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.

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  1. 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. The power of the study is the large number of subjects and the use of ELISA technology to quantitate Aß.

    There has never been any debate about whether Aß accumulates in AD, and for years it has been known that the topography of Aß deposition differs substantially from the topography of neuronal and neuritic alterations. Thus the finding that Aß accumulates in frontal cortex prior to tangles was expected from previous mapping studies; the likelihood is that the opposite result would have obtained if the hippocampus or entorhinal cortex had been examined. There is no doubt that most nondemented individual have essentially no Aß deposits (although interestingly some nondemented individuals have a good deal, especially of diffuse deposits), whereas everyone with Alzheimer's disease has alot (by definition). It makes sense that there must be an in between stage, something suggested by the present study.

    The question of whether Aß accumulates with increasing severity of dementia is an interesting one and, from a morphological perspective, a complex one. Morphological studies suggest that the type of amyloid changes over the years, with increasing amounts of thioflavine S positive deposits, whereas the more amorphous so called "diffuse" plaques seem not to change very much or alter the brain very much. The ELISA techniques used end up assessing a biochemical measure, but anatomic information becomes lost, so that what exactly is being measured in terms of type of Aß deposit is unclear. A challenge for future studies will be to try to bring together both biochemical and morphological information.

    Whether or not Aß is a "culprit" seems well established from the last decade of genetics studies. In my opinion whether or not Aß, by itself, is sufficient to cause dementia remains an open question.

  2. Please see the following comments related to this article: Alzheimer's disease and amyloid beta protein Koudinov AR et al Science online,> Published 25 June 2002 [ Full Text ] Dangers of the amyloid-beta vaccination. Smith MA et al. Acta Neuropathol (Berl) 2002 Jul;104(1):110 [ PubMed ] Alzheimer’s anti-amyloid vaccination and statins: two approaches, one dogma. The time for change. Koudinov and Koudinova BMJ 20 March 2002 [ Full Text ]

    View all comments by Alexei Koudinov
  3. The study shows that both the 40 and 42 amino acid amyloid peptides were elevated early in Alzheimer's disease and that levels of both peptides are strongly correlated with cognitive decline. These are novel and important observations. However, as with all correlative studies, a correlation does not prove causation. It is important to know when, in relation to the dementia of Alzheimer's disease, the amyloid peptides are deposited.

    It also appears that several of these cases have amyloid deposits in frontal cortex without tau pathology, suggesting that the amyloid comes first. But as Brad Hyman points out, the result is likely to be the opposite in entorhinal cortex: does this mean that in some regions tau pathology comes first and leads to amyloid deposition, and in others the opposite? A great deal more work will be needed to establish these points, and this is just another step in the right direction.

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Papers

  1. . Is Parkinson's disease a prion disorder?. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12571-2. PubMed.

Primary Papers

  1. . The origins of Alzheimer disease: a is for amyloid. JAMA. 2000 Mar 22-29;283(12):1615-7. PubMed.
  2. . Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 2000 Mar 22-29;283(12):1571-7. PubMed.