HONOLULU—Newly proposed diagnostic criteria for Alzheimer’s disease—which include a preclinical stage and a stage for mild cognitive impairment (MCI)—were presented at the 2010 Alzheimer’s Association International Conference on Alzheimer’s Disease. The first draft reports of the guidelines, expected to be adopted in the fall after a public feedback period, were written by three workgroups organized by the National Institute on Aging and the Alzheimer’s Association and will represent the first update since 1984, when the original guidelines were created.
“The criteria have not been revised in 26 years, and during that interval there have been two general movements in the field,” Ronald C. Petersen, MD, PhD, Director of the Mayo Alzheimer’s Disease Research Center, Mayo Clinic, in Rochester, Minnesota, told Neurology Reviews. “We can now suspect the diagnosis of Alzheimer’s disease at an earlier point in the clinical spectrum—in particular, at the MCI stage. And there have been many advances in imaging and other biomarkers that increase our certainty that the underlying pathophysiology of the clinical syndrome is, in fact, Alzheimer’s disease.
“The original guidelines dealt only with the dementia phase of Alzheimer’s disease,” noted Dr. Petersen, who is also Chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council. “This stage is now being modified to incorporate imaging and other biomarkers, but the real changes are in the proposed MCI and preclinical stages of the disease. These predementia conditions had not been considered previously.”
Neurology Reviews spoke with members of the workgroups regarding the creation of the newly proposed criteria for preclinical Alzheimer’s disease, MCI due to Alzheimer’s disease, and Alzheimer’s disease dementia. The committee members discussed why the guidelines were updated, the key revisions that were made, and what the new guidelines will mean for clinicians and researchers, as well as for drug development.
What’s Changed Since 1984?
The original guidelines—known as the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA) criteria—have been widely used in clinical trials and research and have been generally reliable in diagnosing patients with probable Alzheimer’s disease.
But a number of significant advances have been made during the past two decades, including the identification of three genes associated with autosomal dominant forms of Alzheimer’s disease—amyloid precursor protein, presenilin 1, and presenilin 2. In addition, the ε4 allele of the apolipoprotein E (APOE) gene has been identified as the strongest genetic risk factor for Alzheimer’s disease, and CSF amyloid-beta42 and tau proteins have been recognized as biomarkers of pathologic changes in the brain.
“It’s long been known what the pathology was, but we didn’t have any biomarkers back then to actually identify this pathology in living people,” said Anne Fagan, PhD, Research Associate Professor of Neurology at the Washington University School of Medicine in St. Louis. “So the guidelines really needed updating, given these increases in our knowledge base.”
“A lot of people felt that the guidelines were a little bit outdated and that things had changed,” commented Richard Mayeux, MD, Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology, and the Director of the Gertrude H. Sergievsky Center at Columbia University in New York City. “A new entity—MCI—had been introduced, and people were interested to know if there was some way to determine whether it was possible to identify biomarkers from that entity that would increase the assurance of Alzheimer’s disease or predict who would go on to get Alzheimer’s disease with any sort of reasonable accuracy.”
In addition, the original guidelines did not distinguish between a diagnosis of Alzheimer’s disease and other kinds of dementia, noted Sandra Weintraub, PhD, Professor of Psychiatry, Neurology, and Psychology, Northwestern University, in Chicago. “We have learned a great deal about other types of neurodegenerative diseases that produce a dementia that resembles the manifestations of Alzheimer’s disease, so that’s helped us to differentiate Alzheimer’s disease from other kinds of disorders and led to more accurate differential diagnosis at the clinical level,” said Dr. Weintraub.
Detecting Early Signs of Alzheimer’s Disease
Aided by advances in neuroimaging, CSF assays, and other biomarkers, researchers have gathered increasing evidence that the pathology of Alzheimer’s disease begins well in advance of a diagnosis of clinical dementia, and thus, criteria for a preclinical phase of the disease were developed. Acknowledgment of the potential importance of very subtle cognitive decline prior to reaching the diagnostic criteria for MCI was also an important step in defining the preclinical phase, according to Dr. Fagan, a member of the preclinical Alzheimer’s disease workgroup. “We struggled with what term to use,” she said. “Was it asymptomatic, presymptomatic, preclinical, prodromal Alzheimer’s disease?”