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Handoko M, Grant M, Kuskowski M, Zahs KR, Wallin A, Blennow K, Ashe KH.
Correlation of Specific Amyloid-β Oligomers With Tau in Cerebrospinal Fluid From Cognitively Normal Older Adults.
JAMA Neurol. 2013 May 1;70(5):594-9.
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The topic is important, and the results are intriguing.
The issue of Aβ oligomerization is a complex one, and several methodological questions could be raised:
1. The immunoprecipitation with 6E10 and Western blotting with 6E10 may not distinguish between Aβ and soluble APP fragments. It is not clear from the paper whether the detected species are Aβ rather than an APP fragment. Of note, the levels of soluble APP in the CSF are about 100-fold higher than Aβ (see Nitsch et al., 1995, Table 2), so even a minor APP fragment would give a lot of signal in the 6E10-based assay.
2. It will be important to control for the possibility that the immunoprecipitation and Western blotting assay procedures themselves induce artifactual aggregation of Aβ (see Esparza et al., 2013, Fig. 2 L). Monomeric Aβ can aggregate at high local concentrations, such as those that occur after immunoprecipitation.
3. Additional controls of interest regarding the assay include test-retest reproducibility, dilutional linearity, and spike-recovery linearity.
4. A future direction could involve quantification of the amount of protein corresponding to the signals detected on Western blot relative to known biochemical standards.
Nitsch RM, Rebeck GW, Deng M, Richardson UI, Tennis M, Schenk DB, Vigo-Pelfrey C, Lieberburg I, Wurtman RJ, Hyman BT.
Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease: inverse correlation with severity of dementia and effect of apolipoprotein E genotype.
Ann Neurol. 1995 Apr;37(4):512-8.
Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL.
Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls.
Ann Neurol. 2013 Jan;73(1):104-19.
The measurements of CSF oligomeric Aβ were done by immunoprecipitation/Western blot using as little as 240 μL per determination (ran as triplicate, then averaged). Using such a low volume suggests it may be possible to integrate similar measurements in longitudinal studies. It is disappointing that CSF levels of Aβ dimers could not be determined due to the experimental design (the acrylamide content in the gel cannot resolve small species). Concentrations of Aβ1-42 and tau/pt181-tau were determined by ELISA, as it is traditionally done for biomarker studies.
Both oligomeric Aβ species (Aβ*56 and Aβ trimers) detected in the CSF correlated with tau/ptau concentrations in aged, unimpaired subjects, while presumably monomeric Aβ1-42 did not. By extrapolation, it could indicate that the elevation of trimer-based Aβ oligomers seen in aging and AD is linked to abnormal tau changes. This interpretation is consistent with the notion that Aβ*56 and Aβ trimers may initiate the disease process during the latent phase of AD (i.e., preclinical AD).
In impaired individuals (including MCI and AD groups), CSF Aβ trimers and Aβ1-42 correlated to tau/ptau concentrations (in opposite fashion). These observations could indicate that: 1) soluble Aβ trimers might still drive abnormal tau changes in the AD brain, but their effects are reduced (based on comparing correlation coefficients); 2) Aβ*56 might not be as "active" a toxin in AD as in preclinical AD; and 3) tau changes become less dependent on oligomeric Aβ as disease progresses (none of these scenarios are mutually exclusive). Whether these scenarios would apply to other oligomeric forms of Aβ remains to be examined.
Overall, the data presented are consistent with the hypothesis that Aβ*56 and Aβ trimers (and presumably trimer-based oligomers) play important roles in the prodromal stages of the disease. These findings are also in agreement with alterations in CSF Aβ levels occurring early in asymptomatic individuals.
Development of valid and quantitative assays for oligomeric Aβ species is considered by many to be the Holy Grail in the AD fluid biomarker field. Such assays are technologically challenging for many reasons. Several groups have reported such assays, but establishing an assay’s validity has been problematic, and none has stood the test of time. Dr. Ashe’s group has been interested in oligomeric Aβ species for several years, reporting in 2006 the presence of the Aβ*56 form in Tg2576 mice and its memory-disrupting ability when injected into rats. In this current paper, they report the presence of Aβ trimers as well as the Aβ*56 species in human CSF samples using a combined immunoprecipitation and immunoblotting procedure. Although the assay appears not to be quantitative (instead, semi-quantitative), the reported percent coefficient of variation among triplicates was good (Assuming the assay is indeed valid for detecting these specific oligomeric species, the data are very interesting and support several current hypotheses regarding Aβ metabolism in AD. The observation that these species were elevated in cognitively normal individuals at risk for developing AD dementia (defined as those with a high tau/Aβ42 ratio) suggests that they are involved in the very early (preclinical) stages of the disease. It would have been nice to see the relationship between monomeric Aβ42 (the proposed analyte quantified in the INNOTEST ELISA assays) and the various oligomeric species, as well as the distribution of levels of these species in the various clinical groups. It would also be interesting to know whether levels were elevated in MCI (or control) individuals who later progressed to AD, but were not elevated in MCI (or control) individuals who remained stable (hypothesized not to have underlying AD). The analysis of individuals as a function of the tau/Aβ42 ratio at baseline suggests that this would be the case, and I expect future studies that include longitudinal clinical follow-up in this cohort will be able to shed light on this issue.
The relationship between levels of Aβ trimers/Aβ*56 and tau/ptau in cognitively normal individuals and its attenuation in symptomatic cases is arguably the most interesting finding of this study. Such a relationship is not observed between levels of monomeric Aβ42 and tau, suggesting a potential unique role of oligomeric species in the pathologic cascade at the earliest stages of the disease. While interesting in its own right to those striving to understand the normal evolution of AD pathobiology, this finding also has potentially important implications for the design and evaluation of therapies targeting Aβ and/or amyloid. Hopefully, the assay can be developed into a truly quantitative platform with higher throughput that will permit the evaluation of large numbers of samples from individuals who have been well characterized clinically over time and with multiple biomarker assessments. Then, perhaps, we can add a line to the left of the Aβ42/amyloid line in the hypothesized biomarker trajectory schematic.