The Clinical Application of Optimized AT(N) Classification in Alzheimer’s Clinical Syndrome (ACS) and non-ACS Conditions

Background: Cerebrospinal fluid (CSF) biomarkers reflect the pathological process underlying Alzheimer’s disease (AD) and improve the accuracy of AD diagnosis. AT(N) classification using these CSF biomarkers was applied to define AD continuum in the research framework. However, there has been little research into the utility of AT(N) classification in clinical practice. Methods We measured the CSF levels of amyloid-β (Aβ) 42, Aβ40, phosphorylated tau, total tau (tTau), and neurofilament light chain (NfL) in samples from 640 clinical cases, comprising 230 patients with Alzheimer’s clinical syndrome (ACS) and 410 patients with non-ACS. The concordance between two A-markers (i.e., Aβ42 alone and the Aβ42/Aβ40 ratio) and the two N-markers (i.e., tTau and NfL) were analyzed. We evaluated the prevalence of biological AD and the frequency of each AT(N) category in the ACS and non-ACS samples. Results The concordance of A-markers was not significantly different between the ACS (87.4%) and non-ACS (73.2%) groups. However, the frequency of discordant cases with A Aβ42−alone +/A Aβ−ratio − was significantly higher in the non-ACS (24.9%) than in the ACS group (7.4%). The concordance of N-markers was 40.4% in the ACS group and 27.1% in the non-ACS group. In the ACS samples, the frequency of biological AD (i.e., A + T+) in N tau + cases was 95% while that in N NfL + cases was 65%. When Aβ42 was used as the A-marker, the proportion of biological AD was 60.4% in the ACS and 22.7% in the non-ACS group. When the Aβ42/Aβ40 ratio was used as the A-marker, the proportion of biological AD was 64.3% in ACS samples and 22.2% in non-ACS samples. Notably, the proportion of AD continuum in the non-ACS group was substantially different between using the Aβ42 alone and the Aβ42/Aβ40 ratio as an A-marker. Conclusions Although the AT(N) classification was intended for use in research, it may also be useful for clinical diagnosis. As an A-marker, the Aβ42/Aβ40 ratio reflects Aβ deposition more accurately than Aβ42 alone. As an N-marker, NfL reflects neurodegeneration more accurately than tTau, particularly in non-ACS patients. Thus, we recommend the use of AT(N) classification defined by CSF A Aβ−ratio TN NfL in clinical practice.