Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments
Listed in
This article is not in any list yet, why not save it to one of your lists.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.
