These new criteria represent one of two parallel efforts internationally to modernize the diagnosis with pathophysiological and biomarker research. Led by Bruno Dubois of the Salpêtrière Hospital, Paris, a working group of European and North American clinicians previously proposed a similar new research diagnosis as well as a terminology to go along with it (Dubois et al., 2010; Dubois et al., 2007). Both sets of criteria share some authors in common.

Many clinicians in the U.S. and abroad today use guidelines from the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) published in 1984 (McKhann et al., 1984). In the Alzheimer’s Association/NIA criteria published today, some things are staying the same. The criteria still emphasize that a diagnosis of Alzheimer’s disease be made on clinical grounds, though it leaves the door open for biomarker evidence to assist in the diagnosis in the future. According to Bill Thies of the Alzheimer’s Association, the practice of medicine as applied to Alzheimer’s disease has not changed due to these new criteria.

The most significant change comes with the formal recognition that Alzheimer’s disease has three phases and that its pathology begins years before the clinical manifestation. Outlined in separate papers, three working groups propose criteria for diagnosing “Alzheimer’s disease,” diagnosing “mild cognitive impairment due to Alzheimer’s disease” (a new term designed to clearly identify people with underlying AD pathology as opposed to people with age-associated cognitive decline), and defining preclinical stages of AD, respectively. The three sets of recommendations are the result of working group deliberations led by Guy McKhann at Johns Hopkins University, Baltimore, Maryland; Marilyn Albert, also there; and Reisa Sperling, Brigham and Women’s Hospital, Boston, Massachusetts, respectively.

The biggest changes lie in the push to use biomarkers for research purposes. Over the last 20 years, research has made tremendous strides toward identifying fluid and imaging biomarkers with diagnostic potential, but as first author Clifford Jack, Mayo Clinic, Rochester, Minnesota, and colleagues write in an accompanying introductory paper, “There was a broad consensus within all three workgroups that much additional work is needed to validate the application of biomarkers for diagnostic purposes.” The distinction between the fitness of biomarkers for use in research settings and in community clinics was the main flashpoint for debate last summer.

For research purposes then, the working groups see biomarkers as helping to determine whether someone with mild cognitive impairment has underlying AD pathology and is therefore likely to progress to frank dementia. In preclinical phases, the researchers see biomarkers as being essential for staging. Within that earliest phase, three preclinical stages are proposed. Amyloid accumulation, as judged by analysis of cerebrospinal fluid or brain imaging, defines Stage 1. Beyond that, Stage 2 requires a marker of neuronal injury, such as a positive tau result in CSF or an abnormal brain glucose metabolism on an MRI scan. Stage 3 adds evidence of subtle cognitive change. Again, in this early phase, the criteria are research criteria intended to determine the relationship between those markers and subsequent Alzheimer’s disease; the stages are not validated for clinical use at this point.

In a press conference to discuss the work, Sperling emphasized that one of the changes since these criteria first debuted last July is the acknowledgement that people with a positive biomarker may or may not progress to the clinical stage of AD. “We are trying to make a researcher framework that lets us best test hypotheses,” she said.

Thies said that the new criteria will be validated over the next few years. “They will drive research into earlier diagnoses, better treatments, and better understanding of the public health impact of Alzheimer’s disease.”

The 9th Annual Mild Cognitive Impairment Symposium to be held 29-30 April 2011 in Miami, Florida, will feature discussion of both the Alzheimer’s Association/NIA and the criteria of Dubois et al. Watch for Alzforum coverage of this important topic.—Tom Fagan.

References:
Jack CR, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH. Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):257-62. Abstract

McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. Abstract

Albert MS, Dekosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. Abstract

Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. Abstract