Scientists have established a detailed chronology of the human brain’s long, slow descent into Alzheimer’s disease.
The timeline, developed by scientists at Washington University School of Medicine in St. Louis, shows that the earliest changes can be detected 25 years before the onset of the disease.
As part of an international research partnership known as the Dominantly Inherited Alzheimer’s Network (DIAN), researchers evaluated a variety of pre-symptomatic markers of Alzheimer’s disease in 128 subjects from families genetically predisposed to the disease.
Individuals in the study have a 50 percent chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age, the researchers report.
Using medical histories of the subjects’ parents, the scientists assembled a timeline of changes in the brain leading to the memory loss and cognitive decline that characterizes Alzheimer’s. The earliest of these changes, a drop in spinal fluid levels of the key ingredient of Alzheimer’s brain plaques, can be detected 25 years before the anticipated age of onset.
“A series of changes begins in the brain decades before the symptoms of Alzheimer’s disease are noticed by patients or families, and this cascade of events may provide a timeline for symptomatic onset,” says first author Randall Bateman, MD, from Washington University School of Medicine in St. Louis.
Bateman notes that the new data show that plaques become visible on brain scans 15 years before memory problems become apparent. Researchers plan to give treatments that remove or block plaque formation at this early stage of the disease and monitor subjects to see not only if the plaques can be prevented or reduced, but also whether other Alzheimer’s biomarkers improve.
Primarily funded by the National Institutes of Health (NIH), the DIAN partnership is researching the rare, familial form of Alzheimer’s disease that can cause symptoms to appear in affected people in their 30s and 40s, decades earlier than the more common form that typically occurs after age 65.
Other results from the new study include:
- Elevated spinal fluid levels of tau, a structural protein in brain cells, appear 15 years before Alzheimer’s symptoms;
- Shrinkage in key brain structures becomes discernible 15 years before symptoms; and
- Decreases in the brain’s use of glucose and slight impairments in a specific type of memory are detectable 10 years before symptoms.
Researchers also tested participants from DIAN families who do not have any of the mutations that cause inherited Alzheimer’s.
“Family members without the Alzheimer’s mutations have no detected change in the markers we tested,” Bateman says. “It’s striking how normal the Alzheimer’s markers are in family members without a mutation.”
Bateman is leading the development of Alzheimer’s prevention and treatment trials in DIAN participants. He and his colleagues hope to launch trials later this year.
“As we learn more about the origins of Alzheimer’s to plan preventive treatments, this Alzheimer’s timeline will be invaluable for successful drug trials,” he said.
DIAN researchers now offer an expanded 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 DIANXR.org, where they can register for follow-up contact from researchers to determine whether their family is eligible for participation in DIAN studies.
The study appears in The New England Journal of Medicine.