CEP-IP with CMRF in SEA-AD Microglia: A Mitochondrial Co-expression Module Linked to Cognition
- 1Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
Abstract
Single-nucleus RNA-seq (snRNA-seq) studies of Alzheimer's disease (AD) routinely filter nuclei by mitochondrial percentage (%MT), yet whether these reads carry information about cognition is rarely examined. In the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) microglia snRNA-seq dataset, a transcriptome-wide screen identified a module of MT-CO3 and eight co-expressed mitochondrial genes. Three microglial populations were analyzed: PVM_3, M4 (Mic.13-like), and PVM_1, with a housekeeping-gene control. The CEP-IP pipeline with a copula monotone recovery filter (CMRF) used per-cell Spearman and Kendall scores, an inflection point (IP), and a cross-validated copula space boundary to isolate MT-CO3 Module cells. The donor percentage of Module cells past the IP (Module post-IP%) was significantly associated with worse cognition (MMSE and CASI; FDR<0.05) in all three populations. In PVM_3 and M4, these associations remained significant after adjustment for tissue quality, plaque burden, tangle burden, and contamination, and after doublet removal. PVM_3 and M4 Module post-IP% repeated in each donor's regions beyond chance, and no per-cell %MT cutoff reproduced the Module cells. In two external datasets without cognitive scores, the MT-CO3 module and its IP replicated. However, at the donor level, Module post-IP% could not be separated from mean %MT, and the source of the mitochondrial transcripts (e.g., retained cytoplasm or a true change in mitochondrial content) remains unresolved. Routine %MT filtering in AD snRNA-seq may therefore remove cells that carry information about cognition. The R package cepip, the pipeline code, and a software container that reproduced the findings are publicly available.
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BibTeX
@misc{wong2026cepip,
title = {{CEP-IP with CMRF in SEA-AD Microglia: A Mitochondrial Co-expression Module Linked to Cognition}},
author = {Kah Keng Wong},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.761284},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.761284v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - CEP-IP with CMRF in SEA-AD Microglia: A Mitochondrial Co-expression Module Linked to Cognition
AU - Kah Keng Wong
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.761284
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.761284v1
AB - Single-nucleus RNA-seq (snRNA-seq) studies of Alzheimer's disease (AD) routinely filter nuclei by mitochondrial percentage (%MT), yet whether these reads carry information about cognition is rarely examined. In the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) microglia snRNA-seq dataset, a transcriptome-wide screen identified a module of MT-CO3 and eight co-expressed mitochondrial genes. Three microglial populations were analyzed: PVM_3, M4 (Mic.13-like), and PVM_1, with a housekeeping-gene control. The CEP-IP pipeline with a copula monotone recovery filter (CMRF) used per-cell Spearman and Kendall scores, an inflection point (IP), and a cross-validated copula space boundary to isolate MT-CO3 Module cells. The donor percentage of Module cells past the IP (Module post-IP%) was significantly associated with worse cognition (MMSE and CASI; FDR<0.05) in all three populations. In PVM_3 and M4, these associations remained significant after adjustment for tissue quality, plaque burden, tangle burden, and contamination, and after doublet removal. PVM_3 and M4 Module post-IP% repeated in each donor's regions beyond chance, and no per-cell %MT cutoff reproduced the Module cells. In two external datasets without cognitive scores, the MT-CO3 module and its IP replicated. However, at the donor level, Module post-IP% could not be separated from mean %MT, and the source of the mitochondrial transcripts (e.g., retained cytoplasm or a true change in mitochondrial content) remains unresolved. Routine %MT filtering in AD snRNA-seq may therefore remove cells that carry information about cognition. The R package cepip, the pipeline code, and a software container that reproduced the findings are publicly available.
SN - 2692-8205
ER -