Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments
Year: 2026
Type: preprint
Abstract: Background Plasma p-tau217 identifies Alzheimer’s disease pathology, but performance in mixed cohorts may not extend to conditional tau-positivity dis-crimination within amyloid-positive individuals or to MRI-defined hippocampal neurodegeneration. We compared plasma prediction across PET- and MRI-defined AT(N) outcomes and conducted separate axis-specific assessments. Methods This retrospective secondary study used Alzheimer’s Disease Neuroimaging Initiative (ADNI) data. Tasks were amyloid positivity (A; 1,097 participants, 496 positive), tau positivity (T; 929, 195), T within A+ (361, 161), study-defined hippocampal neurodegeneration (N; 1,303, 248), and joint A+T+ (852, 161). Repeated nested cross-validation used fold-internal preprocessing and calibration. Post-hoc assessments comprised a Bio-Hermes A-axis staged random-forest analysis using Lilly p-tau217 and C2N A β 40/A β 42 (908 participants; 328 and 324 positive under the primary and alternative PET classifications), and an A4 ordinal p-tau217 analysis against an A4-specific medial-temporal tau-PET endpoint in A+ participants. Results ADNI random-forest AUROCs were 0.9425 (95% CI 0.9271–0.9562) for A, 0.9495 (0.9325–0.9645) for T, 0.8852 (0.8485–0.9163) for T within A+, 0.7865 (0.7553–0.8151) for N, and 0.9614 (0.9484–0.9726) for joint A+T+. At thresholds targeting 90% sensitivity, specificity was 87.5% for T overall and 60.7% within A+. In Bio-Hermes, adding A β 40 and A β 42 to p-tau217 increased AUROC from 0.894 to 0.916 (paired difference 0.022, 95% conditional interval 0.010– 0.035) and changed Brier score by -0.011 ( -0.017 to -0.005 ); the alternative PET classification was concordant. In A4, ordinal p-tau217 had AUROC 0.7356 (95% CI 0.6775–0.7907), average precision 0.5657 (0.4732–0.6677), and Spearman ρ = 0.4718 (0.3824–0.5528). Conclusions ADNI identified task-dependent performance boundaries, particularly attenuated conditional T discrimination within A+. Separate-cohort evidence supported moderate single-marker conditional-T discrimination in A4 and modest complementary A-axis information from plasma A β in Bio-Hermes, but only within those respective axes and assay implementations.
Source: medRxiv
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Eli Lilly and Company, Biogen, Alzheimer's Disease Neuroimaging Initiative, Northern California Institute for Research and Education, National Institute for Health and Care Research, Göteborgs Universitet, National Institutes of Health, Canadian Institutes of Health Research, National Institute on Aging
OpenAlex ID: W7222969944