Plasma proteomic signatures of preclinical Alzheimer's disease in clinically unimpaired older adults

Mol Neurodegener. 2026 Apr 24;21(1):31. doi: 10.1186/s13024-026-00941-5.

ABSTRACT

BACKGROUND: Multi-analyte plasma proteomic panels that can accurately detect initial Alzheimer’s disease (AD) pathology in preclinical populations and simultaneously measure related biological processes relevant for disease risk are critical for advancing early detection and prognosis. METHODS: Using the NULISAseq™ CNS panel, we measured plasma proteomics from 315 clinically unimpaired (CU) older adults across two independent cohorts: the Stanford Aging and Memory Study (SAMS; n = 193) with paired cerebrospinal fluid (CSF) and plasma analyzed with Lumipulse, and the Attention, Memory, and Aging Study at Stanford (AMASS; n = 122) with paired florbetaben (FBB) amyloid PET. We evaluated correspondence of core AD-relevant biomarkers pTau217, pTau181, Aβ42/Aβ40, pTau217/Aβ42, GFAP, and NfL measured using multiplex NULISAseq and single-plex Lumipulse immunoassays. ROC curve analyses compared performance for detecting amyloid-positivity (A+) (a) across platforms in SAMS and (b) across brain-derived (BD) and total-pTau assays in AMASS, leveraging novel NULISAseq immunoassays. Linear models were applied across all NULISAseq CNS proteins to explore proteomic abundance patterns associated with age, sex, APOE-ε4, amyloid burden (CSF Aβ42/Aβ40, amyloid PET), and tau burden (CSF pTau181, PI-2620 tau PET) using an FDR-corrected p-value of < 0.05 to identify significant targets. RESULTS: In SAMS, moderate to high correlations were observed between NULISAseq and Lumipulse plasma biomarkers. NULISAseq pTau217/Aβ42 (AUC: 0.940) and pTau217 (AUC: 0.879) performed as well as corresponding single-plex Lumipulse assays (pTau217/Aβ42, AUC: 0.907; pTau217, AUC: 0.838) for detecting CSF A+ in SAMS. In AMASS, BD-pTau217 (AUC: 0.920) and BD-pTau181 (AUC: 0.920) exhibited the highest performance in discriminating PET A+, providing significant performance gains compared to total-pTau measures (pTau217, AUC: 0.861; pTau181, AUC: 0.763). Exploratory proteomic abundance analyses across NULISA CNS targets revealed pTau isoforms as most differentially expressed with amyloid burden across cohorts, together with upregulation of GFAP and downregulation of Aβ42 in SAMS. Tau burden was associated with upregulation of plasma pTau217, independent of amyloid burden, together with proteins related to astrocyte activation, inflammation, and synaptic integrity. CONCLUSIONS: NULISAseq multiplex immunoassays, including novel BD-pTau assays, accurately detect AD pathology among CU older adults and identify multiple biological pathways related to aging and early biomarker abnormality that may become dysregulated in preclinical AD.

PMID:42032756 | PMC:PMC13244826 | DOI:10.1186/s13024-026-00941-5