The year was 1984. Ronald Reagan was campaigning for his second term in office. Prince and the Revolution had the top pop song, When Doves Cry. At the Oscars, Terms of Endearment won best picture. The Soviet Union pulled out of the summer Olympic Games. The Detroit Tigers won the World Series. Apple Computer sponsored the first commercial for “personal computers” during the Super Bowl (won by the Chicago Bears). And, leaders at the National Institute on Aging (NIA) decided it was time to develop a national, interdisciplinary research program specifically focused on the causes and course of Alzheimer’s disease (AD) and the differences between AD and normal aging.
In the early years, NIA’s AD research program faced many hurdles, including a lack of scientific interest and few trained investigators. Funding focused on dementia was also scarce. In fact, in 1975, Robert N. Butler, M.D., the first Director of NIA, could find “only 12 grants across the whole National Institutes of Health (NIH) pertaining to aging and the brain, averaging $60,000 each.” Dr. Butler decided that “AD and related dementias were catastrophic diseases that must be identified as major national research priorities.”
In 1976, an editorial by Robert Katzman, M.D., an influential neurologist then at the Albert Einstein College of Medicine in New York, described AD as a major public heath problem. The following year, three NIH Institutes, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke (NINDS), and NIA held a national conference that further focused attention on AD. In the mid-1980s, T. Franklin Williams, M.D., established the Office of Alzheimer’s Research at NIA, and with the support of NIH Director James Wyngaarden, M.D., began to consolidate the NIA’s coordination of AD research.
"We had come to recognize that Alzheimer's dementia was probably the greatest scourge and disaster for older people and their families in the United States, and as well the growing potential in our scientific community to address its challenges. We made Alzheimer's research our highest priority", says Dr. Williams.
As NIA was assuming the lead Federal research role, the concept of a network of centers that would foster research on Alzheimer’s began to germinate. Such a network could create the necessary infrastructure to promote longitudinal clinical-pathological studies; integrate basic and clinical research; standardize clinical assessment tools, methods, and clinical trials; and establish national data banks to share resources for clinical, neuropathological, and genetic studies.
First centers formed in 1984
This “center network” concept formed the basis of the creation in 1984 of the legislatively-mandated Alzheimer’s Disease Centers (ADCs) program. NIA awarded funding, after applications were submitted and peer-reviewed, to teams of scientists based at five institutions—Harvard University, Johns Hopkins University, Mount Sinai Medical School, the University of California at San Diego, and the University of Southern California. The original centers were called Alzheimer’s Disease Research Centers (ADRCs), and their funding awards totaled $3.5 million. Researchers were sent forth on a scientific quest that continues to this day.
Zaven Khachaturian, Ph.D., former Associate Director, Neuroscience and Neuropsychology of Aging Program (NNA) and the first Director of the Office of Alzheimer’s Research, is widely regarded as the architect of the ADRC program. Of those early days, Dr. Khachaturian says, “The challenges that NIA faced in launching the national initiative to increase interest in aging and AD research seemed insurmountable; but now it is heartening to see how much of a difference the Institute has made. The successes of NIA’s program were largely due to unwavering support and encouragement by Dr. Williams and other NIA staff, primarily Drs. Teresa Radebaugh and Creighton (Tony) Phelps.”
A brief history of dementia research: the early days
Dementia did not suddenly appear in society in 1906 when Dr. Alois Alzheimer, using newly-developed silver stains, examined the brain tissue of a 51-year-old German woman and described what we now know as plaques and tangles. In fact, dementia was described as early as 500 BC. Until the late 1800s, clinicians believed that an accumulation of “phlegm” caused “senility,” which was simply a symptom of old age. Dr. Alzheimer’s patient was diagnosed with a form of mental disorder called “presenile dementia” due to her relative young age. Because of her age, clinicians did not consider the possibility that the plaques and tangles Dr. Alzheimer described could also be the cause of dementia in old age. So, Alzheimer’s disease was originally characterized as a presenile dementia.
Up until the late 1940s, the medical community widely believed that dementia in old age—senile dementia—was a normal part of aging caused by cerebral arteriosclerosis. It was still often termed senility. But researchers in the 1950s and 60s showed that the brains of many patients with senile dementia did contain the plaques and tangles of presenile dementia and began to investigate their biological structure.
In the 1970s, as neurological research brought further understanding of the structure and function of the brain, scientists observed deficiencies in the neurotransmitter acetylcholine in people with senile dementia. Researchers began challenging the common belief that senile dementia was a normal part of aging, concluding that the brain pathology was identical to that which Dr. Alzheimer described in presenile dementia.
“Alzheimer’s disease” became a common term in the late 1970s to describe both the presenile and senile forms of dementia. Neuroscientists and physicians began using clinical criteria to diagnose AD more frequently, and it became clear that the senile form of AD was by far the most prevalent. Emerging technologies and more sophisticated biochemistry techniques were contributing to growing scientific enthusiasm to find the causes of AD, and the increasing numbers of elderly in the population contributed a sense of urgency to do so.
AD coalitions begin forming
In the mid to late 1970s, a coalition of grass-roots AD advocacy groups consisting primarily of involved family members began to influence public policy discussions and rally public interest in the national AD research agenda. In 1980, leaders of the NINDS and NIA met with coalition members, who would establish the Alzheimer’s Disease and Related Disorders Association (ADRDA), later named the Alzheimer’s Association. By the early 80s, efforts by the ADRDA succeeded in creating a growing public awareness of the incidence and prevalence of AD and the enormous costs borne by society, and they lobbied Congress to provide funding for the NIA to create the ADRC program.
Mission of the ADRC program
The cadre of scientists at the first five ADRCs became the foundation of a network that today reaches across the country and has grown to 30 institutions. Their mission is to promote research, training and education, technology transfer, and collaboration to improve diagnosis, treatment, and overall understanding of AD and related dementias through clinical, pathology, and education cores. Areas of investigation range from the basic mechanisms of AD to managing the symptoms and helping families cope with the effects of the disease.
Centers provide investigators and research groups with well-characterized patients and control subjects, family information, and tissue and biological specimens for use in research projects. Early research projects funded by the centers focused on possible causes of AD and changes in brain chemistry. Researchers were looking at calcium transport, glucose metabolism, protein synthesis, accumulation of metals, possible viral agents, genetic factors, and related dementias.
In 1985, Congress appropriated funds for five additional ADRCs. Duke University, the University of Kentucky, Washington University at St. Louis, the University of Pittsburgh, and the University of Washington joined NIA’s growing AD research network as a result of this Request for Application (RFA) competition.
In 1986, the Alzheimer’s Disease Patient Registries (ADPR) were established, which included the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), an early collaboration among the centers. Under the leadership of Albert Heyman, M.D., a Duke University neurologist, CERAD standardized the definition, assessment, and profile of AD, and the criteria for pathological diagnosis of AD. These criteria are still widely used. Another ADPR project at the Mayo Clinic provided much of the foundation for the current interest and advances concerning mild cognitive impairment (MCI).
Also in 1986, a small clinical trial showed that a cholinesterase inhibitor called tacrine (later marketed as Cognex) had some promise in treating moderate AD. The Alzheimer’s Association worked with NIA, several ADRC directors, and the drug company Warner-Lambert to set up a large, multi-site clinical trial to test tacrine further. This trial provided evidence to the Food and Drug Administration (FDA) that led to approval of tacrine as the first drug specifically targeting AD.
Large clinical trials supported
Collaboration on the tacrine trial also spawned, in 1991, the formation of a consortium of centers and affiliated organizations to test new treatments as they emerge. The consortium, named the Alzheimer’s Disease Cooperative Study (ADCS), was created to conduct clinical trials on compounds not of interest to large pharmaceutical companies. This includes drugs that are off patent, drugs that were patented and marketed for another use but might be useful to treat AD, or novel compounds from investigators or small companies that do not have adequate resources to conduct clinical trials. The ADCS program today continues to organize large clinical trials and to develop trial methodologies that are widely used by both academics and industry.
“When the ADC program was created, NIA’s leaders hoped that an environment of cooperation would stimulate AD researchers to seek new pathways to scientific discovery and to share their findings. The program has done just that. In the collaborative atmosphere of the centers, specialists in biomedical, behavioral, pathological, and clinical science are studying the causes, and possible prevention of AD, and developing new lines of multidisciplinary research. As scientists at the centers uncover the complexities of dementia, they spark a certain friendly competition with other research scientists throughout the world. Their brilliance and enthusiasm creates an excellent training ground for up and coming investigators, and inspires others to devote their energies to AD research,” says Tony Phelps, Ph.D., Program Director, Alzheimer’s Disease Centers, NNA.
Cell repository created
In 1989, the NIA, working with the Duke University ADRC, created a genetics cell repository at the Indiana University ADC. This repository has grown and is now independently funded and called the National Cell Repository for AD (NCRAD). A cell repository banks DNA and cells and builds a database of family histories and medical records for genetic research. NCRAD provides genetic researchers with cell lines and/or DNA samples from people with well-documented AD and normal controls. Because supplies of DNA are finite and cannot easily be regenerated, NCRAD makes “immortalized” cell lines—cells continuously regenerated in the laboratory from the blood samples—to provide samples for studies searching for AD genes.
Wealth of information in 20 years ”When you look at what we knew in 1984 and what we know now, the research advances contributed by ADC scientists represent remarkable progress. I’ve witnessed this from within the ADC system as a research scientist and from my vantage point at NIA,” says Marcelle Morrison-Bogorad, Ph.D., Director, NNA program. Dr. Morrison-Bogorad came to NIA in 1996 from the University of Texas Southwestern Medical Center at Dallas, where she did research on protective proteins in AD brains and was a professor of neurology. “Almost every day, this collective research system adds new understanding of what happens in the brain before and after the symptoms of AD appear. In 20 years we’ve made giant strides and added an immense wealth of information.”
Core Centers and Satellite Clinics established
Starting in 1990, the NIA began to fund Alzheimer’s Disease Core Centers (ADCCs) to expand and diversify the program geographically. Core Centers do not include the large research projects conducted by ADRCs. At that time, all of the centers were also asked to develop a strategy to recruit minority and ethnically diverse research subjects. Several centers created satellite diagnostic and treatment clinics targeting minority, rural, or other underserved populations. Over time, the program has grown to include 26 such satellites, helping accelerate minority patient enrollment to increase the heterogeneity of the research pool, and helping to ensure that research results would be applicable to minorities as well as to Caucasians.
Collecting and pooling data
The National Alzheimer’s Coordinating Center (NACC) was established in 1999 to provide access to larger, standardized data sets collected from the ADCs and to allow characterization of the rarer and mixed phenotypes and genetic and ethnic differences in the patient mix. NACC enables researchers to pool patient information more effectively as they study the unique aspects and subtypes of this complex and heterogeneous disease process. The NACC has data on thousands of subjects and offers qualified AD researchers website access to data sets. It has awarded 13 competitive grants to groups of centers, and NIA has issued two RFAs to conduct collaborative project using patient records and specimens for research projects.
Beginning in 1996, the centers’ application process was changed, allowing new applicants to compete with existing centers for funding. While always peer-reviewed, once funded, the centers did not compete directly with other centers until 1996. By 2004, the program had grown to 30 centers, with funding of $46.9 million (10.3% of NIA’s AD budget that year). More than 60,000 patients and healthy control subjects have been enrolled in ADC programs, and more than 7,000 autopsies have been performed, with the brain material stored in brain banks.
Of cores, of cores…
In addition to an administrative core, clinical core, and a neuropathology core, each center has an education core, which helps recruit and retain subjects for trials, spearheads outreach programs to educate families, and supports innovative staff development to improve clinical skills through training workshops, seminars, and continuing education programs.
Physician education includes lectures, grand rounds, and mini-residencies or internships to help practicing physicians gain skills in assessing, treating, and managing dementia patients. Educational programs often are held in conjunction with State and local agencies and the Alzheimer’s Association. In addition to providing private research funds, Association chapters work closely with many of the scientists and other health professionals based at the centers.
Improving information flow
Changes in how the centers function and improvements in information flow were among the suggestions from panels of researchers and outside experts during planning workshops held in 2001 and 2002. Among the recommendations:
- permit greater flexibility in structure of the individual centers to take advantage of local resources and tailor the center’s organization to emphasize local interests and expertise. For example, it was suggested that centers might enroll and follow special patient populations such as people living in retirement communities or nursing home residents, rather than studying only clinic populations
- permit contracts with an organization such as the Alzheimer’s Association for educational services, or with another center to provide neuropathological evaluations
- continue and accelerate standardized clinical data collection across centers to promote better collaborative clinical studies
- promote better use and increased sharing of tissue and data resources among the centers and the general scientific community
- concentrate cutting-edge research more on the transition from normal aging to MCI and to AD instead of later stages of AD, and focus on comparisons to and overlap with other neurodegenerative diseases
These recommendations were implemented in the succeeding center RFAs. Importantly, efforts were accelerated to establish a universal data set (UDS) among the centers, so that patients enrolled at all centers would be assessed in a standardized manner. The UDS will go into operation in 2005 and will permit even better collaborative research projects among centers and other scientists.
New and ongoing projects
In 2003, the NIA launched a major new initiative to speed the process of creating a large repository of DNA and cell lines from families with multiple cases of late-onset (over age 65) AD. The centers are playing a significant role to recruit families, collect clinical data and blood samples, and provide blood to NCRAD so that DNA and cell lines can be made available to all qualified researchers. The goal of the study, called the Late-Onset Alzheimer’s Disease study (also known as the AD Genetics Initiative), is to identify remaining risk factor genes and possible environmental factors, and the interactions of genes and the environment.
In 2004, NIA announced the Alzheimer’s Disease Neuroimaging Initiative (ADNI), another multi-center initiative. The 5-year study will use neuroimaging (magnetic resonance imaging or MRI, and positron emission tomography or PET) to identify biomarkers of disease progression to help measure effectiveness of therapies under study in clinical trials. Most of the ADCs are participating in the initiative, which is a partnership among the NIA/NIH, academic investigators, the FDA, and, through the Foundation for NIH, the pharmaceutical and imaging equipment industries, the Alzheimer’s Association, and the Institute for the Study of Aging.
ADC grants continue today
The NIA is committing about $16 million in Fiscal Year 2005 to fund 13 new and/or competing renewal ADC grants for a 5-year period. As in previous years, each ADC grant will also support small pilot projects often designed to determine whether a larger study has promise.
The ADCs play a major role in AD research. “This program continues to fulfill its initial goals of attracting outstanding investigators to the field of research in AD and aging, as well as increasing the quality and quantity of research. We’ve helped develop medications that ease symptoms and improve quality of life, and working with the Alzheimer’s Association, helped reduce the stigma of AD in society. Our current large initiatives will help us uncover some of the complexity surrounding the causes of AD and learn more about the possibility of reversing or preventing it. We’re very excited with the public-private partnership model and the shape of our future research direction. We’ve had great successes so far but are mindful that answers to some of our fundamental questions remain elusive. We will continue our strong commitment and focus,” commented Richard J. Hodes, M.D., Director, NIA.
For more information:
- National Institutes of Health 
- National Institute on Aging 
- Alzheimer’s Disease Education and Referral (ADEAR) Center 
- National Cell Repository for AD 
- National Alzheimer’s Coordinating Center 
- Alzheimer’s Disease Cooperative Study 
- Alzheimer’s Association 
ADCs Contribute Significant AD Research Advances
ADC teams have contributed to many of the most significant AD research discoveries in the past 20 years, including:
- developing new concepts such as MCI, a transitional cognitive state between normal function and mild AD, and helping increase emphasis on evaluation of cognition in normal aging and the transition to MCI and early dementia
- furthering understanding of cellular processes and cholinergic and neurotoxic mechanisms that play key roles in formation of neuritic plaques and neurofibrillary tangles, loss of connections, and cell death
- developing and testing the Alzheimer’s Disease Assessment Scale (ADAS) and the Clinical Dementia Rating (CDR), which are instruments for AD screening
- identifying the importance of genetics in development of AD, including identifying the mutations in genes on chromosomes 14, and 1 as major causes of early-onset AD, and identifying the apolipoprotein E4 variant of the apolipoprotein gene on chromosome 19 as a risk factor gene for late-onset AD
- supporting molecular studies and work in related dementias, such as discovering that the a-synuclein protein is deposited in Lewy bodies in AD, Parkinson’s disease (PD), and in Lewy body dementia, and recognizing the common properties of other abnormal proteins associated with neurodegenerative diseases such as PD, as well as identifying tau mutations on chromosome 17, causing frontotemporal dementia with parkinsonism
- conducting clinicopathological studies, for example, how early memory and cognitive abnormalities correlate with changes in the hippocampus and entorhinal cortex
- organizing neuroimaging studies to define the clinical course, signs, and symptoms of AD, and developing a compound known as Pittsburgh Compound-B (PIB), which penetrates the blood-brain barrier, sticks to amyloid plaques, and permits the level of amyloid to be determined on positron emission tomography (PET) scans of living patients
- identifying potential chemical biomarkers in cerebrospinal fluid and serum in clinically well-characterized individuals, including tau, amyloid, isoprostanes, and lipids
- helping to define the contributions of cardiovascular and cerebrovascular diseases and other co-morbidities such as diabetes in the development and severity of AD
- creating transgenic mouse models expressing specific mutated genes, including amyloid precursor protein (APP), presenilin 1, apoE alleles, and tau proteins, as well as gene knockout models such as BACE, which allow scientists to study cellular pathologies so that treatments can be developed to retard or prevent their formation
- supporting studies of inflammatory mechanisms and the role of oxidative stress, calcium, glutamate, and mitochondrial dysfunction
- helping recruit African Americans, Caribbean Hispanics, Mexican Americans, Native Americans, and Chinese Americans for multi-cultural studies
- defining models for caregiver support groups; examining the relationship between caregiver stress and depression; studying how AD affects driving skills; improving behavior management; discussing competency issues, such as loss of financial capacity; using telecomputing; and adapting strategies for managing patients with late-stage dementia
- supporting population studies, such as the Religious Orders Study and the Nun Study
- participating in many ongoing trials examining promising therapies and prevention.