PARIS—Changes in tau protein and amyloid-beta 42 levels as measured in the CSF may predict the onset of inherited Alzheimer’s disease as long as 20 years before symptoms occur, researchers reported at the 2011 Alzheimer’s Association International Conference. These results also suggest that prevention trials could be feasible in the future.
“The individuals we studied in the Dominantly Inherited Alzheimer Network (DIAN)—all of whom come from families in which there is a known mutation that causes early-onset Alzheimer’s disease—who are currently asymptomatic but inherited the mutation from their affected parent will develop Alzheimer’s-related dementia with 100% certainty,” John C. Morris, MD, Director of DIAN and Professor of Neurology at the Washington University School of Medicine in St. Louis, told Neurology Reviews. “The fact that the biomarkers in these DIAN mutations also are positive is very strong support for the concept that these biomarkers herald the eventual appearance of dementia.”
Patients with inherited Alzheimer’s disease tend to develop symptoms at a younger age, typically in their 40s and 50s but sometimes as early as their 30s, the researchers noted. “We want to prevent damage and loss of brain cells by intervening early in the disease process—even before outward symptoms are evident, because by then it may be too late,” Randall Bateman, MD, Associate Professor of Neurology at Washington University and Associate Director of DIAN, said. “We propose accelerating efforts to prevent Alzheimer’s disease by treating people at highest risk for dementia caused by Alzheimer’s disease.”
DIAN Study Population and Interim Results
Dr. Bateman, who presented the research with other DIAN investigators, and his team analyzed data from the first 150 enrollees in the DIAN registry, which includes information from 11 research centers in the United States, United Kingdom, and Australia. Participants completed a four-day testing battery, including clinical assessment, standard and novel psychometric measures, structural and functional MRI, PET, and blood and CSF assays for amyloid-beta 42 and tau proteins. Patients’ expected age of dementia onset, defined as the age of the parent from whom they inherited the gene mutation when they first started experiencing symptoms, was also noted.
Asymptomatic DIAN participants had a mean age of 37; the average age of onset for their parents was 45.8. More than half (51%) of asymptomatic participants carried the Alzheimer’s gene mutation. The mean age of onset in symptomatic participants was 46.1.
Brain Chemistry Changes Involved in Disease Onset
The researchers examined the CSF and blood samples from approximately 110 DIAN participants for amyloid-beta 42 and tau proteins. They found that, compared with family members without the genetic mutation, asymptomatic patients who carried the gene mutation had lower levels of CSF amyloid-beta 42 and higher levels of tau proteins. These findings were consistent with previous research that suggests people with Alzheimer’s-related dementia have lower levels of CSF amyloid, reflecting the presence of amyloid plaques in the brain, and elevated tau levels, reflecting the presence of neurofibrillary tangles and/or brain cell death.
“It is important to note that the only definitive way to know when biomarkers begin to change is to characterize longitudinal biomarker changes within individuals over time, as they progress in their disease,” Anne Fagan, PhD, Research Professor of Neurology at Washington University and coauthor of the study, told Neurology Reviews. “However, based on the cross-sectional analyses we have performed on samples from individuals obtained at one point in time, the data suggest that changes begin to become apparent several decades before the onset of symptoms.”
“We can measure brain chemistry abnormalities in the Alzheimer’s gene carriers that begin at least 10 years, and maybe even 20 years, before the age that their parents saw Alzheimer’s disease symptoms and when they too would be expected to see them,” said Dr. Bateman. “As a result, we believe that the DIAN results will help to elucidate the chronology of Alzheimer’s disease progression prior to its symptomatic stages.”
Dr. Fagan added, “CSF amyloid-beta 42 levels appear to drop first, about 20 years prior to the estimated age of dementia onset, whereas increases in CSF levels of tau and ptau181 become apparent a bit later, around 10 to 20 years prior to symptoms.”
According to Dr. Bateman, PET imaging results also suggested that the deposition of amyloid begins many years before the development of dementia symptoms. In addition, the researchers saw distinct differences between the regional distribution of amyloid in the brains of patients with inherited Alzheimer’s disease and those with the more common sporadic late-onset Alzheimer’s disease. “The findings of the DIAN study indicate that inherited Alzheimer’s disease is largely similar to the much more common late-onset Alzheimer’s disease,” Dr. Bateman told Neurology Reviews. The latter is rarely caused by the genetic mutations that increase amyloid-beta production, he noted, but the observation that amyloid deposition in the brain begins 15 or more years before symptoms appear makes the two disease forms similar in most ways. “These findings suggest that treatment and prevention trials in inherited Alzheimer’s disease are likely to be applicable to late-onset Alzheimer’s disease.”
Implications for Clinical Practice and Prevention Trials
“Based on what we see in our population, brain chemistry changes can be detected up to 20 years before the expected age of [disease] onset,” Dr. Bateman stated. “These Alzheimer’s-related changes can be specifically targeted for prevention trials in these patients with genetic Alzheimer’s disease.”
In the future, the DIAN Therapeutic Trials Unit plans to implement prevention trials. The FDA and European Medicines Agency have also expressed support for prevention trials in this population. In addition, 11 compounds have been nominated by the pharmaceutical industry for use in these trials.
“For some years, there has been growing acceptance of the concept of a preclinical stage of Alzheimer’s disease, in which brain lesions accumulate in the absence of any symptoms,” said Dr. Morris. This concept, he noted, was supported by postmortem studies, in which cognitively normal individuals were found to have Alzheimer’s disease neuropathology. “The implicit corollary of the concept of preclinical Alzheimer’s disease is that these individuals eventually will develop the symptoms of Alzheimer’s disease—that is, ultimately they would develop dementia if they continued to live…. There have been insufficient numbers of cognitively normal, biomarker-positive older adults followed long enough to know whether the corollary is accurate.
“From a clinical standpoint, then, the take-home messages are that there indeed is a preclinical stage of Alzheimer’s disease of many years duration, and that disease biomarkers do reflect the presence of Alzheimer’s disease brain lesions that, with time, will culminate in dementia,” said Dr. Morris. “None of this has been carefully examined outside of research settings, however, so issues of biomarker reliability, validity, reproducibility, false positives, and false negatives all need to be established in clinical populations before they are appropriate for clinical use.” Due to the ongoing work in the field, he predicts that biomarkers will soon be available for use in clinical practices.
“This information fills a gap in the cascade of events causing Alzheimer’s disease and represents a unique opportunity for prevention trials,” Dr. Bateman concluded. “Clinical trials in people with genetic Alzheimer’s disease will pioneer the way to prevention trials for all forms of Alzheimer’s disease.”