Utilization of plasma Aβ and <i>p</i> ‐tau217 in predicting Aβ accumulation in PET A‐ non‐demented participants

Abstract Background As Alzheimer's disease studies increasingly utilize plasma biomarkers, the associations of plasma and PET biomarkers of β‐amyloid (Aβ) in relation to Aβ accumulation and progression from PET A‐ to A+ must be better understood. Methods We evaluated 58 non‐demented participants from ADNI and 170 from the University of Pittsburgh (UPitt) who had plasma Aβ42/Aβ40 measures and longitudinal Aβ‐PET. We additionally evaluated 124 UPitt participants who had p ‐tau217 measures. All participants were PET A‐ at baseline. Plasma Aβ42/40 values were derived through either the C 2 N mass spectrometry‐based assay (ADNI) or Simoa assay (UPitt). p ‐tau217 values were derived through the Janssen p ‐tau217+ Simoa assay. Cut‐off values of 0.15 and 0.11 determined Aβ42/40 status for the ADNI and UPitt datasets, respectively, A cut‐off of 0.083 pg/mL was used for p ‐tau217. Kaplan‐Meyer survival models evaluated the association of plasma Aβ42/40 status with risk of progression to PET A+. Linear regression models, adjusting for baseline PET Aβ values, sex, age, and APOE*4 status, assessed the association of plasma Aβ42/40 values with Aβ accumulation. Results Kaplan‐Meyer survival analysis results showed that plasma Ab status distinctly differentiates PET A‐ trajectories, (Figure 1) with plasma A+ progressing to PET A+ in a median time of 4.0 years in both datasets. Only 3 (2.4%) of the 124 PET A‐ participants presented high p ‐tau217 values. Linear regression models of the continuous measures revealed that, even with the inclusion Aβ‐PET and the other covariates, plasma Aβ42/40 was significantly associated with Aβ accumulation (ADNI: b=‐142.29, p = 0.002; UPitt: b=‐0.27, p = 0.02) (Figure 2). Plasma A+ presented significantly higher Aβ accumulation compared to plasma A‐. (Figure 3) Conclusions While a better predictor of high Ab deposition than plasma Aβ42/40, p ‐tau217 is not elevated in PET A‐. On the other hand, plasma Aβ42/40 can predict progression from PET A‐ to A+. This follows the notion that soluble Aβ, measured in plasma or CSF, becomes abnormal before high insoluble Aβ is detectable with PET. Therefore, plasma Aβ‐positive/Aβ‐PET negative identify individuals at the very early stages of Aβ deposition, at risk of progression, requiring a closer follow‐up and likely to benefit the most from anti‐Aβ therapy.