Plasma amyloid-β concentrations in Alzheimer's disease : an alternative hypothesis.

Fullwood, Nigel J. and Hayashi, Yoshihito and Allsop, David (2006) Plasma amyloid-β concentrations in Alzheimer's disease : an alternative hypothesis. Lancet Neurology, 5 (12). pp. 1000-1001. ISSN 1474-4422

Abstract

The findings of van Oijen and colleagues,1 M van Oijen, A Hofman, HD Soares, PJ Koudstaal and MM Breteler, Plasma Aβ1–40 and Aβ1–42the risk of dementia: a prospective case-cohort study, Lancet Neurol 5 (2006), pp. 655–660. Article | PDF (99 K) | View Record in Scopus | Cited By in Scopus (33)1 and 2 showing that increased concentrations of plasma Aβ1–40 are associated with an increased risk of dementia, are intriguing, if somewhat inconsistent with other reports of reduced plasma Aβ concentrations in patients with Alzheimer's disease. However, we believe that these seeming inconsistencies can be explained by a more detailed consideration of one of the key mechanisms underlying the development of the disease, namely the process of Aβ oligomerisation. There is increasing evidence that small Aβ oligomers are responsible for the toxic effects of Aβ towards neuronal cells.3 Recent work lends support to the idea that these toxic effects are, at least in part, due to the generation of reactive oxygen species during the early stages of the oligomerisation process.4 What conditions trigger Aβ oligomerisation in vivo is not known, but the formation of toxic oligomers is probably the earliest stage at which Alzheimer's disease could feasibly be detected since it is likely that this process predates the formation of mature senile plaques by many years. The problem with interpreting data from current ELISA methods, including those presented in van Oijen and colleagues' study,1 is that it is unclear whether these assays can distinguish between monomeric and oligomeric Aβ. Some antibodies could have their epitopes masked when Aβ becomes oligomerised. If one of the antibodies used in a sandwich ELISA recognises Aβ peptide in monomers, but not Aβ peptide in oligomers, then increased levels of oligomerisation could produce an apparent decrease in detected Aβ, even when overall Aβ concentrations are constant (figure, scenario 1). Thus, increased levels of Aβ oligomerisation could explain the finding of decreased concentrations of Aβ in the cerebrospinal fluid5 or plasma of patients with Alzheimer's disease. Full-size image (37K) Figure. Interpretation of data from ELISA methods Scenario 1: When the ELISA detection antibody (red) recognises Aβ peptide only in its monomeric form, the signal is apparently decreased when oligomers are present. Scenario 2: When the detection antibody (blue) recognises the peptide in both its monomeric and oligomeric forms, the signal is apparently increased when oligomers are present. Capture antibody (black) recognises Aβ peptide in both monomeric and oligomeric forms. View Within Article Alternatively, other antibodies could bind to Aβ peptide in both its monomeric and oligomeric forms; in this case Aβ in a small oligomeric form could actually result in a higher ELISA signal than a similar plasma concentration of monomeric Aβ (figure, scenario 2). In this case, the increased concentrations of Aβ1–40 reported in van Oijen and colleagues' study1 could theoretically be due to increased oligomerisation rather than increased overall levels of Aβ1–40. Thus, to interpret these contradictory results it must be absolutely clear what epitopes the assays are detecting, and, most importantly, whether they can distinguish between monomeric and oligomeric Aβ. In future work, the specific detection of the small oligomers will be of critical importance since they are believed to be the most toxic species. Finally, we congratulate Van Oijen and colleagues on an excellent study linking plasma Aβ concentrations to the development of dementia. This study lends support to the hypothesis that changes in plasma concentrations of Aβ are connected, however indirectly, to changes in the brain and provides hope for the development of a simple diagnostic test for the early detection of Alzheimer's disease. We have no conflicts of interest.