For the first time in 27 years, new criteria and guidelines for the diagnosis of Alzheimer’s disease have been published by three expert workgroups spearheaded by the Alzheimer’s Association and the National Institute on Aging (NIA) of the National Institutes of Health (NIH).
The workgroups published four articles including ready-to-use clinical diagnostic criteria for Alzheimer’s disease dementia and mild cognitive impairment (MCI) due to Alzheimer’s. A research agenda was proposed for preclinical Alzheimer’s. The use of biomarkers in Alzheimer’s dementia and MCI due to Alzheimer’s was also proposed as a research agenda only, and is not intended for application in clinical settings at this time.
The articles – collectively, the National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines for Alzheimer’s Disease – expand the definition of Alzheimer’s to include two new phases of the disease: (1) presymptomatic and (2) mildly symptomatic but pre-dementia, along with (3) dementia caused by Alzheimer’s. This reflects current thinking that Alzheimer’s begins creating distinct and measurable changes in the brains of affected people years, perhaps decades,
before memory and thinking symptoms are noticeable.
“It is our hope that incorporating scientific knowledge gained and technological advances made over the past quarter century will improve current diagnosis, bring the field closer to earlier detection and treatment, and ultimately lead to effective disease-modifying therapies,” said William Thies, Ph.D., Chief Medical and Scientific Officer at the Alzheimer’s Association. “Development and publication of these articles is a major landmark in the field. That said, publication of these articles is not yet the end of the process of developing new diagnostic criteria for Alzheimer’s, but is another major step in the process.”
“The new guidelines reflect today’s understanding of how key changes in the brain lead to Alzheimer’s disease pathology and how they relate to the clinical signs of mild cognitive impairment and Alzheimer’s disease dementia,” said Creighton Phelps, Ph.D., Program Director of the Alzheimer’s Disease Centers Program at the National Institutes of Health. “We are also beginning to be able to detect these changes at a preclinical stage, long before symptoms appear in many people. With further research on biomarkers, as set forth in the new guidelines, we may ultimately be able to predict who is at risk for development of mild cognitive impairment and Alzheimer’s dementia, and who would benefit most as interventions are developed.”
The proposed new Alzheimer’s disease diagnostic guidelines were published online today by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. Hard copy publication is scheduled for the May 2011 issue of the journal.
Three Stages of Alzheimer’s Disease:
The current diagnostic criteria for Alzheimer’s*, for the most part, focus on reliable diagnosis when signs of problems in thinking, learning, and memory are noticeable to an individual, family, and friends. But research tells us that Alzheimer’s likely begins years, maybe even decades, prior to symptoms appearing.
The new articles refer to three phases of Alzheimer’s disease progression over time:
Preclinical Alzheimer’s Disease – Measurable changes in biomarkers (such as brain imaging and spinal fluid chemistry) that indicate the very earliest signs of disease, before outward symptoms are visible. Currently, there are no clinical diagnostic criteria for this phase, but the group provides a scientific framework to help researchers better define this stage of Alzheimer’s. (See supplement 5.)
Mild cognitive impairment (MCI) due to Alzheimer’s Disease – Mild changes in memory and thinking abilities, enough to be noticed and measured, but not impairment that compromises everyday activities and functioning.
Dementia due to Alzheimer’s Disease – Memory, thinking and behavioral symptoms that impair a person’s ability to function in daily life. (For more details, see supplement 3.)
A biomarker is a naturally occurring, measurable substance or condition in the body that reliably indicates the presence or absence of disease or the risk of later developing a disease; for example, blood glucose levels are a biomarker of diabetes, and cholesterol levels are a biomarker of cardiovascular disease risk. Both fluid and imaging measures are being tested as possible biomarkers for Alzheimer’s. (See supplement 4.)
There was a broad consensus within the workgroups that much additional research needs to be done to validate the application of biomarkers as they are proposed in the newly-published articles. According to the authors, “The definitive studies … are likely to take more than a decade to fully accomplish. Thus, we must move quickly … and adjust our models and study designs as new data become available.”
“If we can definitively determine the risk of developing Alzheimer’s dementia in people who have biomarker evidence of brain changes but are not showing outward symptoms, we will open an important window of opportunity to intervene with disease-modifying therapies, once they are developed,” Thies said.
“In addition, the new criteria give us powerful tools to accelerate our knowledge in the fight against Alzheimer’s disease. They give us guidelines for getting a more accurate assessment of Alzheimer’s prevalence. In that way we can better assess the need for everything from research dollars to care services, to patient and caregiver education materials, to nursing home beds, to the number of gerontologists and nurses that we need. And, they give us a basis for creating the next generation of Alzheimer’s treatments that will be effective in each stage of the disease,” Thies said.
According to the authors, in order to facilitate the possibility of future presymptomatic treatment of Alzheimer’s, it was important to define the disease from the earliest changes in the brain, not only the observable, symptomatic stages of the disease. The authors propose that Alzheimer’s begins with a long asymptomatic period during which detrimental changes are progressing in the brain, and individuals with biomarker evidence of these changes are at increased risk for developing cognitive and behavioral impairment and progression to Alzheimer’s dementia.
Accelerating scientific discovery has sharpened our understanding of Alzheimer's disease. In response to the pace of insight, the National Institute on Aging (NIA) and the Alzheimer's Association convened three workgroups to explore the need for new diagnostic criteria that reflect the full clinical continuum of the disease from its earliest effects to its eventual impact on mental and physical function.
Each workgroup released its proposed recommendations at the 2010 Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD). The new guidelines, revised to reflect input from the professional community at large, are now published as free-access papers in Alzheimer's and Dementia: The Journal of the Alzheimer's Association and are available as PDFs below.
Key elements of the new diagnostic criteria and guidelines:
- Update widely used existing guidelines for Alzheimer's disease originally established in 1984 by the National Institute of Neurological Disorders and Stroke (NINDS) and the Alzheimer's Association (then known as the Alzheimer's Disease and Related Disorders Association).
- Refine existing guidelines for diagnosing mild cognitive impairment (MCI). People with MCI experience a decline in memory, reasoning or visual perception that's measurable and noticeable to themselves or to others, but not severe enough to be diagnosed as Alzheimer's or another dementia. The new guidelines formalize an emerging consensus that everyone who eventually develops Alzheimer's experiences this stage of minimal but detectable impairment, even though it's not currently diagnosed in most people. However, although everyone with Alzheimer's experiences an MCI stage, not everyone with MCI eventually develops Alzheimer's. MCI may also occur for other reasons. The guidelines designate the condition of minimal impairment preceding Alzheimer's as “MCI due to Alzheimer's disease,” and define four levels of certainty for arriving at this diagnosis.
- Broaden the conceptual framework for thinking about Alzheimer's disease to include a “preclinical” stage characterized by signature biological changes (biomarkers) that occur years before any disruptions in memory, thinking or behavior can be detected. The new guidelines do not specify which biomarkers should be considered signatures of preclinical Alzheimer's. Instead, they propose a research agenda that builds on promising preliminary data emerging from recent studies, including the federally funded Alzheimer's Disease Neuroimaging Initiative (ADNI). Promising investigational biomarkers include brain imaging strategies and certain proteins in spinal fluid.
- Establish a framework for eventually adding biomarker benchmarks to the diagnosis of Alzheimer's disease. The guidelines for MCI due to Alzheimer's disease include specific biomarkers that may be used now in research settings, with the expectation that these recommendations are a work in progress that will evolve as knowledge advances. Understanding signature biomarkers may reveal how these benchmarks change over time, enabling more precise and clinically useful characterization of all stages of Alzheimer's.
National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Disease fromAlzheimer's and Dementia: The Journal of the Alzheimer's Association
Clifford R. Jack Jr., et al. “Introduction to the Recommendations from the National Institute on Aging and the Alzheimer's Association Workgroups on Diagnostic Guidelines for Alzheimer's Disease.”
Guy M. McKhann and David S. Knopman, et al. “The Diagnosis of Dementia Due to Alzheimer's Disease: Recommendations from the National Institute on Aging and the Alzheimer's Association Workgroup.”
Workgroup members: Proposed criteria for Alzheimer's disease dementia
Marilyn S. Albert, et al. “The Diagnosis of Mild Cognitive Impairment Due to Alzheimer's Disease: Recommendations from the National Institute on Aging and Alzheimer's Association Workgroup.”
Workgroup members: Proposed criteria for mild cognitive impairment due to Alzheimer's disease
Reisa A. Sperling, et al. “Toward Defining the Preclinical Stages of Alzheimer's Disease: Recommendations from the National Institute on Aging and the Alzheimer's Association Workgroup.”