Glia inflammation and cell death pathways drive disease progression in preclinical and early AD.

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.