Immunoprecipitation mass spectroscopy assays are superior in detecting CSF and PET amyloid abnormalities

Plasma amyloid beta (Aβ) 42/40, quantified with certain mass spectrometry (MS) -based methods, identified patients with abnormal Aβ levels in the brain more accurately than immunassay-based Aβ42 / 40 measurements, according to a study in JAMA Neurology.

The development of advanced MS and immunodetection methods has made it possible to obtain reliable measurements of Aβ in blood. In previous research, Aβ42 / 40, as determined by immunoprecipitation-coupled mass spectrometry (IP-MS), correlated with Aβ positron emission tomography (PET) and had high accuracy in identifying patients with abnormal Aβ exposure Brains or those with high levels of Aβ could be at risk of converting to Aβ-PET positivity. There are many blood tests available to predict amyloid plaques in the brain, but they vary in accuracy for detecting cerebrospinal fluid (CSF) and PET amyloid positivity.

The aim of the current study was to compare eight blood Aβ tests in the same group of early-stage Alzheimer’s patients from the Swedish BioFINDER study.

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The researchers compared plasma Aβ42 / 40 as measured by the following 8 assays: an IP-MS developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography-MS from Araclon (LC-MS-Arc) and immunoassays from Roche Diagnostics (IA-Elc); Euroimmune (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences and Quanterix (IA-N4PE). Plasma Aβ42 / 40 was also measured with an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and an immunoassay from Quanterix (IA-Quan) with 227 participants.

From 2010 to 2014, a total of 286 people were recruited from the prospective SwedishBioFINDER-1 cohort – 182 were cognitively non-impaired older adults and 104 had mild cognitive impairment (MCI). The group had a mean (SD) age of 71.6 (5.6) years and 141 (49.3%) were women. Participants were enrolled in 3 hospitals in Sweden and had Aβ positron PET imaging and CSF and plasma collection.

122 participants (51 cognitively normal, 51 with MCI and 20 with Alzheimer’s dementia) who had an Aβ-PET and plasma Aβ assessment were enrolled in a validation cohort from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This group had a mean (SD) age of 72.4 (5.4) years and 53 (43.4%) were women.

For the identification of participants with abnormal CSF Aβ42 / 40 in the total cohort, Plasma-IP-MS-WashU Aβ42 / 40 had a significantly better differentiation accuracy (area under the operating characteristic of the recipient [AUC], 0.86; 95% CI, 0.81-0.90) vs. plasma LC-MS-Arc Aβ42 / 40 (AUC, 0.78; 95% CI, 0.72-0.83; P <0 , 01), IA-Elc Aβ42 / 40 (AUC, 0.78; 95% CI 0.73-0.83; P <.01), IA-EI Aβ42 / 40 (AUC, 0.70; 95% CI , 0.64-0.76; P <.001) and IA-N4PE Aβ42 / 40 (AUC, 0.69; 95% CI, 0.63-0.75; P <0.001).

For 2 subsets of participants in which IP-MS-Shim Aβ42 / 40 or IP-MS-UGOT Aβ42 / 40 and IA-Quan Aβ42 / 40 were also available, IP-MS-WashU Aβ42 / 40 had a higher discriminative accuracy for CSF Aβ42 / 40 status compared to IP-MS-UGOT Aβ42 / 40 (AUC 0.84; 95% CI 0.79-0.89 vs. AUC 0.68; 95% CI 0.61-0 , 75; p <0.001) and IA-Quan Aβ42 / 40 (AUC 0.84; 95% CI 0.79-0.89 vs. AUC 0.64; 95% CI 0.56-0, 71; P <0.001). The difference in AUCs between IP-MS-WashU Aβ42 / 40 and IP-MS-Shim Aβ42 / 40 was not significant (AUC 0.87; 95% CI 0.82-0.92 vs. AUC 0.83; 95 % CI 0.77-0.88; P = .16).

Similar results were observed when Aβ-PET was used as the result, since most assays had numerically lower AUCs than that of CSF Aβ42 / 40.

In the ADNI validation cohort, plasma-IP-MS-WashU Aβ42 / 40 performed better (AUC, 0.85; 95% CI, 0.77-0.92) compared to plasma-IP-MS-UGOT Aβ42 / 40 (AUC, 0.66; 95% CI, 0.57-0.76; P <0.001, IA-Elc Aβ42 / 40 (AUC, 0.74; 95% CI, 0.65-0.83; P <0.05), IA-N4PE Aβ42 / 40 (AUC, 0.69; 95% CI, 0.59-0.78; P <0.01) and IAQuan Aβ42 / 40 (AUC, 0.63; 95% CI, 0.53-0.73; P <0.001), but not IP-MS-Shim composite biomarker score (AUC, 0.82; 95% CI, 0.75-0.89; P = 0 , 54).

Under several study restrictions, IP-MS-Shim Aβ42 / 40, IP-MS-UGOT Aβ42 / 40, and IA-Quan Aβ42 / 40 were not available for the entire cohort. The study also had a relatively small sample of Aβ negative, cognitively unimpaired participants, and assays were performed in different laboratories that could have caused preanalytical variation.

“Certain mass spectrometric plasma tests may be sufficiently powerful to detect Aβ pathology of the brain in Alzheimer’s disease,” the researchers concluded.

Disclosure: Some of the study authors stated links with biotech, pharmaceutical, and / or device companies. For a full list of authors and funding sources, see the original reference.


Janelidze S., Teunissen CE, Zetterberg H, et al. Head-to-head comparison of 8 plasma amyloid-β 42/40 assays in Alzheimer’s disease. JAMA Neurol. Published online September 20, 2021. doi: 10.1001 / jamaneurol.2021.3180

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