WASHINGTON, DC—A combination of biomarkers may significantly help select cognitively normal individuals to include in clinical trials of interventions for Alzheimer’s disease and assess disease progression in response to treatment, according to Marilyn S. Albert, PhD, Director of the Division of Cognitive Neuroscience in the Department of Neurology at Johns Hopkins University School of Medicine and Director of the Johns Hopkins Alzheimer’s Disease Research Center in Baltimore. Dr. Albert is part of an international research effort to identify biomarkers associated with the changes that occur in the brains of normal individuals who later develop Alzheimer’s disease. “By definition, we’re looking for measures—or biomarkers—that might reflect the underlying disease process when the clinical symptoms are minimal,” she said at the Alzheimer’s Association International Conference 2015.
The most recent data from the Biomarkers for Older Controls at Risk for Dementia (BIOCARD) study show that combinations of biomarkers obtained at least six years prior to symptom onset—including measures of cognition, brain structure, and brain proteins that appear to reflect the accumulated Alzheimer’s disease pathology in people who are cognitively normal—can identify which individuals are most likely to progress to mild cognitive impairment (MCI) due to Alzheimer’s disease. “This [finding] suggests that it is possible to use combinations of these measures to predict who is at high risk so that novel treatments could be initiated once they are developed,” said Dr. Albert.
The BIOCARD Study
Dr. Albert and her colleagues are currently running an extension of the original BIOCARD study, which was begun in 1995 by the National Institute of Mental Health (NIMH) with 349 subjects who were cognitively normal. Approximately 75% of participants enrolled at that time had a family history of dementia, but no clinical signs of Alzheimer’s disease. “Alzheimer’s pathology develops when individuals are cognitively normal and then changes and spreads through the brain throughout the course of the disease,” Dr. Albert explained, “so we know that there must be some individuals who are cognitively normal with this pathology.” The main objective of the study is to understand the preclinical phase of Alzheimer’s disease so that it might be possible to intervene when individuals are cognitively normal.
Dr. Albert outlined the considerable challenges to determining what types of biomarkers might be predictive. First, a large group of cognitively normal individuals needs to be followed over a long period of time to measure changes that could reflect early disease. Next, skilled clinicians are needed to evaluate outcomes and ensure that they are related to Alzheimer’s disease, and finally, the study needs to include enough outcomes to enable a useful statistical analysis, she said.
The initial NIMH study was halted in 2005. Johns Hopkins researchers were funded in 2009 to continue the study. They re-enrolled the majority of the original participants (approximately 30 patients had died). Half of the participants were female, and the mean education level was high (17 years). The mean age at the initial time of enrollment was 57. Some participants have been followed for as long as 20 years, and the minimum follow-up is about 10 years, Dr. Albert said.
Data for the original study were collected from each participant in the form of biannual spinal taps to obtain samples from CSF, and structural MRI studies, along with annual cognitive testing and clinical evaluations. Approximately 60 of the participants have developed MCI or dementia due to Alzheimer’s disease.
Combining Measures Improved Accuracy
The investigators performed Cox regression analyses on all measures and calculated hazard ratios (HR) to identify measures associated with the time to onset of clinical symptoms. They found significant associations between baseline levels of amyloid beta and p-tau in CSF and time to onset of MCI. Right hippocampal volume, right entorhinal cortex thickness, and test scores of episodic and incidental memory at baseline also were significantly associated with time to onset of MCI, Dr. Albert reported.
Baseline measures of amyloid beta (HR = 0.72) were found to be lower in people who progressed more rapidly to clinical symptoms, and baseline p-tau (HR = 1.39) levels were higher. In addition, lower right entorhinal cortex (EC) thickness (HR = 0.74) and lower right hippocampal volume (HR = 0.71) were both associated with decreased time to onset of Alzheimer’s disease, said Dr. Albert.
Although nine cognitive tests appear to predict Alzheimer’s disease, the Paired Associates Immediate Recall (PA) test and the Digit Symbol Substitution (DSS) test had the most significant hazard ratios (0.53 and 0.41, respectively) at least six years prior to the onset of clinical symptoms, Dr. Albert observed.