Spatial proximity to AD pathology defines cell-type and genotype-specific characteristics in human AD hippocampus
- 1Sanford Burnham Prebys Medical Discovery Institute
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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BibTeX
@misc{shi2026spatial,
title = {{Spatial proximity to AD pathology defines cell-type and genotype-specific characteristics in human AD hippocampus}},
author = {C. H. Shi and B. Zhu and J. Pina-Crespo and W. N. Chen and G. V. Vo and H. Huang and K. Y. Yip and T. Y. Huang},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759523},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759523v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Spatial proximity to AD pathology defines cell-type and genotype-specific characteristics in human AD hippocampus
AU - C. H. Shi
AU - B. Zhu
AU - J. Pina-Crespo
AU - W. N. Chen
AU - G. V. Vo
AU - H. Huang
AU - K. Y. Yip
AU - T. Y. Huang
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759523
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759523v1
AB - 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.
ER -