Members of three workgroups convened by the National Institute on Aging (NIA) and the Alzheimer’s Association have proposed updates to the diagnostic criteria for Alzheimer’s disease—the first such changes in 25 years. The draft reports from the workgroups were released to coincide with the documents’ presentation at the Alzheimer’s Association International Conference on Alzheimer’s Disease (AAICAD) 2010 in mid-July.
The current criteria for the diagnosis of Alzheimer’s disease were established by a National Institute of Neurological Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINDS/ADRDA) workgroup in 1984. These criteria were almost universally adopted and have survived intact, without modification, for more than 25 years. However, experts note, the field has evolved to a great extent since then.
“Important scientific discoveries have been made in Alzheimer’s, and there have been significant changes in our knowledge and conception of the disease,” said Creighton H. Phelps, PhD, Director of the Alzheimer’s Disease Centers Program, Division of Neuroscience, NIA (part of the NIH). “The NIA and the Alzheimer’s Association, after consultation with the Alzheimer’s scientific and medical community, concluded that the diagnostic criteria may need to be revised to incorporate scientific advances. We decided to convene workgroups to examine the literature and make recommendations.”
Significant Advances
Among the most important advances in the Alzheimer’s field since the publication of the 1984 NINDS/ADRDA diagnostic criteria are:
• Alzheimer’s-driven changes in the brain, as well as the accompanying cognitive deficits, develop slowly over many years, with dementia representing the end stage of years of pathology accumulation. At the same time, it is known that some people have the brain changes associated with Alzheimer’s and yet don’t report symptoms of dementia.
• Predictive genes in early-onset Alzheimer’s indicate that the initial events ultimately leading to both clinical symptoms and pathological brain changes begin with disordered beta-amyloid metabolism.
• The e4 allele of the APOE gene is well accepted as a major genetic risk factor for late-onset Alzheimer’s disease, which is defined as onset at age 65 or older.
• Biomarkers for Alzheimer’s have been developed and are being validated. These fall into several categories:
° Biomarkers of beta-amyloid pathology, including amyloid positron emission tomography (PET) imaging and levels of beta-amyloid in cerebrospinal fluid (CSF).
° Biomarkers of neuronal injury, including levels of CSF tau and phospho-tau.
° Biomarkers of neuronal dysfunction, including decreased uptake of fluorodeoxyglucose (FDG) on PET scans.
° Biomarkers of neurodegeneration, including brain atrophy on structural MRI.
In addition, it has been only in the past decade that a better understanding of the distinctions and overlaps of Alzheimer’s with non-Alzheimer’s dementias has begun to emerge. Knowledge of the non-Alzheimer’s dementias was rudimentary in 1984, and the current diagnostic criteria are vague in defining distinctions between Alzheimer’s and the major alternatives. The common co-existence of Alzheimer’s and cerebrovascular disease is now appreciated. Much more is known about dementia with Lewy bodies, and also about Pick’s disease and other frontotemporal dementias.
Emphasis on Earlier Diagnosis
Alzheimer’s disease is thought to begin years, perhaps even decades, before symptoms are noticeable. But there is no single, generally accepted way to identify the disease in its earliest stages, before symptoms are evident.
According to Phelps, earlier detection of people at highest risk for Alzheimer’s and those who have the earliest forms of the disease will facilitate finding the right individuals to participate in risk-reduction and prevention research studies.
“The NIA and the Alzheimer’s Association hope this process of updating and revising the Alzheimer’s diagnostic criteria with modern technologies and the latest advances will provide standards that move the field further in the direction of early detection and treatment,” said William Thies, PhD, Chief Medical and Scientific Officer of the Alzheimer’s Association.
Each of the NIA/Alzheimer’s Association workgroups was tasked with examining the research and making recommendations on the diagnostic criteria for one of the three stages of Alzheimer’s disease that are now commonly thought to exist: preclinical Alzheimer’s, mild cognitive impairment (MCI) due to Alzheimer’s, and Alzheimer’s dementia. At AAICAD 2010, leaders of the three workgroups presented preliminary reports for initial comment by the Alzheimer’s community.
The proposals would change the 1984 criteria to better reflect the various stages of the disease and the inclusion of Alzheimer’s disease biomarkers. “While the role of biomarkers differs in each of the three stages, much remains to be understood concerning their reliability and validity in diagnosis,” Thies said. “This makes it critical that we thoroughly test any new recommendations.”
The groups’ reports (which are available at www.alz.org/research/diagnostic_criteria) are summarized below:
Preclinical Alzheimer’s. The group outlined a research agenda to identify methods of assessment that may help predict risk for developing the disease. Biomarkers and other clinical assessment tools to identify early cognitive decline are being investigated to establish the presence of Alzheimer’s brain changes in people with no overt symptoms and to identify those who may eventually develop the disease.