A reproducibility-audit framework for generalizable versus dataset-specific molecular transition boundaries in Alzheimer's disease
- 1BIOXP
Abstract
Molecular staging of Alzheimer's disease (AD) increasingly defines transition boundaries along single-cell pseudo-progression trajectories, yet whether such boundaries reproduce across brain regions, cohorts and molecular modalities is rarely tested. We present a permutation-controlled audit that combines nine boundary-detection algorithms with a fixed marker panel and four orthogonal reproducibility axes-algorithmic consensus, region, cohort and modality. On synthetic data with planted ground-truth boundaries the audit reaches 100% sensitivity and 94% specificity, rejecting four distinct artefact classes each by a different axis. Applied to the Seattle Alzheimer's Disease Brain Cell Atlas middle temporal gyrus, it localizes a transition that is robust across algorithms and recovered in most cell types but does not generalize: its leading marker is attenuated or absent in prefrontal cortex, entorhinal cortex and cerebrospinal fluid, and an apparent cross-region conservation of glial metabolic genes proves to be a global-expression offset rather than a shared program. The same audit nonetheless certifies an externally validated marker (astrocytic PTGDS) as reproducible across regions and modalities, showing that it separates generalizable anchors from dataset-specific ones rather than rejecting all signals. We provide this four-axis audit as a transferable, code-available standard to apply before a trajectory boundary is read as a biological stage, in AD and other progressive proteinopathies.
Related
- Genomic Engineering of Gene Dosage: A Generalizable Framework for Modeling Haploinsufficiency-Mediated Human Disorders through Splicing Modulation
- An automated machine vision-based index for Rett Syndrome provides a generalizable framework for modeling rare disease therapeutics
- Culture regime as an experimental variable in Caenorhabditis elegans: Cross-format evidence, reproducibility constraints, and proposed minimum reporting framework.
- Clinical trial data transparency should match data access to scientific purpose: a tiered framework for reproducibility and reuse
- Evidence boundaries and integrated disease management of microbial disease risks in protected Cymbidium faberi production: a translational framework and validation agenda
BibTeX
@misc{kim2026reproducibilityaudit,
title = {{A reproducibility-audit framework for generalizable versus dataset-specific molecular transition boundaries in Alzheimer's disease}},
author = {Y. Kim and W. Heo and S. J. Park and Y. Kim and Y. E. Cho},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.24.746808},
url = {https://www.biorxiv.org/content/10.64898/2026.08.24.746808v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A reproducibility-audit framework for generalizable versus dataset-specific molecular transition boundaries in Alzheimer's disease
AU - Y. Kim
AU - W. Heo
AU - S. J. Park
AU - Y. Kim
AU - Y. E. Cho
PY - 2026
DA - 2026/08/24
PB - bioRxiv
DO - 10.64898/2026.08.24.746808
UR - https://www.biorxiv.org/content/10.64898/2026.08.24.746808v1
AB - Molecular staging of Alzheimer's disease (AD) increasingly defines transition boundaries along single-cell pseudo-progression trajectories, yet whether such boundaries reproduce across brain regions, cohorts and molecular modalities is rarely tested. We present a permutation-controlled audit that combines nine boundary-detection algorithms with a fixed marker panel and four orthogonal reproducibility axes-algorithmic consensus, region, cohort and modality. On synthetic data with planted ground-truth boundaries the audit reaches 100% sensitivity and 94% specificity, rejecting four distinct artefact classes each by a different axis. Applied to the Seattle Alzheimer's Disease Brain Cell Atlas middle temporal gyrus, it localizes a transition that is robust across algorithms and recovered in most cell types but does not generalize: its leading marker is attenuated or absent in prefrontal cortex, entorhinal cortex and cerebrospinal fluid, and an apparent cross-region conservation of glial metabolic genes proves to be a global-expression offset rather than a shared program. The same audit nonetheless certifies an externally validated marker (astrocytic PTGDS) as reproducible across regions and modalities, showing that it separates generalizable anchors from dataset-specific ones rather than rejecting all signals. We provide this four-axis audit as a transferable, code-available standard to apply before a trajectory boundary is read as a biological stage, in AD and other progressive proteinopathies.
ER -