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

Abstract

More neurons die in Alzheimer's disease than form tangles, and tangle-bearing neurons can persist for decades, so tangles alone cannot explain degeneration. We combined 6,000-plex spatial transcriptomics with PHF1 immunofluorescence (167,176 cells; 9 donors) and imaging mass cytometry (170,195 cells; 62 donors), measuring each cell's distance to the nearest tangle. Tangle-bearing layer 2-3 excitatory neurons were enriched late along a trajectory of increasing microtubule-associated, synaptic and V-ATPase expression, with elevated p62 and K48-ubiquitin. Tangle-free neurons shared more of this state the closer they lay to a tangle, including higher chaperone and autophagy scores, p62 and nuclear size. Nearby glia had higher disease-associated scores, with astrocytes expressing less GFAP. Excitatory, but not inhibitory, neuron loss was greatest in subtypes closest to tangles and cortical depths richest in phosphorylated tau. Selective neuronal vulnerability may reflect not only a neuron's susceptibility to forming a tangle but also where it lies relative to one.