Subcellular Spatial Profiling Unveils Links Between Neuritic Plaques with Selective Tau Vulnerability in Alzheimer's Disease

Layer IV neurons in Alzheimer’s disease show attenuated somatic pTau accumulation despite similar plaque-associated neuritic stress, linked to reduced expression of a shared neurite-soma stress program.

• Why it matters: The study addresses why neurons with comparable plaque-associated pathology diverge in intraneuronal tau accumulation across cortical layers, especially the relative resistance of layer IV.
• What they did: It used subcellular spatial transcriptomics with co-registered Aβ and pTau immunohistochemistry to compare plaque-associated neuritic stress and somatic pTau programs across layers, including trajectory analysis.
• The result: Tau-vulnerable versus resistant neuronal states implicate calcium signaling, retrograde transport, and lysosomal function, with astrocytic APOE–neuronal LRP1 co-expression increasing along the vulnerable trajectory and APOE ε4 strengthening coupling to pTau programs.

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