Neuronal and glial transcriptional states vary with proximity to tangle-bearing neurons in the human entorhinal cortex

In human entorhinal cortex, excitatory neuron subtypes closest to PHF1-positive tangle-bearing neurons show the greatest loss, linked to a late transcriptional program.

• Why it matters: Tangles can persist for decades, so their presence alone may not explain degeneration; proximity to tangle-bearing neurons could better capture vulnerability.
• What they did: Using 6,000-plex spatial transcriptomics with PHF1 immunofluorescence (167,176 cells; 9 donors) and imaging mass cytometry (170,195 cells; 62 donors), the team measured each cell’s distance to the nearest tangle.
• The result: Nearby tangle-free neurons shared more of the late microtubule-associated, synaptic, and V-ATPase expression state, while nearby glia showed higher disease-associated scores; this proximity pattern implies selective excitatory vulnerability.

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