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...  Read more

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 Hyman

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 Davies

Two new reports released this week (Villemagne et al., 2010; McDonald et al., 2010) document the prevalence of Aβ dimers in blood and brain samples, respectively, from individuals diagnosed with AD.

The first group used an elegant ProteinChip® array using affinity surfaces coated with various Aβ antibodies including 4G8 or WO2 to measure the levels of species bound to cellular membranes of blood cells in a large human cohort (n = 118). Using this approach, the authors found elevated levels of Aβ monomers and dimers in specimens from AD patients as compared to age-matched controls, though there were large overlaps between clinical groups. They also found that the levels of Aβ dimers strongly correlated with those of monomeric Aβ42. Interestingly, Aβ dimers were not detected when a 40-end specific antibody to Aβ was used as capture agent.

Finally, the authors performed correlation analyses among various clinical and neuroimaging variables, revealing modest but significant correlations between Aβ dimers and cognitive decline. Overall, these findings support the notion that...  Read more

Two new reports released this week (Villemagne et al., 2010; McDonald et al., 2010) document the prevalence of Aβ dimers in blood and brain samples, respectively, from individuals diagnosed with AD.

The first group used an elegant ProteinChip® array using affinity surfaces coated with various Aβ antibodies including 4G8 or WO2 to measure the levels of species bound to cellular membranes of blood cells in a large human cohort (n = 118). Using this approach, the authors found elevated levels of Aβ monomers and dimers in specimens from AD patients as compared to age-matched controls, though there were large overlaps between clinical groups. They also found that the levels of Aβ dimers strongly correlated with those of monomeric Aβ42. Interestingly, Aβ dimers were not detected when a 40-end specific antibody to Aβ was used as capture agent.

Finally, the authors performed correlation analyses among various clinical and neuroimaging variables, revealing modest but significant correlations between Aβ dimers and cognitive decline. Overall, these findings support the notion that Aβ dimers are elevated in AD compared to healthy controls as first reported by Shankar et al., 2008. However, this new report also documents the presence of Aβ dimers in biological samples from cognitively intact controls; this differs from the aforementioned study. Finally, due to the considerable overlap in the levels of Aβ dimers across tested clinical groups, it is unlikely that solely measuring Aβ dimers will represent a confident diagnostic tool for the prognosis of Alzheimer disease. This is disappointing news.

The second study led by Dominic Walsh’s and Dennis Selkoe’s groups can be viewed as a study extending the findings reported by Shankar and colleagues (2008). Here, McDonald et al. determined the levels of monomeric and dimeric Aβ levels in 43 brain specimens using a combination of immunoprecipitation/Western blotting techniques coupled to infrared detection for enhanced sensitivity. The authors report that soluble Aβ monomers, dimers, trimers, and occasionally tetramers were detected in their cohort. Unfortunately, no other oligomers (including Aβ*56) were observed due to the presence of non-specific bands masking potential oligomeric Aβ assemblies between 30 and 75 kDa. Consistent with their previous findings, Aβ dimers were only detected within the AD group compared to the controls, and their calculated concentration rose sharply in the AD group. One possible explanation for this segregation might be explained by differences in postmortem interval delays (24, 18, and 18 hours for the ND, DNAD, and AD groups, respectively) as well as in apparent age at death among groups (means of 81, 92, and 87.5 years). It would be interesting to see whether these variables have an impact on our biochemical analyses of Aβ oligomers.

Finally, the authors identified an association between the levels of Aβ monomers + dimers and intermediate to high brain amyloid loads. Altogether, these findings suggest that the concentration of brain-soluble Aβ dimers might be related to the extent of amyloid deposition in brain tissues.

Granted that both studies used very different biological samples and reported extremely different segregation profiles between controls and AD groups, blood or brain levels of Aβ dimers do appear elevated in AD.

View all comments by Sylvain Lesne