5 April 2000. A central controversy in the Alzheimer's field has been the issue of whether amyloid plaques, comprising primarily Aβ peptide, correlate with the severity of dementia. Inconsistent findings on this point have fueled arguments over the role of plaques in causing neurodegeneration. New data published to considerable media fanfare in the March 22/29 issue of the Journal of the American Medical Association may bring this debate closer to a resolution. In the report, Jan Naslund, Joseph Buxbaum, and colleagues report that total levels of Aβ40 and 42-not just in plaques but in nonplaque forms as well-correlate with dementia. Indeed, roughly half of the subjects had no detectable plaque, but had elevated levels of Aβ, suggesting perhaps that soluble or pre-plaque forms of Aβ could play an important role.
The authors of the JAMA study examined postmortem tissue from Alzheimer's patients using enzyme-linked immunosorbent assays (ELISAs) designed to identify the two major species (Aβ40 and 42). They found that the levels of Aβ increased with degree of dementia, as assessed by clinical dementia tests that had been performed on the patients within six months before they died. Surveying five different cortical areas (ranging from occipital to frontal), they found that the levels of Aβ, and Aβ42 in particular, rose with increasing severity of the disease.
The authors also compared Aβ levels with degree of tau pathology (as measured by reactivity to MC1 antibody) in an attempt to address the question of which pathology develops first. Focusing on frontal cortex, a region that is plaque-free in normal indivduals, they found that Aβ precedes tau pathology.
In an accompanying editorial, Dennis Selkoe of Harvard Medical School writes, "The exciting conclusion that derives from this analysis is that multiple lines of evidence confirm [Aβ] as a rational therapeutic target." Brad Hyman, also of Harvard, agrees that "This is an interesting study that does, indeed, push ahead in some ways the type of correlational studies that have been going on for years." But he cautions that these data do not answer the question of whether Aβ by itself is sufficient to cause dementia. He also points out that tau pathology is likely to precede Aβ in other areas such as the entorhinal cortex, leaving open the question of the pathogenic relationship between the two proteins.
Study coauthor Peter Davies of Yale University, Connecticut, concurs with this last point, but he thinks that the finding of elevated Aβ early in the disease and a correlation between Aβ and dementia levels is novel and important-albeit played far out of proportion in the press.
Reference:Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD. Correlation between elevated levels of amyloid-b-peptide in the brain and cognitive decline. JAMA 2000 Mar 22/29;283(12):1571-7. Abstract
Selkoe DJ. The origins of Alzheimer's disease: a is for amyloid. JAMA 2000 Mar 22/29;283(12):1615-7. Abstract