Direction-specific biomarker profiles and clinical significance of plasma p-tau217/amyloid PET discordance in cognitively normal adults.
- 1Health Management Center, Shenzhen Qianhai Taikang Hospital, Shenzhen, China.
- 2Department of Gerontology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 3Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China.
Abstract
Introduction
Plasma phosphorylated tau (p-tau)217 is increasingly used to triage amyloid testing, but the biological and clinical meaning of discordant plasma p-tau217 and amyloid positron emission tomography (PET) results in cognitively normal adults remains uncertain.Methods
We analyzed cognitively normal participants from the Chinese Preclinical Alzheimer's Disease Study (CPAS; n = 594) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 475). Amyloid PET positivity was defined as Centiloid ≥ 20. Cohort-specific p-tau217 positivity was defined using PET-anchored cutoffs with ≥ 0.90 specificity, yielding four p-tau/PET groups. Linear models assessed cross-sectional biomarker and cognitive differences; mixed-effects and Cox models assessed ADNI longitudinal Centiloid accumulation, cognitive trajectories, and clinical progression.Results
In cross-sectional analyses, compared to p-tau-/PET-, p-tau+/PET- had higher glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) levels across cohorts; p-tau-/PET+ showed a lower plasma amyloid beta 42/40 ratio in ADNI; and p-tau+/PET+ showed the broadest multimodal abnormalities. In ADNI, both p-tau+ groups had higher clinical progression risk and faster decline in selected cognitive domains; both PET+ groups showed faster Centiloid accumulation. Faster Centiloid accumulation in p-tau+/PET- was observed only at lower specificity thresholds.Discussion
Discordant plasma p-tau217 and amyloid PET results should be interpreted according to both the positivity pattern and the p-tau217 cutoff applied. Distinguishing these patterns may aid risk stratification and longitudinal monitoring. Different p-tau217 operating points may support risk enrichment and prioritization for confirmatory amyloid testing, but require validation before clinical use.
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BibTeX
@article{huang2026directionspecific,
title = {{Direction-specific biomarker profiles and clinical significance of plasma p-tau217/amyloid PET discordance in cognitively normal adults.}},
author = {Yanlu Huang and Lin Huang and Liang Cui and Fengfeng Pan and Fang Xie and Hongbo Guo and Qihao Guo and Alzheimer's Disease Neuroimaging Initiative},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2026},
month = oct,
doi = {10.1002/alz.71922},
url = {https://europepmc.org/article/MED/42902436},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Direction-specific biomarker profiles and clinical significance of plasma p-tau217/amyloid PET discordance in cognitively normal adults.
AU - Yanlu Huang
AU - Lin Huang
AU - Liang Cui
AU - Fengfeng Pan
AU - Fang Xie
AU - Hongbo Guo
AU - Qihao Guo
AU - Alzheimer's Disease Neuroimaging Initiative
PY - 2026
DA - 2026/10/01
JO - Alzheimer's & dementia : the journal of the Alzheimer's Association
DO - 10.1002/alz.71922
UR - https://europepmc.org/article/MED/42902436
AB - Introduction Plasma phosphorylated tau (p-tau)217 is increasingly used to triage amyloid testing, but the biological and clinical meaning of discordant plasma p-tau217 and amyloid positron emission tomography (PET) results in cognitively normal adults remains uncertain.Methods We analyzed cognitively normal participants from the Chinese Preclinical Alzheimer's Disease Study (CPAS; n = 594) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 475). Amyloid PET positivity was defined as Centiloid ≥ 20. Cohort-specific p-tau217 positivity was defined using PET-anchored cutoffs with ≥ 0.90 specificity, yielding four p-tau/PET groups. Linear models assessed cross-sectional biomarker and cognitive differences; mixed-effects and Cox models assessed ADNI longitudinal Centiloid accumulation, cognitive trajectories, and clinical progression.Results In cross-sectional analyses, compared to p-tau-/PET-, p-tau+/PET- had higher glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) levels across cohorts; p-tau-/PET+ showed a lower plasma amyloid beta 42/40 ratio in ADNI; and p-tau+/PET+ showed the broadest multimodal abnormalities. In ADNI, both p-tau+ groups had higher clinical progression risk and faster decline in selected cognitive domains; both PET+ groups showed faster Centiloid accumulation. Faster Centiloid accumulation in p-tau+/PET- was observed only at lower specificity thresholds.Discussion Discordant plasma p-tau217 and amyloid PET results should be interpreted according to both the positivity pattern and the p-tau217 cutoff applied. Distinguishing these patterns may aid risk stratification and longitudinal monitoring. Different p-tau217 operating points may support risk enrichment and prioritization for confirmatory amyloid testing, but require validation before clinical use.
SN - 1552-5260
SN - 1552-5279
ER -