Näslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD.
Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.
JAMA. 2000 Mar 22-29;283(12):1571-7.
PubMed.
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.
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.
Comments
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.
View all comments by Bradley HymanDeceased
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.
View all comments by Peter DaviesMake a Comment
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