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bioRxiv · 10.64898/2026.09.03.747935

An Integrated Single-Nucleus Atlas Resolves Cell-Type-Specific Programs and Molecular Subtypes in Alzheimer's Disease

Rahimzadeh, N.·Morabito, S.·Khullar, S.·Shi, Z.·Cao, Z.·Swarup, V.
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Abstract

Interindividual heterogeneity in Alzheimer's disease (AD) remains poorly understood, as disparate single-cell studies leave it unclear whether findings reflect shared architecture or dataset-specific idiosyncrasies. Here, we present panAD, a transcriptomic atlas of >3 million nuclei from 791 individuals across 13 studies, spanning AD, mild cognitive impairment, and cognitively normal aging. AD converges on a reproducible, cell-type-specific molecular architecture: co-expression modules track neuropathology and cognitive decline; GWAS risk genes act predominantly as downstream targets of transcription factor hubs such as microglial SPI1; intercellular communication is remodeled with disease stage; and sex differences concentrate in microglial immune-activation programs. To model patient-level transcriptomic heterogeneity, we developed the Multi-seed Optimization of Neural Embeddings for subTyping (MONET) framework, in which a masked variational autoencoder applied to covariate-adjusted, multi-cell-type profiles resolves four subtypes (Metal-Ion Stress, Neuroinflammatory, Synaptic Integrity, and Tissue Remodeling) that dissociate neuropathological burden from cognitive impairment and nominate predominantly non-overlapping candidate therapeutics. Finally, Stellar Atlas provides an AI-native conversational interface to the atlas.

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Rahimzadeh, N., Morabito, S., Khullar, S., Shi, Z., Cao, Z., Swarup, V.. 2026-09-04. An Integrated Single-Nucleus Atlas Resolves Cell-Type-Specific Programs and Molecular Subtypes in Alzheimer's Disease. https://doi.org/10.64898/2026.09.03.747935

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