This overview of the Nation’s investment in Alzheimer’s disease research describes new programs, initiatives, and research studies initially funded in calendar year 2012 through the first half of 2013. The next section, “Supporting Infrastructure and Initiatives,” highlights the ways in which new and ongoing National Institute on Aging (NIA)-supported programs, centers, and collaborative efforts are advancing Alzheimer’s research.
Alzheimer’s research is supported across the National Institutes of Health (NIH). In fiscal year (FY) 2012, NIH invested $503 million in Alzheimer’s disease research. The challenge now is to make every dollar count by establishing priorities, setting goals that are both ambitious and realistic, and identifying the most promising opportunities for progress through careful planning, coordination, and resource allocation.
As the lead NIH Institute for Alzheimer’s disease research, NIA plans and coordinates activities aimed at finding ways to prevent and treat the disorder. Both the disease and age-related cognitive change are major considerations in NIA’s regular planning process. The Institute also seeks to capitalize on extraordinary opportunities that emerge outside of everyday planning processes that will move the research enterprise forward.
For the most current information about Alzheimer’s disease research at NIH, see ongoing updates on the NIA/NIH Alzheimer’s Disease Education and Referral (ADEAR) Center  Web site.
Fighting Alzheimer’s disease is a priority not just at NIH but across the Department of Health and Human Services and elsewhere in the Federal Government. In January 2011, President Barack Obama signed the National Alzheimer’s Project Act  (PDF, 126K) (NAPA), which called for an aggressive, coordinated national Alzheimer’s disease plan and established an Advisory Council on Alzheimer’s Research, Care, and Services, consisting of some of the Nation’s foremost experts on Alzheimer’s disease.
The National Plan to Address Alzheimer’s Disease,  unveiled in May 2012 and updated in June 2013, sets ambitious goals and outlines the Federal and private-public sector activities currently underway to meet those goals.
The Plan’s key research goal is to find effective ways to treat or prevent Alzheimer’s disease by 2025. NIH is working to meet that goal by strategically funding areas of study and by awarding funds for highly rated investigator-initiated projects. Further, in recognition of important scientific opportunities, NIH allocated additional funding for Alzheimer’s research in fiscal years 2012 and 2013.
The increased investment in FY 2012 went to basic studies and to the start of two major clinical trials seeking to intervene earlier in the disease process. These initiatives included:
Two major clinical trials to speed testing of therapies in people at highest risk of the disease received awards:
In FY 2013, the Office of the NIH Director allocated additional funding to Alzheimer’s disease. That $40 million, along with $5 million in NIA funds, was awarded to test promising drugs aimed at preventing Alzheimer’s and to identify and validate biological targets for novel therapies. The studies  are among the first to be developed in response to recommendations from the 2012 NIH Alzheimer’s Disease Research Summit: Path to Treatment and Prevention  and reflect research goals in the National Plan .
The early-phase and prevention clinical trials will test treatments in symptom-free volunteers at risk for the disease, that is, those in the very earliest stages—timing that could increase the chances of delaying or halting disease progression. The trials are:
Other awards will make possible studies focused on identifying and validating novel therapeutic targets for Alzheimer’s disease:
NIH receives input from many sources when setting research and funding priorities. For Alzheimer’s disease, in addition to scientific workshops, international conferences, and other interactions with the scientific community, these sources include the National Advisory Council on Aging and the Advisory Council on Alzheimer’s Research, Care, and Services, established under the 2011 National Alzheimer’s Project Act.
View a video about the 2012 NIH Alzheimer’s Disease Research Summit: Path to Treatment and Prevention:
In support of the objectives outlined in the National Plan to Address Alzheimer’s Disease, NIH convened two major meetings to help inform the dementia research agenda. In May 2012, NIH hosted the Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention  and in mid-2013, convened the Alzheimer’s Disease-Related Dementias: Research Challenges and Opportunities  workshop on frontotemporal disorders and Lewy body, vascular, and mixed dementias. These meetings brought together scientists from a variety of disciplines to share insights and develop recommendations. NIH neuroscientists who specialize in Alzheimer’s disease, related dementias, and brain aging played key leadership roles in the meetings, and they continue to monitor the research landscape for knowledge gaps, opportunities, and promising new avenues of discovery.
View a video about the Alzheimer’s Disease-Related Dementias: Research Challenges and Opportunities workshop, convened in 2013:
From such meetings, smaller workshops, and other means of scientific discourse, NIH guides the field through the development of funding opportunity announcements (FOAs). These solicitations ask for proposals from the scientific community in areas of particular promise and interest to the agency, to stimulate research growth in those areas. Some FOAs have resources set aside to fund grant applications. Others do not have dedicated funding, but nevertheless send a strong signal of interest to the research community about promising or emerging areas of science. Applications for each FOA are accepted for a set period of time, and FOAs can be reissued or, if scientific priorities change, allowed to lapse. Recent Alzheimer’s-related FOAs include an initiative to support research using optogenetics, a technique that integrates genetics and optics to control the activity of individual cells, to study brain changes in aging and Alzheimer’s disease.
The bulk of NIH’s funding goes to investigator-initiated proposals—that is, proposals that are not developed in response to a specific FOA. Applications for such funding reflect the creativity and innovation of established and new investigators who seek to build on scientific advances or who offer new ways of thinking about Alzheimer’s disease research.
All grants are selected for funding through a rigorous peer-review process in which experts in the field carefully review applications for scientific merit, innovation, and likelihood of success. Competition is intense; currently, only about 20 percent of all applications to NIH are funded. However, this means that experts consider the funded research to be highly promising.
Projects funded by NIH during 2012 and the first half of 2013 are aimed at several overarching goals, outlined below.
Understanding a disease at its most basic level is an important first step toward developing interventions to prevent, slow, halt, or reverse disease progression. A more complete understanding of Alzheimer’s at the molecular and genetic levels will help lead to discovery of new and better targets for prevention and treatment. Recent investments in this area include:
Scientists believe that the pathological hallmarks of Alzheimer’s are present in the brain years or even decades before outward symptoms of memory loss or other signs of cognitive decline begin to appear. Early detection of disease pathology and even early clinical diagnosis provide a window in which effective intervention may eventually be possible by:
The NIH-supported discovery that Alzheimer’s pathology is present in the brain many years before symptoms appear opened the door for early intervention and raised hopes that primary prevention of the disease may be possible. New projects are testing a number of approaches:
Treatment options today are very limited for people with Alzheimer’s dementia. NIH is committed to identifying new interventions to slow or even halt the disease’s progress and to ameliorate its symptoms. Some NIA-supported investigators are exploring innovative strategies for healing the Alzheimer’s brain. For instance, one investigator is developing a new method for converting “reactive astrocytes,” pathological brain cells that are markers of injury, into functional neurons, facilitating brain repair in people with the disease (1R01AG045656-01). Other approaches include:
An Alzheimer’s disease diagnosis is devastating for the entire family and can place a particularly large burden on the affected person’s primary caregiver. The demands of day-to-day care, changing family roles, and difficult decisions about placement in a care facility can be hard to handle.
NIH supports research on new and effective ways to support Alzheimer’s caregivers:
When Congress created NIA in 1974, it mandated that the Institute communicate evidence-based information about aging and aging research to the public, health practitioners, and the research community. Subsequently, the Institute was directed specifically to provide information about Alzheimer’s. NIA fulfills these important missions by communicating directly with various audiences via a robust, user-friendly Web site, along with targeted outreach activities and partnerships. Specific initiatives in Alzheimer’s disease include:
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 discoveries into Alzheimer’s disease prevention and treatment. 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:
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.
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 brain changes that may predict age-related declines in memory or other cognitive functions. Using brain imaging techniques, such as magnetic resonance imaging (MRI), which measures structural changes, and positron emission tomography (PET) scans, which 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 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, multi-center, 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, to 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, 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 non-amyloid therapeutic targets, such as tau, ApoE4, pathogenic signaling cascades, and neurotransmitter receptors. Four of these projects have advanced to the clinical development stage.
This program supports 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 in translational research and clinical trials are:
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 data set 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.
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 150,000 biological samples have been requested and sent to more than 120 investigators and cores across the world, resulting in more than 277 scientific publications, 27 of which were published in 2012.
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. NIAGADS currently houses 22 datasets with nearly 44,000 subjects and more than 24 billion genotypes. 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 established 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.
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 ADNI 2 in 2010. ADNI 2 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 in their 30s, 40s, and 50s. 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 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 cerebrospinal fluid so scientists can test for biomarkers.
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 ADC at Washington University School of Medicine in St. Louis.
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. The ADGC, for example, was one the founding partners of a highly collaborative, international group that announced the identification of 11 new Alzheimer’s risk genes  in 2013. Combining previously studied and newly collected DNA data from 74,076 older volunteers with Alzheimer’s and those free of the disorder from 15 countries, the research offers important new insights into the disease pathways involved in Alzheimer’s 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 84 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.
The Human Connectome Project uses cutting-edge neuroimaging instruments to map the neural pathways underlying human brain function. Courtesy of the Laboratory of Neuro Imaging and Martinos Center for Biomedical Imaging, Consortium of the Human Connectome Project. www.humanconnectomeproject.org 
Human Connectome Project . The NIH Blueprint for Neuroscience Research , a group of 15 NIH institutes and offices engaged in brain-related research, started the Human Connectome Project 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 (see above), 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.
BRAIN Initiative . The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is part of a new Presidential focus aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a revolutionary new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. The BRAIN Initiative aims to accelerate work on technologies that give a dynamic picture of how individual cells and complex neural circuits interact. The ultimate goal is to enhance understanding of the brain and improve prevention, diagnosis, and treatment of brain diseases such as Alzheimer’s. The National Science Foundation and Defense Advanced Research Projects Agency are partnering with NIH in this initiative.