The revised guidelines for diagnosing and researching Alzheimer’s disease define three disease phases and incorporate research on disease biomarkers.

Researchers and clinicians should consider Alzheimer’s disease to have a preclinical phase, a mild cognitive impairment (MCI) phase, and a dementia phase, according to updated guidelines published in the April 22 Alzheimer’s and Dementia. The updates, developed by three workgroups organized by the National Institute on Aging and the Alzheimer’s Association, were proposed at the Alzheimer’s Association 2010 International Conference on Alzheimer’s Disease (ICAD) and modified slightly in response to suggestions received during a public comment period in summer 2010.

Preclinical Changes
Following the 2010 proposals, the workgroup that formulated guidelines on the preclinical phase of Alzheimer’s disease “tried to make it much clearer that we were proposing a research framework and that these recommendations were not intended for clinical use,” Reisa Sperling, MD, Associate Professor of Neurology at Harvard Medical School, Boston, and chair of the workgroup, told Neurology Reviews. “We also more clearly acknowledged that some individuals with evidence of early Alzheimer’s disease pathology in their brains may not progress toward Alzheimer’s disease dementia. Finally, we added some of the subtle behavioral symptoms, in addition to early cognitive changes, that might be indicative of the emergence of clinical symptoms.”

The final preclinical guidelines noted that patients with Alzheimer’s disease tend to have a long, slow rate of decline on cognitive tests and “a period of acceleration of performance decrement that may begin several years before MCI onset.” They added that “self-report of subtle cognitive decline, even in the absence of significant objective impairment on testing, may portend future decline in older individuals.” The guidelines emphasized, however, that, “additional longitudinal studies of older individuals, perhaps combining biomarkers with measures sensitive to detecting very subtle cognitive decline, are clearly needed.”

MCI and Other Changes
Since ICAD 2010, the workgroup on the MCI phase of the disease “clarified the diagnostic criteria for cases in which biomarkers are unavailable or unable to be tested,” said William J. Jagust, MD, Professor of Neuroscience and Public Health at the University of California, Berkeley, and a member of the MCI workgroup. “This is likely to be the most widely used categorization.… The general consensus was that we needed to be clear that there was a path to an MCI diagnosis in standard clinical practice situations (such as community physicians, primary care, etc).”

Dr. Jagust added, “I think the other major change was that we brought the terminology for MCI and Alzheimer’s dementia into better alignment as far as how we categorized biomarkers and how we rated their importance.”

The Alzheimer’s dementia workgroup made no major revisions to its 2010 proposals, Guy M. McKhann, MD, Professor of Neurosurgery and Neuroscience at Johns Hopkins University School of Medicine in Baltimore, told Neurology Reviews.

More updates to the guidelines for all phases of Alzheimer’s disease are forthcoming, noted Clifford R. Jack, Jr., MD, Professor of Radiology at Mayo Clinic in Rochester, New York, and colleagues, in their introduction to the updates. A fourth workgroup is developing revised pathologic criteria for the disease—which were not included in any of the published updates—and is expected to complete its work later this year.

Guidelines Establish Three Distinct Disease Phases
Originally published in 1984, the Alzheimer’s disease guidelines have not been updated previously. The updates are based largely on the findings that Alzheimer’s pathology can be present in the absence of obvious symptoms and that the disease can manifest itself with atypical presentations. The original guidelines did not recognize the preclinical phase or the MCI phase of Alzheimer’s disease, nor did they incorporate research on biomarkers of the disease.

As noted by Dr. Sperling, the new preclinical guidelines are intended exclusively for research purposes. They define the preclinical phase as one in which amyloid buildup and other early nerve cell changes may have begun but no significant clinical symptoms are evident.

The MCI phase guidelines include both clinical and research criteria for diagnosing this phase. The clinical criteria include cognitive decline, preservation of independence, and lack of dementia, while the research criteria include biomarkers reflecting the beta-amyloid protein or neuronal injury. In addition, the guidelines propose four levels of certainty for diagnosing the MCI phase.

The dementia phase guidelines propose that Alzheimer’s dementia be categorized as (1) probable, (2) possible, or (3) probable or possible with evidence of the Alzheimer’s disease pathophysiologic process. They expand the symptoms of Alzheimer’s dementia beyond memory loss to declines in word-finding ability, visuospatial presentation, and reasoning or judgment. Biomarkers of brain amyloid-beta protein deposition, downstream neuronal degeneration or injury, and causative Alzheimer’s disease genetic mutation all increase the certainty that the patient’s dementia is caused by Alzheimer’s pathology, according to the guidelines.

—Jack Baney

New Alzheimer's Disease Guidelines Are Adopted