Biomarker changes in middle age signal Alzheimer's disease

Middle-aged people with no symptoms for Alzheimer’s disease may have detectable biomarkers that signal cognitive decline later in life, according to researchers at Washington University School of Medicine in St. Louis, Missouri.

“It’s too early to use these biomarkers to definitively predict whether individual patients will develop Alzheimer’s disease, but we’re working toward that goal,” said senior author Anne Fagan, PhD, professor of neurology. “One day, we hope to use such measures to identify and treat people years before memory loss and other cognitive problems become apparent.”

In this 10-year study, published JAMA Neurology, researchers followed 169 cognitively normal subjects who were in middle age (ages 45 to 75) when the study began. Participants were organized into three age groups: early-middle age (45-54); mid-middle age (55- 64); and late-middle age (65-74). Each participant received a complete clinical, cognitive imaging and cerebrospinal fluid (CSF) biomarker analysis every 3 years.

Specific biomarkers evaluated were:

• Amyloid beta 42, a protein that is the principal ingredient of Alzheimer’s plaques.
• Tau, a structural component of brain cells that increases in the CSF as Alzheimer’s disease damages brain cells.
• YKL-40, a newly recognized protein that is indicative of inflammation and is produced by brain cells.
• The presence of amyloid plaques in the brain, as seen via amyloid PET scans.

The scientists found that drops in amyloid beta 42 levels in CSF among cognitively normal participants ages 45-54 are linked to the appearance of plaques in brain scans years later. The researchers also found that tau and other biomarkers of brain-cell injury increase sharply in some individuals as they reach their mid-50s to mid-70s, and YKL-40 rises throughout the age groups focused on in the study.

All of these changes were more pronounced in participants who carried a form of a gene (APOE) that significantly increases the risk of Alzheimer’s disease. Scientists have known that people with two copies of a particular version of this gene have up to 10 times the risk of developing Alzheimer’s as those with other versions of the gene.

Previous research has shown that all of these biomarkers may be affected by Alzheimer’s disease, but this is the first large data set to show that the biomarkers change over time in middle-aged individuals. 

“Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline,” the authors concluded.