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  Is plasma amyloid-β 1–42/1–40 a better biomarker for Alzheimer’s disease than AβX–42/X–40?

Klafki, H.-W., Morgado, B., Wirths, O., Jahn, O., Bauer, C., Esselmann, H., et al. (2022). Is plasma amyloid-β 1–42/1–40 a better biomarker for Alzheimer’s disease than AβX–42/X–40? Fluids and Barriers of the CNS, 19(1): 96. doi:10.1186/s12987-022-00390-4.

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Genre: Journal Article
Other : Is plasma amyloid-beta 1-42/1-40 a better biomarker for Alzheimer's disease than A beta X-42/X-40?

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 Creators:
Klafki, Hans-Wolfgang, Author
Morgado, Barbara, Author
Wirths, Oliver, Author
Jahn, Olaf1, Author           
Bauer, Chris, Author
Esselmann, Hermann, Author
Schuchhardt, Johannes, Author
Wiltfang, Jens, Author
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350300              

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 Abstract: Background:
A reduced amyloid-β (Aβ)42/40 peptide ratio in blood plasma represents a peripheral biomarker of the cerebral amyloid pathology observed in Alzheimer’s disease brains. The magnitude of the measurable effect in plasma is smaller than in cerebrospinal fluid, presumably due to dilution by Aβ peptides originating from peripheral sources. We hypothesized that the observable effect in plasma can be accentuated to some extent by specifically measuring Aβ1–42 and Aβ1–40 instead of AβX–42 and AβX–40.

Methods:
We assessed the plasma AβX–42/X–40 and Aβ1–42/1–40 ratios in an idealized clinical sample by semi-automated Aβ immunoprecipitation followed by closely related sandwich immunoassays. The amyloid-positive and amyloid-negative groups (dichotomized according to Aβ42/40 in cerebrospinal fluid) were compared regarding the median difference, mean difference, standardized effect size (Cohen’s d) and receiver operating characteristic curves. For statistical evaluation, we applied bootstrapping.

Results:
The median Aβ1–42/1–40 ratio was 20.86% lower in amyloid-positive subjects than in the amyloid-negative group, while the median AβX–42/X–40 ratio was only 15.56% lower. The relative mean difference between amyloid-positive and amyloid-negative subjects was −18.34% for plasma Aβ1–42/1–40 compared to −15.50% for AβX–42/X–40. Cohen’s d was 1.73 for Aβ1–42/1–40 and 1.48 for plasma AβX–42/X–40. Unadjusted p-values < 0.05 were obtained after .632 bootstrapping for all three parameters. Receiver operating characteristic analysis indicated very similar areas under the curves for plasma Aβ1–42/1–40 and AβX–42/X–40.

Conclusions:
Our findings support the hypothesis that the relatively small difference in the plasma Aβ42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring Aβ1–42/1–40 instead of AβX–42/X–40. A simplified theoretical model explaining this observation is presented.

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Language(s): eng - English
 Dates: 2022-12-03
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1186/s12987-022-00390-4
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Project name : This work was funded by the German Federal Ministry of Education and Research (BMBF) Grant number 13GW0479B.
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Title: Fluids and Barriers of the CNS
Source Genre: Journal
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Pages: - Volume / Issue: 19 (1) Sequence Number: 96 Start / End Page: - Identifier: ISSN: 2045-8118