Investing in Research
This presentation of the Nation’s investment in Alzheimer’s disease research is a new feature of the annual Alzheimer’s Disease Progress Report. It offers an overview of research recently undertaken to accompany the summary of important findings from studies funded several years ago. Programs, initiatives, and research studies initially funded in calendar year 2011 through the first half of 2012 are described here. 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 NIH. In fiscal year (FY) 2011, NIH invested $448 million in Alzheimer’s disease research, while in FY 2012, it invested an estimated $498 million, including $50 million in additional funding dedicated to Alzheimer’s research in the middle of FY 2012.
"We Can’t Wait”: Presidential Initiative Stimulates Alzheimer’s Research
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 Obama signed the National Alzheimer’s Project Act (NAPA), which called for an aggressive and 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. More >>
Moving forward in FY 2013, NIH has issued several Funding Opportunity Announcements (FOA) to solicit research in priority areas identified at the Alzheimer’s Disease Research Summit and in the National Plan to Address Alzheimer’s Disease. Contingent upon available funding, these initiatives will support analysis of data from the Alzheimer’s Disease Genome Sequencing project; updated analysis of the economic costs of Alzheimer’s disease; and projects across the full spectrum of Alzheimer’s drug development, from target identification and validation through prevention and treatment clinical trials.
NIA is the designated lead institute within NIH on Alzheimer’s disease. NIA plans and coordinates a number of activities aimed at finding ways to prevent or 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 everyday planning processes that will move the research enterprise forward.
Determining Research Priorities
In setting research and funding priorities, NIH receives input from many sources. For Alzheimer’s disease , these sources include the National Advisory Council on Aging and the Advisory Council on Alzheimer’s Research, Care, and Services, established in 2011 under the National Alzheimer’s Project Act. In 2012, NIH also received recommendations from the NIH-convened Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention . NIH program staff play a leadership role, in which neuroscientists specializing in Alzheimer’s disease, related dementias, and brain aging constantly monitor the research landscape for knowledge gaps, opportunities, and promising new avenues of discovery.
To view a short video about the Alzheimer's Disease Research Summit, click here .
The Promise of iPS Cells
Scientists who study Alzheimer’s disease use animal models of aging and disease in many ways, from identifying mechanisms of disease to rapidly testing new drugs. More >>
NIH guides the field through publicly available FOAs, through which applications are solicited from the scientific community in areas of particular promise and interest to the agency to stimulate research growth in those areas. Each FOA is “open,” meaning that applications are accepted for a set period of time. FOAs can be reissued or, if scientific priorities change, allowed to lapse. Recent FOAs related to Alzheimer’s include an initiative to support the development of iPS cells and other reprogrammed cells for aging and Alzheimer’s disease modeling and two separate but related announcements encouraging small businesses to apply for grants for Alzheimer’s-related research and development.
The bulk of NIH’s research funding goes to investigator-initiated proposals. Applications for such funding reflect the creativity and innovation of both established scientists and new investigators, who seek to build on progress being made or who offer wholly new ways of thinking about Alzheimer’s disease.
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 the research that is funded is considered by experts to be highly promising.
Projects funded by NIH during 2011 and the first half of 2012 are aimed at several overarching goals.
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. New investments in this area include:
Support for the Alzheimer’s Disease Genetics Warehouse. NIA supports this web-based repository of genetic data from a variety of studies. Warehouse data 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 recently, only one gene, APOE ɛ4, had been shown to increase the risk of late-onset Alzheimer’s disease. However, a number of risk-conferring genes for late-onset Alzheimer’s have been confirmed in recent years, including PICALM, CLU, CR1, BIN1, MS4A4, CD2AP, and TREM2. Several others have been identified and are being further studied. In November 2012, two international teams of researchers, with NIH scientists and support, separately identified a rare variation in the TREM2 gene as a moderate risk factor for late-onset Alzheimer’s disease (Guerriero et al., 2012; Jonsson et al., 2012). TREM2 is a gene involved in inflammation and immune response. One major new study is focused on validating and quantifying the clinical impact of these newly confirmed and/or identified genetic risk factors for the disease in families containing multiple affected individuals (1R01AG041797-01). A number of other studies are ongoing.
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.
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).
Behavioral symptoms. A study using cutting-edge neuroimaging techniques aims to elucidate the relationship among serotonin, amyloid-beta, and early mood and behavioral symptoms of Alzheimer’s, including depression, anxiety, irritability, and agitation (1R01AG041633).
We want to diagnose Alzheimer’s early and accurately.
Scientists believe that the pathological hallmarks of Alzheimer’s are present in the brain years—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 released to the research community the NIH Toolbox for Assessment of Neurological and Behavioral Function , a multidimensional set of brief, royalty-free 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. Recently a team led by NIA and the Alzheimer’s Association devised new research guidelines for the 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 criteria have not yet been validated. One project (1R01AG041851-01) will support validation testing of some aspects of the new preclinical criteria.
Imaging for presymptomatic and earliest signs. Several new projects intensify the study of neuroimaging for defining Alzheimer’s disease. One project will identify genetic and imaging biomarkers for pre-symptomatic 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 become evident on imaging sooner than changes to gray matter, regions where neurons and dendrites are found, and may serve as a biomarker for presymptomatic Alzheimer’s.
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. Meanwhile, one group of researchers funded by NIA 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).
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 clues are under active investigation in more definitive interventional studies. One ongoing study, the Alzheimer’s Disease Multiple Intervention Trial (ADMIT), is 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). In another study, investigators are working to determine whether social engagement can delay the onset of the disease.
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 includes members of the world's largest extended family of early-onset Alzheimer’s mutation carriers in Medellin, Colombia. The API aims to help establish the biological measurements and accelerated regulatory approval pathway needed to rapidly evaluate promising prevention therapies and to find therapies that work 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). For more information about the Colombian research, view this webinar video . The webinar was hosted by the NIH Fogarty Center as part of its “Brain Disorders in the Developing World” program.
We want to treat Alzheimer’s in people for whom the disease has already taken hold.
Treatment options currently are limited for people in whom the disease is clinically evident. NIH is committed to identifying new interventions to slow or even halt the disease’s progress and to ameliorate its symptoms while also turning attention to earlier interventions. Strategies include:
Repurposing existing drugs. One promising approach involves “repurposing” existing drugs as Alzheimer’s treatments. For example, a pilot clinical trial recently demonstrated that a nasal-spray form of insulin was able to delay memory loss and preserve cognition in people with cognitive deficits ranging from MCI to moderate Alzheimer’s disease. These promising findings led to the establishment of a much larger, ongoing clinical trial of intranasal insulin (1RF1AG041845-01). Another compound, the diabetes drug exenatide (Byetta®), has shown promise against neurological disease and is currently being tested in the NIA Intramural Research Program as a potential treatment for early Alzheimer’s.
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 become collaborative participants in this network, receiving both funding and no-cost access to contracted drug development services that are not typically available to the academic research community.
Initiating new trials. A variety of clinical trials of both pharmaceutical and nonpharmaceutical interventions were funded. 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 a Telehealth Technology for Distance Counseling and online educational training modules for the national teledelivery of the evidence-based New York University Caregiver Intervention (NYUCI) model, a psychosocial intervention for families of those 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 are working to develop a new tool for teaching caregivers of people with dementia about preserving functional ability during dressing (1R43AG039172-01A1).
Extending REACH. REACH II (Resources for Enhancing Alzheimer’s Caregiver Health), 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 translated more broadly through the U.S Department of Veterans Affairs, with participating centers in 15 states. The VA is also testing the intervention with caregivers of people with other chronic conditions. The Administration for Community Living is also implementing the REACH intervention at centers in Georgia, North Carolina, and Florida. Finally, 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 to provide information about Alzheimer’s. NIA fulfills these important missions by communicating directly with its various audiences via a robust and reader-friendly Web site, other targeted outreach activities, and partnerships. Specific initiatives in Alzheimer’s disease include:
The 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.
Alzheimers.gov. This new portal Web site, www.alzheimers.gov , was established by the Department of Health and Human Services in 2012 to provide Alzheimer’s families an easier route to the wealth of Federal information and resources. The Web site will undergo further development in 2013.