Plasma biomarkers of Alzheimer’s disease (AD) change during preclinical stages, indicating potential for detecting amyloid-β (Aβ) pathology in cognitively unimpaired (CU) individuals. Given the need for accurate, scalable biomarkers, we evaluated a fully automated plasma panel to detect and monitor longitudinal Aβ accumulation in CU individuals.

In this longitudinal study, we examined a plasma panel (Aβ42/40, p-tau181, GFAP, NfL, p-tau217 and ApoE4) in CU participants at risk for AD. We assessed the biomarkers’ performance to detect Aβ pathology and the cross-sectional and longitudinal relationships between the biomarkers and Aβ accumulation, neurodegeneration and cognition.

We included 400 middle-aged CU participants, of whom 135 (33.8%) were CSF Aβ-positive. All plasma biomarkers differed between Aβ-positive and -negative individuals, with plasma Aβ42/40, p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 showing the best performance in detecting A+ CU individuals. However, plasma Aβ42/40 was sensitive to random variability. Plasma p-tau217/Aβ42 had the highest performance in detecting PET A+ individuals (AUC = 0.94). All baseline plasma biomarkers were associated with longitudinal increases in Aβ deposition (mean follow-up [SD]: 3.27 ± 0.5). Longitudinal changes in plasma p-tau217 and p-tau217/Aβ42 were associated with concurrent changes in Aβ (both CSF and PET) and soluble tau pathology.

In CU individuals, several plasma biomarkers at baseline detect Aβ accumulation and are associated with its short-term change. Plasma p-tau217, and p-tau217/Aβ42 longitudinal changes reflect concurrent Aβ accumulation during this period. These findings help enrich studies in CU individuals at risk of progressing to AD.

Alzheimer

Biomarkers

Dementia

Diagnosis

Plasma

Modelling

© 2025 The Authors. Published by Elsevier B.V.