Integrated genomic meta-analysis identifies cell-type-specific signatures and targets in early Alzheimer's disease
Steinruecke, M.; Baillie, J. K.; Jiwaji, Z.
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Cellular mechanisms in early Alzheimers disease (AD) remain poorly understood despite generation of extensive observational multiomic data. Weighted integration across diverse datasets can prioritise convergent mechanisms and targets. We conducted a systematic review to identify datasets profiling cell-type-specific changes in early AD. We integrated multiomic findings using Meta-Analysis by Information Content (MAIC), a computational method which combines genomic data from diverse experimental sources. Electron transport chain dysfunction in mitochondria emerged as a shared pathway in neurons, microglia, and astrocytes, and Wnt signalling was a prominent astrocyte-specific signature. Pathological neuro-glial signalling mechanisms included APP-CD74, APOE-SORL1, and WNT-FZD/LRP6. Integration with pharmacological data identified therapeutics already under investigation in AD, such as guanfacine, and candidates not previously prioritised, such as eltrombopag and encorafenib. We present a systematic analysis of cell-type-specific changes in early AD to prioritise pathways for investigation and therapeutics for repurposing.
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