Alzheimer’s Research: Investing Today for Tomorrow’s Cure

(NIA) 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.

The National Plan to Address Alzheimer’s Disease

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:

• Accelerating identification, through cutting-edge technologies, of new genetic variants influencing increased risk (risk factors) or reduced risk (protective factors) of Alzheimer’s disease.
• Using new induced pluripotent stem (iPS) cell methods to obtain insights into the cellular processes of Alzheimer’s.
• Awarding small business grants on basic science, the biology and genetics of Alzheimer’s disease, and translational and clinical research to develop and test therapies.

Two major clinical trials to speed testing of therapies in people at highest risk of the disease received awards:

• Intranasal insulin. NIH committed $7.9 million to a one-year trial testing an insulin nasal spray for treating Alzheimer’s disease. In a recent pilot clinical trial, investigators found that this treatment improved memory, cognition, and daily functioning, with no side effects in participants with mild cognitive impairment (MCI) or mild to moderate Alzheimer’s disease. The larger, year-long trial will test the effects of intranasal insulin on cognition and function in a larger group of people with MCI or early Alzheimer’s. In addition, cerebrospinal fluid and imaging biomarkers will be assessed.
• Alzheimer’s prevention. NIH committed $16 million to an international Alzheimer’s prevention effort, the first to focus on testing therapies in people who are cognitively normal but at extremely high risk of developing Alzheimer’s disease. The study includes approximately 300 adult members of a Colombian clan with a family history of rare, early-onset Alzheimer’s, as well as a smaller number of U.S. participants age 30 and older. This group includes both carriers and non-carriers of a genetic mutation known to cause observable signs of Alzheimer’s around age 45. The study will use brain scans, fluid biomarkers, and cognitive testing to track amyloid levels, changes in brain structure and function, and cognitive performance in participants taking an experimental drug. The trial is co-funded by the Banner Alzheimer’s Foundation and Genentech, a biotechnology company that is also providing the test drug, crenezumab.

New Funding for Prevention Trials, Biological Targets

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:

• Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Trial. Dr. Randall Bateman, Washington University, St. Louis, and co-investigators were awarded $1.5 million, with the potential for $6 million over 4 years, to investigate new anti-amyloid-beta drug treatments in volunteers who have an inherited form of Alzheimer’s disease. While early-onset Alzheimer’s is rare, the knowledge gained from this study will be highly relevant to both early- and late-onset forms of the disease. The multi-site international effort will test three anti-amyloid-beta interventions: gantenerumab, solanezumab, and a third, as yet undetermined, drug. This trial is also supported by the Alzheimer’s Association® and several private companies: Roche, Lilly, Avid Radiopharmaceuticals, and CogState. (NIA support: AG 042791-01A1)
• The Alzheimer’s Prevention Initiative APOE4 Trial. Drs. Eric Reiman and Pierre Tariot, Banner Alzheimer’s Institute, Phoenix, and co-investigators received $33.2 million for a 5-year, multi-site prevention trial testing an anti-amyloid drug in cognitively normal older volunteers. The volunteers are at increased risk of developing late-onset Alzheimer’s because they inherited two copies of the APOE ɛ4 allele, the best known genetic risk for late-onset disease. This randomized, controlled clinical trial will evaluate the efficacy of the amyloid therapy in preventing cognitive decline and will, through imaging and biomarker techniques, help identify faster ways to evaluate other promising prevention therapies. Also supported by private funding, the researchers plan to begin the trial in 2015. The test drug has not yet been selected. (NIA support: AG 046150-01)
• Allopregnanolone Regenerative Therapeutic for MCI/Alzheimer’s: Dose Finding Phase 1. Drs. Roberta Brinton and Lon Schneider, University of Southern California, Los Angeles, have been awarded $2.4 million to conduct a 12-week, early-phase clinical trial of the safety and tolerability of allopregnanolone, a natural brain steroid, in treating people with MCI or Alzheimer’s disease. The drug has been shown to promote the generation of new brain cells, reduce amyloid levels, and restore cognitive function in preclinical animal testing. NIA has supported Dr. Brinton’s work for several years, including with basic science grants to understand allopregnanolone’s mechanism of action in the brain, a drug development grant for optimal dose and formulation, and support for preclinical toxicology studies. (NIA support: AG 046148-01)
• Stimulating the Innate Immune System to Prevent Alzheimer’s. Dr. Ted Ashburn, Sanofi Aventis, Cambridge, Mass., in partnership with Baylor College of Medicine, Houston, received $2.2 million for a 3-year, Phase II proof-of-concept study of sargramostim, a drug that stimulates the innate immune system. The study will determine whether the drug clears abnormal deposits of amyloid before they cause damage and, as a result of this clearance, either prevents cognitive decline or improves cognition. This 24-week, randomized, double-blinded, placebo-controlled study will recruit people with MCI, a condition that often leads to Alzheimer’s. (NIA support: AG 046143-01)

Other awards will make possible studies focused on identifying and validating novel therapeutic targets for Alzheimer’s disease:

• Pathway Discovery, Validation, and Compound Identification for Alzheimer’s Disease. Dr. Philip De Jager, Brigham and Women’s Hospital, Broad Institute, Harvard University, Boston, and Dr. David Bennett, Rush University Medical Center, Chicago, were awarded $1.7 million, with the potential of $7.9 million over 5 years. Their study seeks to discover, characterize, and validate complex molecular networks and candidate genes that influence susceptibility to cognitive decline and Alzheimer’s disease. Using cutting-edge computational methods, the multi-disciplinary team will analyze rich clinical, pathological, genomic, and other large-scale molecular data collected from more than 1,000 volunteers from the Religious Orders Study and the Rush Memory and Aging Project. They hope to identify compounds that normalize the activity of dysfunctional features in molecular networks and to identify drugs for several novel therapeutic targets. To accelerate testing of promising therapies for future clinical trials, the investigators will focus on drugs that have already undergone Phase I testing in humans. (NIA support: AG 046152)
• Integrative Biology Approach to Complexity of Alzheimer’s Disease. Dr. Eric Schadt, Icahn School of Medicine at Mount Sinai, New York City, and a team of investigators received $1.6 million with the potential of $8.2 million over 5 years. This study will apply innovative analytical methods to large-scale molecular, cellular, and clinical data from Alzheimer’s patients to construct biological network models and gain new insights into the complex mechanisms of the disease. The team will also employ a computational approach to test whether any existing drugs currently used for other conditions are capable of modulating Alzheimer’s networks and could be repurposed for Alzheimer’s treatment or prevention. (NIA support: AG 046170-01)
• A Systems Approach to Targeting Innate Immunity in Alzheimer’s. Dr. Todd Golde, University of Florida, Gainesville, and colleagues received $1.6 million in FY 2013, with the potential of $7.7 million over 5 years, for a study building on evidence that the innate immune system, which provides immediate defense against infection, and brain inflammation have a significant role in Alzheimer’s disease. To identify and characterize novel therapeutic targets within the innate immune system, this study will use a systems biology approach to integrate genomic, gene expression, and pathological data from Alzheimer’s patients and Alzheimer’s mouse models and analyze them in novel ways. The team will test in animal models of the disease the validity and therapeutic potential of the key factors predicted by the analysis. This research has the potential to speed the discovery and testing of Alzheimer’s disease prevention and treatment therapies by targeting the immune system. (NIA support: AG 046139-01)

Determining Research Priorities

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.

We want to understand Alzheimer’s at its most basic level.

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:

• National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). This web-based repository of genetic data from a variety of studies will be available to qualified investigators worldwide for use in basic science and clinical research studies. This initiative will speed the pace of discovery by providing a centralized resource through which investigators can access, study, and share their own high-quality data relevant to Alzheimer’s disease.
• Understanding genetic risk factors. Until 2009, only one gene, APOE ɛ4, had been shown to increase the risk of late-onset Alzheimer’s disease. Since then, with the advent of genome-wide association studies (GWAS) and other high-throughput technologies, the list of known risk-factor genes has grown substantially to include PICALM, CLU, CR1, BIN1, MS4A, CD2AP, EPHA1, ABCA7, SORL1, and TREM2. In 2013, the largest GWAS ever conducted identified 11 new genes. The research—conducted by the International Genomic Alzheimer’s Project, a collaborative, international study supported in part by the NIH—strengthens evidence about the involvement of certain pathways in the disease, such as inflammation and amyloid deposition. Researchers continue to explore the roles played by these genes.
• Dominantly Inherited Alzheimer’s Network (DIAN). This consortium of scientific investigators is working to identify, recruit, evaluate, and follow up with individuals from families with the rare early-onset, dominantly inherited form of the disease. Newly supported projects in this area aim to identify the sequence of brain changes in early-onset Alzheimer’s before symptoms appear. Understanding this process could provide insight into the more common late-onset form of the disease. NIA anticipates renewing funding for DIAN in 2014.
• Mechanisms of Alzheimer’s. A large program project (a group of linked projects funded under the same umbrella grant) is exploring the role of the lysosomal system, which is involved in the breakdown and recycling of cellular proteins, in Alzheimer’s pathogenesis (2P01AG017617-11A1). In another study, investigators are attempting to pinpoint the mechanism through which the ApoE4 protein contributes to development of Alzheimer’s pathology (1R15AG042781-01A1).

We want to diagnose Alzheimer’s early and accurately.

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:

• Providing tools for assessment. In 2012, NIH unveiled the NIH Toolbox for Assessment of Neurological and Behavioral Function, a multi-dimensional set of brief measures to assess cognitive, sensory, motor, and emotional function that can be administered in 2 hours or less across diverse study designs and settings. The Toolbox capped an 8-year effort by NIH and experts in the research community to develop practical and comparable measures for cognitive assessment.
• Assessing new diagnostic guidelines for Alzheimer’s disease. A team led by NIA and the Alzheimer’s Association recently devised new guidelines for the diagnosis of preclinical through dementia stages of Alzheimer’s disease. Formulation of initial criteria for this previously undefined preclinical phase represents an important advance; however, the new guidelines have not yet been validated. One project (1R01AG041851-01) will support validation testing of some aspects of the new preclinical criteria.
• Enhancing diagnostic and prognostic techniques. Researchers have posited that in early Alzheimer’s disease, changes to the brain occur in a sequential and predictable manner. First, approximately 15 years prior to diagnosis, amyloid biomarkers become abnormal, followed by the appearance of biomarkers of neuronal injury. At this point, a clinical diagnosis of MCI becomes possible. In a continuation of this work, investigators are seeking to confirm, validate, and if necessary revise and extend this model. If validated, it will enable physicians to counsel patients more effectively about the implications of abnormal Alzheimer’s biomarkers and it will aid in design of therapeutic clinical trials in preclinical Alzheimer’s (2R01AG011378-21A1). In another study, investigators are determining which of the current MCI diagnostic approaches best predicts dementia development (2R01AG016495-11).
• Imaging for presymptomatic and earliest signs. Several projects intensify the study of neuroimaging for defining Alzheimer’s disease. One will identify genetic and imaging biomarkers for presymptomatic Alzheimer’s (1R01AG040770-01A1), while another will develop and optimize cognitive and imaging biomarkers to track progression through the early symptomatic stages of the disease (2R01AG027435-06). Another study will look at changes in the brain’s white matter, areas of the brain that contain large bundles of axons that connect neurons in one region of the brain with neurons in other regions. White-matter changes may appear on brain scans earlier than changes in gray matter, regions where neurons and dendrites are found, and may serve as a biomarker for presymptomatic Alzheimer’s (2R01AG031892-03).
• Finding blood-based biomarkers. Investigators are also developing blood-based screening tools for Alzheimer’s. Intramural scientists at NIA have established that levels of clusterin, a protein that regulates amyloid production and clearance, are elevated in the blood of individuals with Alzheimer’s disease, and that clusterin levels correlate with disease severity. One group of NIA-funded researchers is developing a blood-based screening tool incorporating multiple proteins (1R01AG039389-01A1), while another is creating a tool based on measurement of amyloid-beta in blood erythrocytes (2R01007637-21). A third is developing a test that quantifies certain microRNAs, small molecules involved in DNA transcription and expression, to predict which patients with MCI will go on to develop full-blown Alzheimer’s disease (1R01AG044860-01).

We want to prevent Alzheimer’s from developing.

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:

• Lifestyle interventions. NIH has long been a leader in the study of lifestyle interventions such as diet, exercise, and cognitive enrichment as potential preventive interventions for cognitive decline and Alzheimer’s. Results of observational studies and short-term clinical trials suggest that being physically and mentally active and eating plenty of nutrient-rich foods might have a protective effect on cognition. Those findings are under active investigation in more definitive interventional studies. In one study, investigators are working to determine whether aerobic exercise can modify Alzheimer’s pathology in individuals with preclinical disease (1R01AG043962-01A1). In another study, the Alzheimer’s Disease Multiple Intervention Trial (ADMIT), researchers are comparing expert primary care with primary care plus a home-based occupational therapy intervention to improve functioning in older adults with Alzheimer’s (5R01AG034946-03).
• Drug therapies to prevent Alzheimer’s. The NIH-supported Alzheimer’s Prevention Initiative (API), established in 2012, is intended to start evaluating promising experimental treatments in people who, based on their genetic background and age, are at the highest imminent risk of Alzheimer’s. This study, in Medellin, Colombia, includes members of the world’s largest extended family of early-onset Alzheimer’s mutation carriers. The API aims to help establish the biological measurements and regulatory pathways needed to evaluate promising prevention therapies as quickly as possible. The first API trial is a 5-year study of crenezumab to see if it can prevent cognitive decline. The drug is designed to bind to and possibly clear abnormal amounts of amyloid protein in the brains of people with Alzheimer’s (1RF1AG041705-01A1).

We want to treat Alzheimer’s in people for whom the disease has already taken hold.

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:

• Repurposing existing drugs. One pilot clinical trial recently demonstrated that a nasal-spray form of insulin delayed memory loss and preserved cognition in people with MCI or mild to moderate Alzheimer’s disease. These promising findings led to a much larger, ongoing clinical trial of intranasal insulin (1RF1AG041845-01). Another compound, the diabetes drug exenatide (Byetta®), has shown promise and is currently being tested in the NIA Intramural Research Program as a potential treatment for early Alzheimer’s. And in a new study, investigators are performing early tests of the drug gemfibrozil, currently in wide use to treat high lipid levels, in people with early-stage disease (1R01AG042419-01A1).
• Developing new drugs. Through a trans-NIH “Grand Challenge” known as the NIH Blueprint Neurotherapeutics Program, investigators working with small-molecule compounds targeted at neurological diseases, including Alzheimer’s, can gain access to a robust virtual drug development network to develop neurotherapeutic drugs. Participants receive both funding and no-cost access to contracted drug development services not typically available to the academic research community. NIA-supported investigators are also developing new drugs to treat abnormal tau, a pathological hallmark of Alzheimer’s disease, and other forms of dementia (1R01AG044332-01). Other investigators are identifying novel small molecules that target toxic APOE ε4 in the brain (1U01AGA43394-01).
• Initiating new trials. A variety of clinical trials of pharmaceutical and nonpharmaceutical interventions have been funded recently. These trials include a study of deep-brain stimulation in people with Alzheimer’s (1R01AG042165-01A1), a study to determine whether the drug citalopram reduces amyloid-beta levels in the brain (1R01AG041502-01A1), a study of antidepressants in combination with commonly used Alzheimer’s drugs for patients with cognitive impairment and depression (1R01 AG040093-01), and a study of “customized activity” to relieve agitation in people with Alzheimer’s who live at home (1R01AG041781-01A1).

We want to identify and develop better ways to support people caring for those with Alzheimer’s disease.

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:

• Employing new technologies. Investigators are developing and evaluating Telehealth Technology for Distance Counseling and online training modules for national teledelivery of the New York University Caregiver Intervention (NYUCI) model, an evidence-based psychosocial intervention for families of people with Alzheimer’s disease. The NYUCI has been shown to reduce depression in caregivers and delay nursing home placement by 1.5 years, on average, but is not widely available, particularly in rural America (1R44AG043204-01).
• Offering practical help. Investigators developing a new tool to teach caregivers of people with dementia about preserving functional ability during dressing (1R43AG039172-01A1). Others are developing a web-based training module that covers a broad range of topics for Alzheimer’s caregivers (2R44AG032159-02). Because this module will be available online and via mobile devices, and does not require a professional facilitator, it could reach a large segment of the caregiver population that has not previously had access to high-quality training materials.
• Extending REACH. REACH II (Resources for Enhancing Alzheimer’s Caregiver Health II), an NIH-funded study, developed the first intensive caregiver support intervention to be proven effective, through rigorous testing in an ethnically diverse population. The REACH intervention is currently being employed more broadly through the U.S. Department of Veterans Affairs (VA), with participating centers in 15 states. The VA is testing the intervention with caregivers of people with other chronic conditions as well. The Administration for Community Living is also implementing the REACH intervention at centers in Georgia, North Carolina, and Florida, and the first international adaptation of the REACH intervention recently began at the University of Hong Kong.

We want to ensure the dissemination of accurate, up-to-date information about Alzheimer’s.

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:

• The Federal Government’s leading information center on Alzheimer’s. The Alzheimer’s Disease Education and Referral (ADEAR) Center was created in 1990 to compile, archive, and disseminate information concerning Alzheimer’s disease for health professionals, people with Alzheimer’s disease and their families, and the public. Learn more about the ADEAR Center in “Supporting Infrastructure and Initiatives” or visit the ADEAR Center’s Web site at www.nia.nih.gov/alzheimers.
• Alzheimers.gov. This portal Web site, www.alzheimers.gov, was established by the U.S. Department of Health and Human Services in 2012 to provide Alzheimer’s families an easier route to the wealth of Federal information and resources.

Supporting Infrastructure and Initiatives

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:

• Convening and collaborating in workshops addressing 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 goals of improved treatments, new prevention strategies, and better programs for people with Alzheimer’s and their caregivers.

Infrastructure

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:

• 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. These 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, 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 76 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 32 research studies (25 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 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.

Initiatives

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.

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.

Citation

https://www.nia.nih.gov/alzheimers/publication/2012-2013-alzheimers-disease-progress-report/advancing-discovery-alzheimers

National Institute on Aging