Direction‐specific biomarker profiles and clinical significance of plasma p‐tau217/amyloid PET discordance in cognitively normal adults
Year: 2026
Type: article
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.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.71922
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Funders: Foundation for the National Institutes of Health, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, F. Hoffmann-La Roche, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Novartis Pharmaceuticals Corporation, Northern California Institute for Research and Education, National Natural Science Foundation of China, Eisai, Servier, H. Lundbeck A/S, IXICO, National Science and Technology Major Project, National Institutes of Health, Genentech, Canadian Institutes of Health Research, National Institute on Aging
Awards: G1880935189, G29951154, G3146424788, G3553156159, G3752451908, G3870774570, G3966393351, G4079001475, G4501223628, G4959979158, G5209990037, G5235017436, G5483839741, G5654639750, G5740349702, G6371410416, G6881785591, G6899163935, G7414321945, G781725486, G839208290, G9000122335, Alzheimer's Disease Neuroimaging Initiative (ADNI4)
OpenAlex ID: W7223003962