# Utilization of plasma Aβ and p‐tau217 in predicting Aβ accumulation in PET A‐ non‐demented participants

## TL;DR

The study shows that plasma Aβ42/40 can predict future Aβ accumulation in the brain, even when PET scans are still negative, suggesting early detection of Alzheimer's risk.

## Contribution

The study demonstrates that plasma Aβ42/40 is a significant predictor of future Aβ accumulation in non-demented individuals who are initially PET Aβ-negative.

## Key findings

- Plasma Aβ42/40 status significantly predicts progression from PET Aβ-negative to Aβ-positive within 4 years.
- Plasma Aβ42/40 is significantly associated with Aβ accumulation, even after adjusting for covariates like age and APOE*4 status.
- Only a small proportion of PET Aβ-negative participants had elevated p-tau217 levels.

## Abstract

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.

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 C2N 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.

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)

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.