ATN Profile

Overview:

Use: This profile is used to assist in determining the presence or absence of key biological changes that are consistent with Alzheimer's disease pathology.

Limitations: These tests were developed and their performance characteristics determined by Labcorp. They have not been cleared or approved by the Food and Drug Administration.

Methodology: Sysmex chemiluminescence enzyme immunoassay (CLEIA) and Roche Diagnostics electrochemiluminescence immunoassay (ECLIA)

Additional Information: The ATN framework provides an objective approach to determine the status of biological changes that are indicative of Alzheimer’s disease (AD). Overall, the ATN framework for blood-based biomarkers can complement imaging and CSF analysis and create an opportunity for a more effective patient journey. The ATN Profile test employs biomarkers that have been well-studied in clinical research:

A: Plasma Aβ42/40 immunoassay based on Sysmex reagents and technology. In general, Aβ42 proteins are known to have a high adhesion index and are typically referred to as “sticky,” thus complicating their assessment in blood or CSF samples. New technologies—including low binding tubes and high sensitivity immunoassay platforms that can detect down to picogram levels—have enabled better assessments. Ovod et al demonstrated that accurate amyloid beta assessments for AD from blood were possible using mass spectrometry techniques.1 More recently, studies using Sysmex-based technology showed that plasma Aβ42/40 assessments could achieve levels similar to mass spectrometry-based methods for detecting AD pathology.2,3

T: Plasma pTau-181 immunoassay based on Roche reagents and technology. Karikari et al showed the diagnostic utility of plasma pTau-181 in AD4 and additional studies that same year demonstrated that plasma pTau-181 correlates with tau PET,5,6 thereby validating it as an important and useful BBM for AD pathology determination. Subsequent studies have demonstrated the prognostic value of combining Aβ42/40 testing with plasma pTau-181 on a Roche platform.7

N: Plasma NfL immunoassay based on Roche reagents and technology. NfL is an indicator of neurodegeneration but is not specific to any particular disease, as neurofilaments in blood are simply the result of axonal damage, regardless of cause. In CSF, total Tau is a key biomarker for neurodegeneration. However, for a complete blood-based solution, NfL is the more suitable biomarker8 for determining neurodegenerative disease staging.9,10 The new updated draft guidelines do demote NfL from a core biomarker to a secondary one. Labcorp has chosen to leave the marker in the profile for clinical purposes since, even in the setting of normal beta-amyloid results, a raised NfL result may help alert the clinician to another non-Alzheimer’s condition.

Footnotes: 1. Ovod V, Ramsey KN, Mawuenyega KG, et al. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017 Aug;13(8):841-849. PubMed 28734653
2. Yamashita K, Miura M, Watanabe S, et al. Fully automated and highly specific plasma β-amyloid immunoassays predict β-amyloid status defined by amyloid positron emission tomography with high accuracy. Alzheimers Res Ther. 2022 Jun 23;14(1):86. PubMed 35739591
3. Yamashita K, Watanabe S, Ishiki K, et al. Fully automated chemiluminescence enzyme immunoassays showing high correlation with immunoprecipitation mass spectrometry assays for β-amyloid (1-40) and (1-42) in plasma samples. Biochem Biophys Res Commun. 2021 Oct 22;576:22-26. PubMed 34478915
4. Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020 May;19(5):422-433. PubMed 32333900
5. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med. 2020 Mar;26(3):387-397. PubMed 32123386
6. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat Med. 2020 Mar;26(3):379-386. PubMed 32123385
7. Palmqvist S, Stomrud E, Cullen N, et al. An accurate fully automated panel of plasma biomarkers for Alzheimer's disease. Alzheimers Dement. 2023 Apr;19(4):1204-1215. PubMed 35950735
8. Janelidze S, Palmqvist S, Leuzy A, et al. Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Aβ42/Aβ40 and p-tau. Alzheimers Dement. 2022 Feb;18(2):283-293. PubMed 34151519
9. Ebenau JL, Pelkmans W, Verberk IMW, et al. Association of CSF, plasma, and imaging markers of neurodegeneration with clinical progression in people with subjective cognitive decline. Neurology. 2022 Mar 29;98(13):e1315-e1326. PubMed 35110378
10. Iaccarino L, Burnham SC, Dell'Agnello G, Dowsett SA, Epelbaum S. Diagnostic Biomarkers of Amyloid and Tau Pathology in Alzheimer's Disease: An Overview of Tests for Clinical Practice in the United States and Europe. J Prev Alzheimers Dis. 2023;10(3):426-442. PubMed 37357283