Integrative multi-omics reveal glial signatures associated with accelerated cognitive decline in Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder characterised by progressive cognitive decline and memory loss caused by both genetic and environmental factors. Synapse dysfunction and loss are strongly related to cognitive decline in AD. This study integrates genomic, transcriptomic, proteomic and immunohistological (multi-omics) data and longitudinal cognitive data across several AD cohorts to elucidate the molecular drivers associated with astrocytes and microglia involved in these processes. Our findings demonstrate that activation of microglia and astrocytes occurs in specific cell subsets that are enriched in AD risk genes. Transcriptomic evidence for early microglial activation precedes immunohistological expression of severe neuropathology. Proteomic markers of astrocytic response appear to be most strongly associated with accelerated cognitive decline. However, we also found that brains from donors with a history of more rapid cognitive decline showed evidence for reduced SNAP25-VAMP interactions indicative of synaptic dysfunction, exhibited higher neurotoxic astrocyte reactivity, and were associated with the expression of neuronal markers of injury. Related molecular signatures in cerebrospinal fluid and plasma may provide biomarkers to identify patients at higher risk for rapid cognitive decline. Together, our results connect glial activation to synaptic dysfunction and cognitive decline in AD and highlight roles for microglial activation in the genesis of AD and later astrocyte activation as a potential determinant of clinical symptom progression.