New Guidance on Alzheimer's Spells Out Three Stages

Two years ago, leading Alzheimer's disease experts, under the aegis of the National Institute on Aging and the Alzheimer's Association, came together to draw up guidelines on how Alzheimer's should be defined and diagnosed.

Their guidelines have now been published in four papers in the March issue of Alzheimer's & Dementia.

Probably the most salient guideline is that Alzheimer's should now be viewed as consisting of three stages—a stage in which there are no obvious symptoms, but where noxious changes are already brewing in the brain, or what they refer to as the "preclinical phase": a stage in which mild cognitive problems emerge, but daily functions can still be performed, or what they call the "mild cognitive impairment phase"; and a stage in which a person meets clinical criteria for a probable diagnosis of Alzheimer's, or what they call the "Alzheimer's dementia phase."

"Converging evidence suggests that the brain pathophysiological process begins more than a decade before we detect significant clinical impairment," Reisa Sperling, M.D., an associate professor of neurology at Harvard Medical School and one of the scientists who drafted the guidelines, told Psychiatric News.

Another important guideline is that while people who develop Alzheimer's first go through a period of mild cognitive impairment, not everyone with mild cognitive impairment will necessarily develop Alzheimer's. Moreover, even when people show mild cognitive impairment plus evidence of Alzheimer's pathology, they may not necessarily "progress to Alzheimer's dementia, just as not all individuals with precancerous colon polyps or dysplastic skin moles will develop metastatic cancer," Sperling explained. "Early estimates suggest that [only] 15 to 20 percent of people who have mild cognitive impairment and Alzheimer's pathology progress to Alzheimer's dementia each year."

Telling Sign of Alzheimer's Progression

A third guideline is that impairment in the ability to learn and retain new information is usually present in individuals with mild cognitive impairment who will subsequently get Alzheimer's. This impairment can be detected with formal tests such as the California Verbal Learning Test or the Logical Memory I and II of the Wechsler Memory Scale Revised, but also informally. For instance, a clinician might ask a patient to learn a street address and then to recall it a few minutes later.

However, biomarkers can also sometimes be used to solidify a suspicion that a person with mild cognitive impairment is developing Alzheimer's, the authors pointed out. For instance, if a person with mild cognitive symptoms is known to have both an accumulation of beta-amyloid plaques in the brain and neuronal injury, it is highly probable that he or she will progress to Alzheimer's dementia. In contrast, "the definitive absence of evidence of either beta-amyloid deposition or neuronal injury strongly suggests that the mild cognitive impairment syndrome is not due to Alzheimer's," they noted.

The experts also provided a crucial guideline regarding the probable diagnosis of Alzheimer's: the criteria that were drawn up by the National Institute of Neurological Disorders and Stroke and the Alzheimer's Association in 1984 should continue to be used.

In brief, symptoms must have a gradual onset over months to years, not suddenly over hours or days; there must be a clear history of worsening cognition; and there must be impairment in learning and recall of recently learned information plus evidence of dysfunction in at least one other cognitive domain—say, in word-finding, object recognition, reasoning, judgment, or problem-solving. These "core clinical criteria provide very good diagnostic accuracy and utility in most patients," the experts stated.

Moreover, a diagnosis of "probable Alzheimer's" can be made with even more certainty if a person is known to possess one of the genetic mutants known to cause early-onset Alzheimer's, the experts added. However, if a person is known to possess the APOE-e4 gene variant, which is a risk factor for late-onset Alzheimer's, that information is not sufficient to bolster a diagnosis of "probable Alzheimer's," they said.

Direction for Future Research Cited

In their papers, the experts also provided some direction for future research to advance understanding of the preclinical phase of Alzheimer's. For example, researchers should try to identify the earliest pathological change in the Alzheimer's disease process that would signal Alzheimer's rather than some other type of dementia. "Although we hypothesize that the … earliest pathological change will be in the form of beta-amyloid accumulation, it is possible that beta-amyloid accumulation is necessary but not sufficient to produce the clinical manifestations of Alzheimer's," they wrote.

"And if we can more accurately identify the combination of biomarkers that predicts clinical outcome, we could intervene at a point where we are much more likely to alter the course of the disease," Sperling said.

Guy McKann, M.D., who is affiliated with the Johns Hopkins University Zanvyl Krieger Mind/Brain Institute and helped draft the guidelines, agreed: "Our long-term goal is to identify people early in the course of Alzheimer's, perhaps before they have symptoms, and then to start preventive therapy. Such a therapy does not exist at this time, but it will."

The four papers containing these and other guidelines can be accessed at <www.alzheimersanddementia.org> by clicking on the March issue and then "New Criteria and Guidelines for Alzheimer's Disease Diagnosis."