- Combined Aβ and tau pathology induces distinct transcriptional programs not seen in single models, notably disrupting glial lipid metabolism and immune networks.
- Microglia and oligodendrocytes show coordinated immune and synaptic alterations under combined pathology, indicating multicellular network-level disease mechanisms.
- Pathway alterations in immune, lipid and cell cycle programs under combined pathology align most strongly with human AD, supporting translational relevance and therapeutic target prioritisation.
Alzheimers Dement. 2026 Aug;22(8):e71742. doi: 10.1002/alz.71742.
ABSTRACT
INTRODUCTION: Alzheimer’s disease (AD) features amyloid beta (Aβ) plaques and tau tangles, yet how their coexistence reshapes brain transcriptomic programs remains unclear.
METHODS: We performed high-quality, sex-balanced single-nucleus RNA sequencing of 5XFAD (Aβ), PS19 (tau), and combined 5XFAD;PS19 mice.
RESULTS: We identified transcriptional programs that emerged most prominently under combined pathology. These programs included disruption of glial lipid metabolism and immune pathways at the network level, alongside immune and synaptic alterations coordinated between microglia and oligodendrocytes. Cross-species analyses further revealed that the pathway-level alterations under combined pathology, particularly in immune, lipid, and cell cycle programs, exhibited the strongest concordance with human AD datasets, underscoring their translational relevance.
DISCUSSION: Beyond benchmarking mouse models, this study provides a high-quality transcriptomic resource to dissect multicellular disease mechanisms in AD and to prioritize therapeutic targets for a network-level systems pharmacology approach.
PMID:42576162 | DOI:10.1002/alz.71742
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