Revised Definition of Alzheimer's Disease Proposed

Megan Brooks

October 12, 2010

October 12, 2010 — An international working group has proposed a revised definition of Alzheimer's disease (AD) and related conditions in which biomarkers are an essential diagnostic requirement.

The proposed definition provides broader diagnostic coverage of the clinical spectrum of AD and requires a positive biomarker to place a person on the AD continuum.

The proposal, from an International Working Group for New Research for the Diagnosis of AD, was published as a position paper online yesterday and will appear in the November issue of Lancet Neurology. It updates a position paper published by the same working group in 2007.

Meanwhile, this past July, criteria to redefine AD were put forth at the International Conference on Alzheimer's Disease by the National Institute on Aging and the Alzheimer's Association. In an email to Medscape Medical News, Bruno Dubois, MD, first author on the new position paper, said, "The criteria proposed at [International Conference on Alzheimer's Disease] are based on the criteria that we have proposed in 2007, except the fact that they maintain a reference to the [mild cognitive impairment] concept."

"It is very timely to propose a new definition for AD (because) access to reliable biomarkers in vivo has radically changed the definition of the disease," Dr. Dubois, from the Pierre & Marie Curie University and Salpêtrière Hospital in Paris, France, said.

Under this proposed definition of AD, a patient must have episodic memory impairment plus the presence of biological evidence of the disease (at least 1 positive biomarker) shown on magnetic resonance imaging, neuroimaging with positron emission tomography, or cerebrospinal fluid (CSF) analysis. The presence of full-blown dementia is no longer required for a diagnosis of AD.

The clinical phenotype of AD can be typical or atypical; the designation of "probable" and "possible" AD is no longer used in this new definition. In typical AD, the most common clinical phenotype, significant and progressive episodic memory deficits and 1 or more positive biomarkers of Alzheimer's pathology are present.

In atypical AD, clinical syndromes include primary progressive nonfluent aphasia, logopenic aphasia, frontal variant of AD, and posterior cortical atrophy. In the presence of 1 of these clinical presentations, the diagnosis of AD is supported by in vivo evidence of amyloidosis in the brain or in the CSF.

In addition, the new definition outlines 2 different stages of AD: a prodromal, or predementia, stage and a dementia stage. The prodromal stage encompasses episodic memory loss of the hippocampal type, characterized by a free-recall deficit on testing not normalized with cueing. These deficits are not sufficiently severe to affect instrumental activities of daily living and do not warrant a diagnosis of dementia.

In this stage, biomarker evidence from CSF or imaging supports the presence of AD pathological changes. In the dementia stage, cognitive symptoms are sufficiently severe to interfere with social functioning and instrumental activities of daily living, and again, biomarker evidence is present.

The other designations on the AD continuum are mixed AD, preclinical states of AD (including both "asymptomatic at-risk for AD" and "presymptomatic AD"), AD pathology, and mild cognitive impairment.

Defining AD as a clinicobiological entity, the researchers say, means "that there is no longer a reason to wait until patients have developed full-blown dementia or to exclude from diagnosis and treatment a large number of patients who lack functional disability yet express the disease."

"The value of these definitions," they say, "is their potential application in clinical trials of disease-modifying drugs. Individuals identified as 'asymptomatic at risk for AD' or 'presymptomatic AD' might be enrolled in trials aimed at delaying onset of clinical signs. Patients with prodromal AD could be included in trials of drugs targeting progression to more severe stages of AD. Uniformity of definitions will assist in constructing trial populations and comparing results across trials."

Not the End of the Road

Dr. Dubois and colleagues emphasize in their article that this new lexicon serves as a "point of reference for the clinical and research communities, one that requires further discussion, validation, and updating by the scientific community."

Lon S. Schneider, MD, from the University of Southern California Keck School of Medicine, Los Angeles, agrees. "Field trials are needed to establish whether the diagnostic criteria will work effectively in clinical or research situations," he notes in a commentary published with the study.

"Given the importance of biomarkers in this lexicon," he writes, "it should be remembered that, although several biomarkers have been correlated with neuropathological changes of AD, clinical symptoms, and disease stage, none has yet been shown to have clear criterion validity."

Dr. Schneider further points out that biomarkers used as diagnostic aids have to be interpreted with a broad context because some are also associated with different neurodegenerative, cerebrovascular, and other diseases.

The International Working Group received financial funding from Eisai France to support the meeting room costs for the Alzheimer's Association International Conference on Alzheimer's Disease. Dr. Dubois and members of the working group and Dr. Schneider have several financial disclosures, all listed with the original article.

Lancet Neurology. Published online October 11, 2010.

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