Immunoprecipitation Mass-Spec Assays Superior in Detecting CSF and PET Amyloid Abnormality

cerebrospinal fluid
cerebrospinal fluid
Researchers compared the performance of brain amyloid-beta (Aβ)42/40 measured using 8 different Aβ assays to detect abnormal brain Aβ status in patients with early Alzheimer disease.

Plasma amyloid-beta (Aβ)42/40 quantified with particular mass spectrometry (MS)–based methods identified patients with abnormal brain Aβ burden more accurately than immunoassay-based Aβ42/40 measures, according to a study in JAMA Neurology.

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

The objective of the current study was to perform a side-to-side comparison of 8 blood Aβ tests in the same group of patients with early Alzheimer disease from the Swedish BioFINDER study.

Researchers compared plasma Aβ42/40 measured with use of 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); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured with use of 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) in 227 participants.

A total of 286 individuals from the prospective SwedishBioFINDER-1 cohort were recruited from 2010 to 2014—182 were cognitively unimpaired 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. The participants were enrolled at 3 hospitals in Sweden and had Aβ positron PET imaging and CSF and plasma collection.

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

For identifying participants with abnormal CSF Aβ42/40 in the total cohort, plasma IP-MS-WashU Aβ42/40 had significantly better discriminative accuracy (area under the receiver operating characteristic curve [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 < .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 <.001).

For 2 subgroups 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 higher discriminative accuracy for CSF Aβ42/40 status compared with 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 <.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 <.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).

Comparable results were observed when Aβ-PET was used as the outcome, as most assays had numerically lower AUCs vs those for 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) vs plasma IP-MS-UGOT Aβ42/40 (AUC, 0.66; 95% CI, 0.57-0.76; P <.001), IA-Elc Aβ42/40 (AUC, 0.74; 95% CI, 0.65-0.83; P <.05), IA-N4PE Aβ42/40 (AUC, 0.69; 95% CI, 0.59-0.78; P <.01), and IAQuan Aβ42/40 (AUC, 0.63; 95% CI, 0.53-0.73; P <.001) but not IP-MS-Shim composite biomarker score (AUC, 0.82; 95% CI, 0.75-0.89; P =.54).

Among several study limitations, 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 conducted at different laboratories, which could have introduced pre-analytical variation.

“Certain mass spectrometry–based plasma tests might have sufficient performance to detect brain Aβ pathology in Alzheimer disease,” the researchers concluded.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures and funding sources.


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