Characterizing the onset and progression of Alzheimer's pathologies using amyloid and tau PET imaging and plasma p-tau217

Brain Commun. 2025 Nov 18;7(6):fcaf449. doi: 10.1093/braincomms/fcaf449. eCollection 2025.

ABSTRACT

Characterizing the onset and progression of Alzheimer's disease pathologies relative to one another is important for biological staging and clinical trial design. Recent advances in blood plasma assays of Alzheimer's disease amyloid and tau pathology have enabled detection of Alzheimer's disease pathophysiology during life, but it remains unclear when plasma biomarker abnormalities are detectable relative to established amyloid and tau PET imaging biomarkers, and the extent to which plasma biomarkers can be used for biological disease staging. This work applies a novel temporal modelling approach to amyloid PET and plasma p-tau217 data from two different assay platforms to characterize when plasma p-tau217 become abnormal relative to amyloid PET, tau PET, and cognitive decline in a predominantly cognitively unimpaired cohort. This study included a subset of 172 Wisconsin Registry for Alzheimer's Prevention participants (mean (standard deviation (SD)) age at baseline plasma = 63.2 (6.3) years; 149 cognitively unimpaired at last cognitive assessment) with available amyloid PET imaging and plasma p-tau217 data assayed on the Lilly Meso Scale Delivery and Quanterix Alzpath platforms. We estimated the within-person onsets of detectable amyloid PET and plasma p-tau217 using sampled iterative local approximation and investigated the impact of this timing on downstream tau PET accumulation and cognitive decline using linear mixed-effects models. Longitudinal modelling revealed that on average, amyloid PET positivity preceded p-tau217 positivity, and both amyloid and p-tau217 preceded detectable changes in brain tau accumulation. Comparisons of 'time from biomarker onset' indicated that time from p-tau217 onset explained more variability in tau PET accumulation and cognitive decline than time from amyloid PET onset for the Lilly assay but did not differ for the Alzpath assay. Overall, the timing between amyloid PET and p-tau217 onset (in a subset positive for both) ranged from -5.5-24.6 years. These results suggest that plasma p-tau217 follows a predictable path once above thresholds thereby enabling estimation of p-tau217 + age and suggesting these assays may be useful for disease staging. Information regarding the timing of abnormal detection of amyloid PET, plasma p-tau217, and tau PET in relation to preclinical cognitive decline suggests that an optimal window for secondary prevention of Alzheimer's disease may be within ten years of amyloid PET positivity and within five years of plasma p-tau217 positivity. Future work is needed to identify sources of observed interindividual heterogeneity in the timing of biomarker abnormalities and cognitive decline and impairment following biomarker positivity.

PMID:41322203 | PMC:PMC12661573 | DOI:10.1093/braincomms/fcaf449