A parsimonious three-gene mitochondrial classifier from frontal cortex for Alzheimer's disease: Nested cross-validation and multicenter external validation.

Authors

Mengnan Wang, Chenxi Jing, Tianci Wu, Daming Wang

Published in

Journal of Alzheimer's disease : JAD. Pages 13872877261487424. Sep 15, 2026. Epub Sep 15, 2026.

Abstract

BackgroundMitochondrial dysfunction is a hallmark of Alzheimer's disease (AD). The frontal cortex is among the earliest and most severely affected regions, yet no AD diagnostic classifier based on frontal cortical mitochondrial genes exists.ObjectiveWe aimed to construct a parsimonious diagnostic classifier from frontal cortex mitochondrial gene expression and rigorously validate it across independent cohorts.MethodsFour public brain transcriptomic datasets were downloaded from the NCBI Gene Expression Omnibus (GEO) database: GSE48350, GSE5281, GSE44770, and GSE33000. The training set (n = 103) was restricted to superior frontal gyrus samples. After ComBat correction, differentially expressed genes (adj. p < 0.2, |log₂FC|>0.3) were intersected with MitoCarta 3.0. A 10-fold nested cross-validation (CV) was applied to eliminate pre-selection bias: mitochondrial DEGs were re-selected in each fold, followed by LASSO regression. The final model was externally validated on GSE44770 (n = 230) and GSE33000 (n = 467).ResultsFrom 25 candidate genes, LASSO retained three: PRKACA, ACSM3, and BIK. Nested CV AUC was 0.635 (95% CI 0.527-0.744); external AUCs reached 0.714 (GSE44770) and 0.753 (GSE33000). The 25 genes were enriched in oxidative phosphorylation. Calibration was acceptable, and decision curve analysis indicated net benefit for guiding confirmatory testing. In external cohorts, BIK was upregulated and PRKACA downregulated, while ACSM3 showed a non-significant downward trend. With an optimized threshold, the model achieved a sensitivity of 0.726 and a specificity of 0.682 on the largest cohort.ConclusionsA three-gene mitochondrial signature derived from the frontal cortex provides a highly parsimonious, externally reproducible diagnostic tool for AD, with biological plausibility and clinical potential.

PMID:
42742534
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.