheimer’s Coordinating Center (NACC; see below) as the Uniform Data Set. The ADCs serve as sites for a number of major studies, such as national clinical trials and imaging and biomarker research.
Alzheimer’s Disease Translational Research Program: Drug Discovery, Preclinical Drug Development and Clinical Trials. NIA has a longstanding commitment to translational research for Alzheimer’s disease. In 2005, the Institute put this effort into high gear by launching a series of initiatives aimed at supporting all steps of drug discovery through clinical development. The goal of the program is to seed preclinical drug discovery and development projects from academia and from small biotechnology companies and, in doing so, increase the number of investigational new drug candidates that can be tested in humans.
This strategic investment has led to the relatively rapid creation of a large and diverse portfolio of projects aimed at discovery and preclinical development of novel candidate therapeutics. To date, NIA has supported more than 50 early drug discovery projects and 18 preclinical drug development projects through this program. Fifteen of the 18 preclinical drug development projects are for compounds against nonamyloid therapeutic targets, such as tau, ApoE4, pathogenic signaling cascades, and neurotransmitter receptors. Three of these projects have advanced to the clinical development stage.
Key components of NIA’s Alzheimer’s Disease Translational Research Program are the outreach and education activities held at regular investigators’ meetings and at an annual drug discovery training course organized by the Alzheimer’s Drug Discovery Foundation . These meetings provide much-needed networking opportunities for NIA-funded investigators and industry and regulatory experts, as well as education of a new cadre of academic scientists.
Two major program initiatives are:
- Alzheimer’s Disease Pilot Clinical Trials Initiative. This initiative, begun in 1999, seeks to increase the number and quality of preliminary clinical evaluations of interventions for Alzheimer’s, MCI, and age-associated cognitive decline. Currently, 32 trials are investigating drug and nondrug prevention and treatment interventions. The goal is not to duplicate or compete with the efforts of pharmaceutical companies but to encourage, complement, and accelerate the process of testing new, innovative, and effective treatments. The National Institute on Nursing Research (NINR), part of NIH, also participates in this initiative. See Testing Therapies to Treat, Delay, or Prevent Alzheimer’s Disease  to learn more about the trials and to see a complete list of treatment and prevention trials.
- Alzheimer’s Disease Cooperative Study  (ADCS). NIA launched the ADCS in 1991 to develop and test new interventions and treatments for Alzheimer’s disease that might not otherwise be developed by industry. Currently operated under a cooperative agreement with the University of California, San Diego, this large clinical trials consortium comprises more than 75 sites throughout the United States and Canada. The ADCS focuses on evaluating interventions that will benefit Alzheimer’s patients across the disease spectrum. This work includes testing agents that lack patent protection, agents that may be useful for Alzheimer’s but are under patent protection and marketed for other indications, and novel compounds developed by individuals, academic institutions, and small biotech companies. The ADCS also develops new evaluation instruments for clinical trials and innovative approaches to clinical trial design. Since its inception, the ADCS has initiated 30 research studies (23 drug and 7 instrument development protocols.) The ADCS also provides infrastructure support to other federally funded clinical efforts, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). (Read more about these studies below.)
National Alzheimer’s Coordinating Center  (NACC). NIA established NACC in 1999 with the goal of pooling and sharing data on participants in ADC studies. By 2005, NACC had collected data from some 77,000 ADC study participants, including neuropathological data from 10,000 brain autopsies. NACC then added clinical evaluations and annual follow-ups to its protocol, enriching the database with detailed longitudinal data from 26,500 participants and 2,100 brain autopsies. The data are available to Alzheimer’s researchers worldwide.
NACC data are helping to reveal different symptom patterns in different subsets of people with Alzheimer’s, patterns that would not have become apparent without analyzing a dataset of this size. NACC also helps coordinate other NIA efforts, such as the identification and selection of appropriate post mortem material collected at ADCs to send to the National Cell Repository for Alzheimer’s Disease (see below).
National Cell Repository for Alzheimer’s Disease  (NCRAD). This NIA-funded repository, located at Indiana University Medical Center in Indianapolis, provides resources that help researchers identify the genes that contribute to Alzheimer’s and other types of dementia. NCRAD collects and maintains biological specimens and associated data on study volunteers from a variety of sources, primarily people enrolled at the ADCs as well as those in ADNI, the Alzheimer’s Disease Genetics Consortium, and other studies. NCRAD also houses DNA samples and data from more than 900 families with multiple members affected by Alzheimer’s.
Qualified research scientists may apply to NCRAD for samples and data to conduct genetic research. Since it was funded 22 years ago, more than 85,000 biological samples have been requested and sent to more than 100 investigators across the world, resulting in more than 244 scientific publications, 42 of which were published in 2011.
NIA Genetics of Alzheimer’s Disease Data Storage Site  (NIAGADS). Located at the University of Pennsylvania, NIAGADS is a Web-based data warehouse for Alzheimer’s disease genetic data. All genetic data derived from NIA-funded studies on the genetics of late-onset Alzheimer’s are deposited at NIAGADS, another NIA-approved site, or both. Data from genome-wide association studies (GWAS) that are stored at NIAGADS are also made available through the database of Genotype and Phenotype (dbGaP) at the National Library of Medicine’s National Center for Biotechnology Information, which was developed to archive and distribute the results of large-scale GWAS analyses. Through dbGaP, datasets from multiple GWAS done on different platforms can be merged, and data from thousands of study participants can be analyzed together, increasing the probability of gene discovery.
Alzheimer's Disease Education and Referral (ADEAR) Center . Congress created the ADEAR Center in 1990 to compile, archive, and disseminate information concerning Alzheimer's disease for health professionals, people with Alzheimer’s disease, their families, and the public. Operated by NIA, the ADEAR Center is a current and comprehensive resource for Alzheimer's disease information and referrals. All of its information about research and materials on causes, diagnosis, treatment, prevention, and caregiving are carefully researched, evidence-based, and reviewed for accuracy and integrity.
Major NIA research program initiatives include:
Alzheimer’s Disease Neuroimaging Initiative  (ADNI). NIA launched this groundbreaking initiative in 2004. It is the largest public–private partnership to date in Alzheimer’s disease research, receiving generous support from private-sector companies and foundations through the Foundation for the National Institutes of Health. ADNI’s goal is to find neuroimaging and other biological markers that can detect disease progression and measure the effectiveness of potential therapies.
In the first phase of ADNI, researchers recruited 800 participants, a mix of cognitively healthy people and those with Alzheimer’s disease or MCI. To speed the pace of analysis and findings, ADNI investigators agreed to make their collected data widely available. MRI and PET scan brain images as well as clinical, genetic, and fluid biomarker data are available to qualified researchers worldwide through a Web-based database.
Findings from this initiative have generated excitement about using brain and fluid biomarkers to identify people at risk for developing Alzheimer’s or to characterize the pace of deterioration. Accomplishments include new findings about how changes in the structure of the hippocampus may help gauge disease progression and the effectiveness of potential treatments, and the establishment of biomarker and imaging measures that predict risk for cognitive decline and conversion to dementia.
A follow-on effort, ADNI-GO, was launched with American Recovery and Reinvestment Act funds in 2009, followed by ADNI2 in fall 2010. ADNI2 builds on the success of earlier ADNI phases to identify the earliest signs of Alzheimer’s disease. It set a 5-year goal to recruit 550 volunteers, age 55 to 90, at 55 sites in the United States and Canada. The volunteers include people with no apparent memory problems, people with early and late MCI, and people with mild Alzheimer’s disease.
The volunteers will be followed to help define the changes in brain structure and function that take place when they transition from normal cognitive aging to MCI, and from MCI to Alzheimer’s dementia. The study uses imaging techniques and biomarker measures in blood and cerebrospinal fluid specially developed to track changes in the living brain. Researchers hope to identify who is at risk for Alzheimer’s, track progression of the disease, and devise tests to measure the effectiveness of potential interventions. ADNI2 continues to follow participants recruited for the other ADNI cohorts.
ADNI has been remarkably fruitful. To date, more than 430 papers using ADNI data have been published from investigators around the world, and many more will come as more data are collected and analyzed. The success of ADNI has also inspired similar efforts in Europe, Japan, and Australia.
Dominantly Inherited Alzheimer’s Disease Network  (DIAN). NIA launched the 6-year DIAN study in 2008 to better understand the biology of early-onset Alzheimer’s, a rare, inherited form of the disorder that can occur in people as early as their 30s and 40s. People born with a certain gene mutation not only develop Alzheimer’s disease before age 60 but have a 50–50 chance of passing the gene along to their children. When Alzheimer's disease is caused by a genetic mutation, about 50 percent of the people in the family tree get the illness before age 60.
Scientists involved in this collaborative, international effort hope to recruit 300 adult children of people with Alzheimer’s disease to help identify the sequence of brain changes that take place even before symptoms of the disorder appear. By understanding this process, researchers hope to gain additional insights into the more common late-onset form of the disease.
Until DIAN, the rarity of the condition and geographic distances between affected people and research centers hindered research. Today, volunteers age 18 and older with at least one biological parent with the disorder are participating in DIAN at a network of 13 research sites in the United States, England, Germany, and Australia. Each participant receives a range of assessments, including genetic analysis, cognitive testing, and brain scans, and donates blood and CSF so scientists can test for biomarkers.
In early 2013, the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN TU) at Washington University School of Medicine in St. Louis will begin testing three investigational drugs in 160 volunteers with inherited mutations for early-onset Alzheimer’s. More >> 
DIAN researchers are building a shared database of the assessment results, samples, and images to advance knowledge of the brain mechanisms involved in Alzheimer’s, eventually leading to targets for therapies that can delay or even prevent progress of the disease.
The study is led by the Alzheimer’s Disease Center at Washington University School of Medicine in St. Louis. Research collaborators include Massachusetts General Hospital; Brigham and Women’s Hospital; Brown University; Columbia University; Indiana University; University of California, Los Angeles; University College, London Institute of Neurology at Queen’s Square; German Center for Neurodegenerative Diseases, Munich; German Center for Neurodegenerative Diseases, University of Tübingen; and a consortium of the Universities of Melbourne and New South Wales and Edith Cowan University in Australia.
Alzheimer’s Disease Genetics Initiative (ADGI) and Alzheimer’s Disease Genetics Consortium  (ADGC). The study of Alzheimer’s disease genetics is complicated by the likelihood that the risk of late-onset Alzheimer’s is influenced by many genes, each of which probably confers a relatively small risk. Identifying these genes requires analyzing the genomes of large numbers of people. ADGI was launched in 2003 to identify at least 1,000 families with multiple members who have late-onset Alzheimer’s as well as members who do not. In 2009, NIA funded the ADGC to support the use of large-scale, high-throughput genetics technologies, which allow the analysis of large volumes of genetic data, needed by researchers studying late-onset Alzheimer’s.
These initiatives are achieving important results. In April 2011, an ADGC-led study confirmed one gene variant and identified several others that may be risk factors for late-onset Alzheimer’s disease, the most common form of the disorder. (For more on risk-factor genes, go to The Genetics of Alzheimer’s Disease ). In the largest GWAS ever conducted in Alzheimer’s research, investigators studied DNA samples from more than 56,000 study participants and analyzed shared datasets to detect gene variations that may have subtle effects on Alzheimer’s risk. In addition to providing new insight into the pathology of Alzheimer’s and suggesting therapeutic targets, these recent gene discoveries may also one day help predict who is at risk for the disease.
Research Partnership on Cognitive Aging. The Foundation for the National Institutes of Health, NIA, and the McKnight Brain Research Foundation convened Cognitive Aging Summits in 2007 and 2010 that focused on healthy brain aging and function. The first Summit helped galvanize the field and served as a catalyst for two subsequent research initiatives. The first initiative is testing pilot interventions to reverse age-related decline or maintain successful function. The second initiative is determining the neural and behavioral profiles of age-related cognitive change and identifying components of these profiles that distinguish normal age-related change from pathological decline. During the second Summit, researchers shared progress from studies and identified future research directions. Investigators supported by the partnership have had 70 papers published in scientific journals.
NIH Toolbox for Assessment of Neurological and Behavioral Function . Supported by the NIH Blueprint for Neuroscience Research and the NIH Office of Behavioral and Social Sciences Research, researchers developed this set of brief tests to assess cognitive, sensory, motor, and emotional function, particularly in studies that enroll many people, such as epidemiological studies and clinical trials. These royalty-free tests, developed under a contract with NIH, were unveiled in September 2012. Available in English and Spanish and applicable for use in people age 3 to 85 years, the measures enable direct comparison of cognitive and other abilities at different ages across the lifespan.
Human Connectome Project . Supported through the NIH Blueprint for Neuroscience Research, a group of 15 NIH Institutes and offices engaged in brain-related research, the Human Connectome Project was started in 2010 to develop and share knowledge about the structural and functional connectivity of the healthy human brain. This collaborative effort uses cutting-edge neuroimaging instruments, analysis tools, and informatics technologies to map the neural pathways underlying human brain function. Investigators will map these connectomes in 1,200 healthy adults—twin pairs and their siblings—and will study anatomical and functional connections among regions of the brain.
The data gathered will be related to behavioral test data collected using another NIH Blueprint research tool, the NIH Toolbox for Assessment of Neurological and Behavioral Function, and to data on the genetic makeup of the participants. The goals are to reveal the contributions of genes and environment in shaping brain circuitry and variability in connectivity, and to develop faster, more powerful imaging tools. Advancing our understanding of normal brain connectivity may one day inform Alzheimer’s research.