Relevance of Aβ42/40 Ratio for Detection of Alzheimer Disease Pathology in Clinical Routine: The PLMR Scale

Abstract

Background: Cerebrospinal fluid (CSF) biomarkers (Aβ peptides and tau proteins) improved the diagnosis of Alzheimer's disease (AD) in research and clinical settings. We previously described the PLM-scale (Paris-Lille-Montpellier study), which combines Aβ42, tau, and phosphorylated ptau(181) biomarkers in an easy to use and clinically relevant way. The purpose of this work is to evaluate an optimized PLM_R-scale (PLM ratio scale) that now includes the Aβ42/Aβ40 ratio to detect AD versus non-AD (NAD) participants in clinical routine of memory centers. Methods: Both scales were compared using 904 participants with cognitive impairment recruited from two independent cohorts (Mtp-1 and Mtp-2). The CSF Aβ42/Aβ40 ratio was measured systematically in Mtp-1, and only on biologically discordant cases in Mtp-2. Two different ELISA kit providers were also employed. The distribution of AD and NAD patients and the discrepancies of biomarker profiles were computed. Receiver Operating Characteristic curves were used to represent clinical sensitivity and specificity for AD detection. The classification of patients with the net reclassification index (NRI) was also evaluated. Results: Nine hundred and four participants (342 AD and 562 NAD) were studied; 400 in Mtp-1 and 504 in Mtp-2. For AD patients, the mean CSF Aβ42 and CSF Aβ42/40 ratio was 553 ± 216 pg/mL and 0.069 ± 0.022 pg/mL in Mtp-1 and 702 ± 335 pg/mL and 0.045 ± 0.020 pg/mL in Mtp-2. The distribution of AD and NAD differed between the PLM and the PLM_R scales (p < 0.0001). The percentage AD well-classified (class 3) increased with PLM_R from 38 to 83% in Mpt-1 and from 33 to 53% in Mpt-2. A sharp reduction of the discordant profiles going from 34 to 16.3% and from 37.5 to 19.8%, for Mtp-1 and Mtp-2 respectively, was also observed. The AUC of the PLM_R scale was 0.94 in Mtp-1 and 0.87 in Mtp-2. In both cohorts, the PLM_R outperformed CSF Aβ42 or Aβ42/40 ratio. The diagnostic performance was improved with the PLM_R with an NRI equal to 44.3% in Mtp-1 and 28.8% in Mtp-2. Conclusion: The integration of the Aβ42/Aβ40 ratio in the PLM_R scale resulted in an easy-to-use tool which reduced the discrepancies in biologically doubtful cases and increased the confidence in the diagnosis in memory center.

Keywords: Alzheimer’s disease; biomarkers; cerebrospinal fluid (CSF); screening scale.

FIGURE 1

The distribution in percentage of AD and NAD patients in the two cohorts (A: MTP-1 and B: MTP-2) when classified using the PLM-scale or the PLM_R scale. Note important shift in the distribution of the AD patients between the two scales (ANOVA, p < 0.0001, PLM-AD vs. PLM_R-AD).

FIGURE 2

The ROC curve of the PLM, PLM_R-scales and CSF Aβ42, Aβ42/40 ratio are plotted (Supplementary Table 1). Statistical analysis (Supplementary Table 2) confirmed that the PLM_R outperformed all the other situations in both cohorts. (A) MTP-1 and (B) MTP-2.