In 2006, Dr. Fagan and colleagues found evidence of plaque pathology in the absence of dementia symptoms through the use of Pittsburgh Compound-B (PIB) binding visualized with PET and assessing CSF amyloid-beta42 levels. Other preclinical imaging measures include impairments in FDG PET and structural MRI changes, including brain shrinkage and atrophy in the hippocampus. “All these biomarker data really point to a protracted preclinical phase,” said Dr. Fagan. “We think it’s really important to know this information, because ultimately it’s going to inform treatment decisions.”
The workgroup had difficulty agreeing on what specific biomarkers constituted valid diagnostic measures for research criteria, noted Dr. Fagan. “So far, the data in the literature, from clinical as well as animal model studies, indicate that changes in amyloid-beta metabolism are the first changes to occur in Alzheimer’s disease,” she said. The committee thus defined having biomarker evidence of amyloid-beta accumulation as stage 1 in the operational research criteria for preclinical Alzheimer’s disease. Stage 2 requires additional biomarker evidence of synaptic dysfunction and/or early neurodegeneration, and stage 3 requires additional evidence of subtle cognitive decline but not yet meeting the criteria for MCI or dementia.
“The data support the notion that people in the preclinical phase go from being completely asymptomatic with biomarker evidence suggestive of Alzheimer’s disease all the way to individuals who demonstrate subtle cognitive decline but yet do not meet the standardized criteria for MCI,” said Dr. Fagan. She emphasized that the preclinical criteria are intended for use by researchers only and are not ready for clinical application. “First, we need to know with certainty that people with an Alzheimer’s disease biomarker signature in the preclinical phase are all going to go on to develop dementia.”
A Continuum of Disease
The preclinical stage is a continuum of MCI due to Alzheimer’s disease, which is a continuum of Alzheimer’s disease dementia, Dr. Fagan explained. “We talk about conversion to Alzheimer’s disease or conversion to MCI, but it’s not really a conversion,” she said. “It’s not like a switch is made and you go from a normal brain, to all of a sudden you have MCI. It’s really a continuum of a pathologic process that develops over years, probably decades.”
The proposed MCI stage also includes the use of biomarker data. Biomarkers were grouped into those reflecting molecular neuropathology, downstream measures of structural and functional change, and associated biochemical change. The committee then categorized biomarker criteria according to level of certainty of a diagnosis of MCI due to Alzheimer’s disease.
Overall, the key aspects of the MCI criteria, “concern the proposal to increase the certainty that the underlying cause of the MCI syndrome is due to the Alzheimer’s disease process,” said Dr. Petersen, a member of the MCI workgroup. “The use of neuroimaging and fluid biomarkers will enhance our ability to be certain that the MCI state is being produced by Alzheimer’s disease changes in the brain.”
In updating the criteria for the third stage—Alzheimer’s disease dementia—workgroup members sought to create guidelines that could be used by general health care providers and specialized investigators.
“You don’t have to have a specific test [to assess cognitive decline], and you don’t have to have a fancy set of laboratory testing if it’s not available to you,” said Dr. Weintraub, a member of the Alzheimer’s disease dementia workgroup. “We didn’t want to have two sets of criteria that were different for researchers and for clinicians, because with research we need to be very stringent about who gets into a study, for purposes of validation and reliability, and you don’t have the same requirements in the clinical setting. So we tried very hard to make it user friendly for the general clinician, but also to make it specific enough so that researchers could make sure that if they are doing studies on Alzheimer’s disease, that they are all talking about the same population.”
According to Dr. Weintraub, based on data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a multicenter, longitudinal study of the course from normal aging to Alzheimer’s disease, different biomarkers might be useful for different stages of dementia, and not all the biomarkers are going to be useful at the same point in time. Clinical tests do not generally become abnormal until well into the disease course, whereas some biomarkers—most notably, CSF amyloid and tau—are evident in presymptomatic or earlier stages.
“What the incorporation of biomarkers into the criteria for ‘probable Alzheimer’s disease’ has done is really to increase our level of certainty,” said Dr. Weintraub. “None of these biomarkers is like strep. They are not 100% diagnostic. But they are trying to try to move in that direction with Alzheimer’s disease and develop some kind of a simple measure that has biologic validity and that is going to say, ‘Yes, you have this disease,’ or ‘You will have the disease in a certain period of time.’”