Single-Nuclei Transcriptomic Characterization of APOE4-Associated Alzheimer's Disease

Murtha, K.; Chongtham, A.; Song, W.-M.; Ilkov, M.; Wang, M.; Chen, C. Q.; De Sanctis, C.; Datta, R.; Purohit, D.; Lee, E. B.; Zhang, B.; Pereira, A. C.

doi:10.64898/2026.04.03.715591

bioRxiv · 10.64898/2026.04.03.715591

Single-Nuclei Transcriptomic Characterization of APOE4-Associated Alzheimer's Disease

Murtha, K.·Chongtham, A.·Song, W.-M.·Ilkov, M.·Wang, M.·Chen, C. Q.·De Sanctis, C.·Datta, R.·Purohit, D.·Lee, E. B.·Zhang, B.·Pereira, A. C.

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Abstract

Apolipoprotein E (APOE) genotype contributes significantly to Alzheimers disease (AD) risk and pathogenesis. Cell-type specific effects of APOE alleles have been studied. However, due to the variable prevalence of APOE genotypes within human populations, characterization of cell-type specific transcriptomes across APOE genotypes has been challenging. Here, we integrated previous and newly generated single-nuclei sequencing (snRNA-seq) data in the prefrontal cortex (PFC) from individuals across APOE genotypes (2/2, 2/3, 3/3, 3/4, 4/4). Clustering analysis revealed distinct excitatory and microglial subpopulations that were uniquely enriched or depleted for APOE4/4 AD. Notably, an excitatory neuronal cluster exhibited neurofibrillary tangle (NFT) signatures and was selectively depleted in APOE4/4 AD cases. In addition, several microglial subpopulations were influenced by both APOE4 dosage and disease status. Among these, the putative AD risk gene FRMD4A emerged as APOE4 dose and AD-dependent. These findings were validated by RNAscope in an extended cohort. Together, our findings provide insights into how APOE4 reshapes cellular states and contributes to cell-type-specific vulnerability in AD.

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Murtha, K., Chongtham, A., Song, W.-M., Ilkov, M., Wang, M., Chen, C. Q., De Sanctis, C., Datta, R., Purohit, D., Lee, E. B., Zhang, B., Pereira, A. C.. 2026-04-04. Single-Nuclei Transcriptomic Characterization of APOE4-Associated Alzheimer's Disease. https://doi.org/10.64898/2026.04.03.715591

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