Working with study subjects known to have mutations that confer a 50 percent risk for Alzheimer's disease, investigators were able to determine that clinical, cognitive, and biomarker changes occurred at least 20–25 years before the expected onset of cognitive decline.
Scientists have long suspected that the mutations that cause Alzheimer's disease (AD) damage the brain long before symptoms set in. Now, they present evidence from a comprehensive series of experiments that show changes in biomarkers in the brain for AD decades before it was anticipated that the study subjects would develop cognitive problems.
The investigators are part of the Dominantly Inherited Alzheimer's Network (DIAN), an international research partnership that is set to study around 400 young adults who were born into families riddled with AD. The study, which receives funding support from the National Institute on Aging, now includes 276 participants and is still recruiting patients.
In a July 11 online edition of the New England Journal of Medicine, Randall Bateman, MD, the Charles F. and Joanne Knight distinguished professor of neurology at Washington University School of Medicine in St. Louis, and his DIAN colleagues provide an analysis of data on the first 128 DIAN participants.
The investigators designed the study to measure virtually every known biomarker for AD — brain scans to detect amyloid beta (Abeta) deposition and atrophy, genetic tests, blood and CSF markers, clinical measures, and family history data — to determine whether the biomarkers in currently asymptomatic individuals are predictive of a disease that will present itself down the road. All of the data reported were cross-sectional but study investigators are also following people over time to collect longitudinal data.
The international DIAN enrollees — ranging in age from 19 to 80 — have a 50 percent chance that they will inherit one of three known mutations causing early-onset AD — the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin2 (PSEN2). They develop clinical signs on average around 45 years old.
The DIAN investigators found that only individuals who inherited one of the mutations tested positive for the biomarker changes. What's more, the scientists were able to use the study design to create a detailed chronology from the start of the brain pathology when the individuals still are asymptomatic to the beginnings of cognitive decline to full-blown dementia.
The earliest change was a drop in CSF levels of Abeta. This change was first detected 20–25 years before the asymptomatic mutation carriers are expected to develop clinical signs, based on the age at which their affected parent became symptomatic.
The investigators reported that plaques were seen on the PET scans about 15 years before cognitive problems are expected to emerge. Elevated CSF levels of tau and shrinkage in key brain structures also were observed 15 years before symptoms are expected, followed by decreases in glucose metabolism and mild impairments on some memory tests a decade before symptoms are expected to appear.
According to Dr. Bateman, each of the three mutations leads down the same road: an initial increase in Abeta 42 before it decreases 20–25 years before the estimated age of symptoms onset, followed by brain amyloidosis, tauopathy, brain atrophy, and decreased glucose metabolism, and then years later the first signs of cognitive impairment. The investigators suspect that there is a similar timeline in people who develop sporadic AD later in life.
“We've been interested in developing indicators, or biomarkers, of AD in pre-clinical stages when people are cognitively normal,” said John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman distinguished professor of neurology, director of the Charles F. and Joanne Knight Alzheimer's Disease Research Center at Washington University in St. Louis, and principal investigator of the DIAN study. “Now that we have tools in hand — tests to measure Abeta 42 and tau in spinal fluid, PET scans that measure cerebral deposits of amyloid plaque, MRI scans to look for atrophy — we wanted to figure out when these pathological changes were taking place. There was a lot of evidence to suggest it was years, even decades, before the clinical signs appear.”
“The study validates the biomarkers,” Dr. Morris added.
DR. RANDALL BATEMAN and colleagues were able to create a detailed chronology from the start of the brain pathology when the individuals still are asymptomatic to the beginnings of cognitive decline to full-blown dementia.
Next month, the DIAN investigators are meeting with federal regulators at the FDA to seek approval of prevention trials with an amyloid-clearing agent for DIAN participants with a genetic mutation. That the pathology begins decades earlier than the clinical signs opens up the possibility that medicines to clear amyloid from the brain may work if used much earlier in the pre-clinical process. To date, all clinical trials of experimental agents that target the presumed mechanisms of AD have been in people with AD dementia and all have failed to demonstrate benefit. “It may be that the timing of the interventions, when AD is already symptomatic, is too late in the disease process,” said Dr. Morris.
“The symptomatic phase of AD typically lasts seven to 10 years,” said Dr. Morris, “and represents the end stage of an illness that is developing in the brain for at least two decades before symptoms.” He added that the finding “sets the stage for the timing of the intervention to delay or prevent the disease.”
“The results from our study offer the hope that there is a window of opportunity to intervene before too much damage has occurred,” he said. “All of the failed clinical trials may be due to the fact that the brain had already been irreversibly damaged.”
“This is the most exciting time in AD research,” he added. “Now we have the ability to reliably detect the disease pre-clinically and that raises the possibility for intervention.”
The experimental medicines that remove or block plaque formation will be tested to see whether this would push back the onset of clinical symptoms or prevent them altogether. The scientists would also be able to use the biomarkers to judge the efficacy of the intervention.
Of course, Dr. Morris added, it is possible that amyloid is not the right target and the medicines might not work. “But this allows us to really test the amyloid hypothesis,” he said.
“This is a very important study,” said Zaven Khachaturian, PhD, editor-in-chief of Alzheimer's & Dementia, a journal of the Alzheimer's Association, and a senior advisor to the organization, who was not involved with the study. “For the first time, it provides clear and convincing evidence that the disease starts many years before the clinical signs. This has been suspected but this study really nails it down.” Scientists suspect that a similar pathological process is occurring in those who develop sporadic forms of AD, he added, noting that only 1 percent of patients have an autosomal dominant mutation.
He said that researchers should design a prospective trial to follow these families over time to see how the biomarkers truly predict disease progression. “The DIAN study raises a new set of questions for the field. If the disease starts decades before the clinical signs, when do you begin treatments? What will your outcome measures be?”
“Many of us have been saying that prevention is the key. I am thrilled that it is finally happening,” Dr. Khachaturian added. “Unless we have accurate markers to track important aspects of the disease process, prevention trials will be long and expensive and require a large number of people.”
DR. ZAVEN KHACHATURIAN: “The DIAN study raises a new set of questions for the field. If the disease starts decades before the clinical signs, when do you begin treatments? What will your outcome measures be?”
DR. JOHN C. MORRIS: “The results from our study offer the hope that there is a window of opportunity to intervene before too much damage has occurred. All of the failed clinical trials may be due to the fact that the brain had already been irreversibly damaged.”
Gary Small, MD, a professor of psychiatry and director of the UCLA Longevity Center at the Semel Institute for Neuroscience, agrees that this study and prevention trials in those with the mutations is critical. “The challenge is that even if we find a treatment it won't help those with run-of-the-mill AD. The disease process begins so many years — even decades — before they know what's in store for them.”
Such prevention trials using biomarkers to track amyloid will also help answer the question of whether amyloid deposition tracks with the disease and responds to treatment. He likened it to using cholesterol-lowering drugs to reduce the risk for heart disease and stroke.
The DIAN researchers have created a registry for families with inherited Alzheimer's mutations. They encourage anyone with a family history of multiple generations of Alzheimer's diagnosed before age 55 to visit www.DIANXR.org to register for follow-up contact from researchers to determine whether their family is eligible for participation in DIAN studies. For more about the DIAN, see www.dian-info.org .
Lead DIAN investigator John C. Morris, the Harvey A. and Dorismae Hacker Friedman distinguished professor of neurology at Washington University in St. Louis, and director of the Charles F. and Joanne Knight Alzheimer's Disease Research Center, discusses in more detail the biomarker changes that occurred 20–25 years prior to the onset of cognitive decline in people who had a 50 percent chance of developing Alzheimer's disease http://bit.ly/rCBryX .