There are important differences in the diagnostic accuracy of blood tests used to screen for Alzheimer’s disease (AD). Some mass spectrometry (MS)–based plasma tests can detect brain amyloid β (Aβ) pathology.
Investigators compared the performance of eight plasma Aβ42/40 assays in detecting abnormal brain Aβ for patients with early AD. The patients were drawn from two cohorts.
In both cohorts, two MS-based assays — IP-MS-WashU and IP-MS-Shim — were superior to the other assays in determining cerebrospinal fluid (CSF) Aβ42/40 and Aβ-positron-emission tomography (PET) status.
“Our study shows that the accuracy of different Aβ42/40 assays vary substantially when it comes to their ability to detect brain amyloid in patients with early Alzheimer’s disease [and] that certain mass spectrometry–based assays are clearly better than other types of assays,” lead investigator Shorena Janelidze, PhD, a researcher at the Clinical Memory Research Unit, Lund University, Lund, Sweden, told Medscape Medical News.
“Our results from two specialized cohorts indicate which assays have the greatest potential for use in clinical practice and trials,” she said.
The study was published online September 29 in JAMA Neurology.
Variable Performance
“Blood tests for detecting amyloid-β (Aβ) pathology in Alzheimer’s disease would be a major advancement for biomarker implementation in clinical care and highly useful in drug trials,” but “reliable measurements of Aβ in blood proved challenging until the development of advanced mass spectrometry and immunodetection methods,” the investigators note.
In previous studies of MS-based assays, performance varied, Janelidze said. In part, this could be because of differences in cohort characteristics, such as sample size, diagnostic groups, outcome measures, and preanalytic sample handling procedures.
To minimize these biases, the investigators compared the various tests in the same cohort of individuals from the Swedish BioFINDER study. Of these individuals, 182 were cognitively unimpaired, and 104 had mild cognitive impairment (MCI); 49.3% were women, and the mean age was age 71.6 years.
“To verify the robustness of our finding, we replicated the results from BioFINDER in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort,” said Janelidze.
All of the participants had undergone Aβ PET imaging, and CSF and plasma were collected.
The following assays were used to measure plasma Aβ42/40 in the BioFINDER cohort:
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Immunoprecipitation-coupled mass spectrometry, developed at Washington University (IP-MS-WashU)
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Antibody-free liquid chromatography MS, developed by Araclon (LC-MS-Arc)
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Immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); Amsterdam University Medical Center; ADx Neurosciences; Quanterix (IA-N4PE)
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IP-MS–based method from Shimadzu (IP-MS-Shim)
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IP-MS–based method from the University of Gothenburg (IP-MS-UGOT)
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Another immunoassay from Quanterix (IA-Quan)
ADNI participants underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.
Top Performer
The plasma IP-MS-WashU Aβ42/40 assay showed “significantly higher accuracy” than the other assays for identifying participants with abnormal CSF Aβ42/40 in the whole cohort.
| Plasma assay (Aβ42/40) | Area under the curve (AUC) (95% CI) | P value |
|---|---|---|
| IP-MS-WashU | .86 (.81 – .90) | < .01 |
| LC-MS-Arc | .78 (.72 – .83) | < .01 |
| IA-Elc | .78 (.73 – .83) | < .001 |
| IA-EI | .70 (.64 – .76) | < .001 |
| IA-N4PE | .69 (.63 – .75) | < . 001 |
In two subcohorts for which IP-MS-Shim, IP-MS-UGOT, and IA-Quan were also available, IP-MS-WashU also showed superior accuracy in flagging abnormal CSF Aβ42/40.
| Plasma assay (Aβ42/40) | AUC (95% CI) | P value |
|---|---|---|
| IP-MS-WashU vs IP-MS-UGOT | .84 (.79 – .89) vs .68 (.61 – .75) | < .001 |
| IP-MS-WashU vs IA-Quan | .84 (.79 – .89) vs 64 (.56 – .71) | < .001 |
The difference in AUCs between IP-MS-WashU and IPMS-Shim was not significant (P = .16) in the two subcohorts for which biomarkers were available.
Similar findings were obtained when Aβ-PET was used as the outcome.
The highest Spearman coefficients were found for correlations of CSF Aβ42/40 with plasma IP-MS-WashU and IP-MS-Shim (r, .65 and r, .56, respectively; for both, P < .001).
These findings from the BioFINDER cohort were replicated in the ADNI cohort (n = 51 cognitively unimpaired individuals, 51 with MCI, and 20 with AD dementia; 43.4% women; mean age, 72.4 [SD, 5.4] years). The IP-MS-WashU assay “performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay,” the researchers report.
“These findings can help inform the future clinical use of blood tests for Aβ pathology in AD,” the investigators note.
“However, before large-scale implementation in clinical practice, prospective studies in the intended population in primary care are needed where patient samples are analyzed in a consecutive manner — ie, not all samples at the same time,” said Janelidze.
Room for Improvement
Commenting for Medscape Medical News, Adam Boxer, MD, PhD, endowed professor in memory and aging and director, Neurosciences Clinical Research Unit, Department of Neurology, University of California, San Francisco, called the study “important.”
Boxer, who is also the director of the AD and FTD [frontotemporal dementia] Clinical Trials Program, was not involved in the research. He said, “These data provide further support for the potential utility of blood tests to screen for brain amyloidosis, but also suggest that there is room for improvement.”
There are “important differences between different AD blood testing technologies,” noted Boxer. “Other blood tests that measure other proteins, such as phosphorylated tau, are likely to be more accurate and may have advantages for clinical use,” he said.
The study was supported by the Swedish Research Council, the Knut and Alice Wallenberg foundation, the Marianne and Marcus Wallenberg foundation, the Strategic Research Area MultiPark at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, the Parkinson Foundation of Sweden, the Skåne University Hospital Foundation, Regionalt Forskningsstöd, and the Swedish federal government under the ALF agreement. Grants to individual researchers are listed on the original article. Janelidze reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Boxer reports no relevant financial relationships.
JAMA Neurology. Published online September 20, 2021. Full text
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