Cerebrospinal fluid levels of amyloid-beta 42 may be a biomarker for the early, asymptomatic phase of Alzheimer's disease—a long-awaited leap forward in the quest for preclinical diagnosis, reported Dr. Elaine R. Peskind of the University of Washington, Seattle, and her associates.
Adults who carry the apolipoprotein E4 allele but are cognitively normal show a marked decline in cerebrospinal fluid (CSF) levels of amyloid-beta 42 (Aβ42), presumably because the protein is precipitating out of the CSF and being deposited in plaques within the brain parenchyma, Dr. Peskind and her colleagues noted.
This decline of Aβ42 in cerebrospinal fluid appears to begin in early adulthood and to rapidly accelerate between the ages of 50 and 60 years in apo E4 carriers, long before clinical manifestations of Alzheimer's disease (AD) typically appear.
The finding bolsters the theory that Aβ42 deposition in the brain is a key initiating factor in the pathogenesis of AD, the researchers said. The findings may also point the way to new therapies and preventive strategies (Arch. Neurol. 2006;63:936–9).
Dr. Peskind and her associates assessed both the apo E genotype and CSF concentrations of Aβ42 in 184 healthy adults aged 21–88 years. The 94 men and 90 women had normal cognition and function. Those with the apo E allele not only had lower levels of Aβ42, but their levels also declined in a linear fashion as age increased. CSF levels also dropped off precipitously between the ages of 50 and 60 years. In contrast, subjects who did not carry the apo E4 allele showed a slight rise in Aβ42 levels until age 50 and then a slight and slow decline afterward.
Further research is needed, but researchers and clinicians should note that “therapeutic strategies aimed at prevention of AD may need to be applied in early midlife or even younger ages to have maximal effect on amyloid deposition,” the researchers concluded.
In an editorial, Dr. Roger N. Rosenberg of the University of Texas Southwestern Medical Center, Dallas, said the findings suggest that treatment should target “soluble Aβ and tau levels rather than insoluble plaques and tangles” (Arch. Neurol. 2006;63:926–8).
The “plaques and tangles that have captivated our visual attention for a century may not be the key targets for effective therapies after all,” said Dr. Rosenberg.