LONGITUDINAL EVALUATION OF THE NATURAL HISTORY OF Aβ IN PLASMA AND BRAIN

Abstract

Plasma amyloid-β (Aβ) peptides have recently been shown to have high accuracy to predict Aβ burden in the brain. These Aβ plasma markers will allow a wider screening of the population but also simplify and reduce screening costs for therapeutic trials by identifying individuals at-risk of developing Alzheimer's disease (AD) at the preclinical/prodromal stages. While several studies reported the relationship between plasma and brain Aβ they have not evaluated how they change over time in relation to each other. The aim of this study was to determine how changes in blood Aβ track with changes in brain Aβ. We evaluated data from AIBL individuals that had a minimum of three assessments and deemed Aβ accumulators (N=133; Table 1) from the Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. Total protein Aβ42/40 plasma ratios (TP42/40) were determined using ABtest® assays in cognitively normal (NC, n=111), mild cognitively impaired (MCI, n=7) and AD (n=15) participants. PET-Aβ was quantified using CapAIBL1 and expressed in Centiloids2. We applied our method for obtaining natural history trajectories from short term data3,4 to measures of TP42/40 and PET-Aβ. This resulted in two curves detailing the natural history of the Aβ changes. To allow comparison between the curves, they were each aligned at the median values exhibited by the AD participants. Cross-sectional analysis showed a robust inverse association between TP42/40 and PET-Aβ. The natural history trajectory of TP42/40 appears to approximately mirror that of PET-Aβ, with both spanning decades (Figure 1). Both of the measures of Aβ have similar rates of change in the linear, dynamic stage of their trajectory. These rates of change are 7.9% and 8.8%, for TP42/40 and PET-Aβ, respectively. This fast-moving part of the curves appear to start ∼19 years before typical mild-AD for PET-Aβ but ∼23 years before typical mild-AD for TP42/40.