Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects

Abstract

It is currently unclear whether plasma biomarkers can be used as independent prognostic tools to predict changes associated with early Alzheimer's disease. In this study, we sought to address this question by assessing whether plasma biomarkers can predict changes in amyloid load, tau accumulation, brain atrophy and cognition in non-demented individuals. To achieve this, plasma amyloid-β 42/40 (Aβ42/40), phosphorylated-tau181, phosphorylated-tau217 and neurofilament light were determined in 159 non-demented individuals, 123 patients with Alzheimer's disease dementia and 35 patients with a non-Alzheimer's dementia from the Swedish BioFINDER-2 study, who underwent longitudinal amyloid (18F-flutemetamol) and tau (18F-RO948) PET, structural MRI (T1-weighted) and cognitive testing. Our univariate linear mixed effect models showed there were several significant associations between the plasma biomarkers with imaging and cognitive measures. However, when all biomarkers were included in the same multivariate linear mixed effect models, we found that increased longitudinal amyloid-PET signals were independently predicted by low baseline plasma Aβ42/40 (P = 0.012), whereas increased tau-PET signals, brain atrophy and worse cognition were independently predicted by high plasma phosphorylated-tau217 (P < 0.004). These biomarkers performed equally well or better than the corresponding biomarkers measured in the CSF. In addition, they showed a similar performance to binary plasma biomarker values defined using the Youden index, which can be more easily implemented in the clinic. In addition, plasma Aβ42/40 and phosphorylated-tau217 did not predict longitudinal changes in patients with a non-Alzheimer's neurodegenerative disorder. In conclusion, our findings indicate that plasma Aβ42/40 and phosphorylated-tau217 could be useful in clinical practice, research and drug development as prognostic markers of future Alzheimer's disease pathology.

Keywords: MRI; PET; amyloid-β; cognition; plasma biomarkers; tau PET.

Figure 1

Plasma P-tau217 levels independently predict longitudinal tau accumulation in non-demented individuals. Predicted trajectories for temporal tau accumulation (z-scores) in relation to baseline plasma P-tau217. (A) The models were fit using continuous P-tau217 values but for illustration purposes the plots show the trajectories for individuals with high, medium and low plasma P-tau217 tertiles. (B) The voxel-wise analyses using longitudinal tau images showed a positive correlation between plasma P-tau217 and increased tau accumulation in temporal and parietal areas, after FDR corrections.

Figure 2

Plasma Aβ42/40 levels independently predict longitudinal amyloid-PET deposition in non-demented individuals. Predicted trajectories for global amyloid-PET accumulation (z-scores) in relation to baseline plasma Aβ42/40 in a subsample (n = 86) with available amyloid-PET data. The models were fit using continuous Aβ42/40 values but for illustration purposes the plots show the trajectories for individuals with high, medium and low individuals with high, medium and low plasma Aβ42/40 tertiles. Plasma Aβ42/40 did not show significant results in the voxel-wise analyses, after adjusting for multiple comparisons.

Figure 3

Plasma P-tau217 and NfL levels independently predict longitudinal brain atrophy in non-demented individuals. Predicted trajectories for temporal cortical thickness and hippocampal volumes (z-scores) in relation to baseline plasma P-tau217 and plasma NfL. (A–C) The models were fit using continuous P-tau217 and NfL values but for illustration purposes the plots show the trajectories for individuals with high, medium and low plasma P-tau217 tertiles for (A) temporal cortical thinning and (B) hippocampal volume loss as well as (C) individuals with high, medium and low plasma NfL tertiles. (D) The voxel-wise analyses showed a positive correlation between plasma P-tau217 and longitudinal brain atrophy in parietal and occipital areas, after FDR corrections. Plasma NfL did not show significant results in the voxel-wise analyses, after adjusting for multiple comparisons.

Figure 4

Plasma P-tau217 levels independently predict cognitive decline in non-demented individuals. Predicted trajectories for global cognitive decline measured with the MMSE (z-scores) in relation to baseline plasma P-tau217. The models were fit using continuous P-tau217 values but for illustration purposes the plots show the trajectories for individuals with high, medium and low plasma P-tau217 tertiles.