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bioRxiv · 10.64898/2026.10.15.759523

Spatial proximity to AD pathology defines cell-type and genotype-specific characteristics in human AD hippocampus

Shi, C. H.·Zhu, B.·Pina-Crespo, J.·Chen, W. N.·Vo, G. V.·Huang, H.·Yip, K. Y.·Huang, T. Y.
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Abstract

How amyloid-{beta} (A{beta}) plaques and tau phosphorylation spatially relate to cell response and genetic variation in Alzheimer's disease (AD) brain is currently unclear. We established a pipeline to concurrently annotate A{beta} and AT8 ptau pathology and cell-specific MERFISH expression profiles in human control and AD hippocampus. We characterized expression signatures in glia and neurons proximal or distal to A{beta} plaques, AT8 ptau-enriched neurons, or A{beta} and AT8 ptau in combination, and used spatially-defined transcriptional signatures to infer pathology-associated states in large snRNA-seq datasets lacking spatial context. We characterized variants from 120 gene loci associated with AD risk that affect cell-specific gene expression within local pathological contexts. Astrocyte APOE4/E4 expression was specifically suppressed in proximity to A{beta} plaques, whereas other APOE genotypes were unaffected by A{beta} proximity. Together, this analysis pipeline couples expression profiles in proximity to A{beta} and tau pathology, and implicates AD cis-gene variants with spatial sensitivity to AD pathology.

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Shi, C. H., Zhu, B., Pina-Crespo, J., Chen, W. N., Vo, G. V., Huang, H., Yip, K. Y., Huang, T. Y.. 2026-10-21. Spatial proximity to AD pathology defines cell-type and genotype-specific characteristics in human AD hippocampus. https://doi.org/10.64898/2026.10.15.759523

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