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Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments
Xu J, Michopoulou S, Costen F, the Alzheimer’s Disease Neuroimaging Initiative.. medRxiv, 2026-10-19
Topic: Plasma and spinal-fluid biomarkers
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.
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APA 7th
Xu, J., Michopoulou, S., Costen, F., & the Alzheimer’s Disease Neuroimaging Initiative. (2026). Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments. medRxiv. https://doi.org/10.64898/2026.10.15.26365631
Vancouver
Xu J, Michopoulou S, Costen F, the Alzheimer’s Disease Neuroimaging Initiative. Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments. medRxiv. 2026. doi:10.64898/2026.10.15.26365631.
BibTeX
@article{xu2026-c9526c45,
author = {Xu, J. and Michopoulou, S. and Costen, F. and {the Alzheimer’s Disease Neuroimaging Initiative}},
title = {{Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.10.15.26365631},
url = {https://doi.org/10.64898/2026.10.15.26365631}
}
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Key findings
- 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+.
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Study details
- Study designpost-hoc analysis
- Participants1,097
- Effect size87.5%; 60.7%
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 37 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 62 points we could judge it on, which is 37 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | Design recorded as “post-hoc analysis”, which our rubric does not rank (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,097 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 23 of the 62 points we could judge it on is 37 out of 100. |
| Total | 37 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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