Scientists have assembled the most detailed chronology to date of the human brain's long, slow slide into full-blown Alzheimer's disease.
The timeline, developed through research led by scientists at Washington University School of Medicine in St. Louis, appears July 11 in The New England Journal of Medicine.
As part of an international research partnership known as the Dominantly Inherited Alzheimer's Network (DIAN), scientists at Washington University and elsewhere evaluated a variety of pre-symptomatic markers of Alzheimer's disease in 128 subjects from families genetically predisposed to develop the disorder. 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.
Using medical histories of the subjects' parents to estimate the age of the onset of symptoms for the study participants, the scientists assembled a timeline of changes in the brain leading to the memory loss and cognitive decline that characterizes Alzheimer's.
"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, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis. "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."
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.
The plaques in the brain become visible on a brain scan 15 years before memory problems become apparent and other signs, increased levels of a structural protein in brain cells called tau in the spinal fluid appears and the shrinkage of parts of the brain become evident at around the same time.
Decreases in the brain's use of the sugar 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."