The Caudate Nucleus Exhibits Distinct Pathology and Cell Type-Specific Responses Across Alzheimer's Disease

Kana, O. Z.; Postupna, N.; Agrawal, A.; Long, B.; Travaglini, K.; Gabitto, M.; Lai, H.-Y.; Mahoney, J. T.; Xiao, M.; Bajwa, T.; Hulsey-Vincent, H.; Oyaizu, S. L.; Mena, G. E.; Hong, J.; Gelfand, E. C.; Kaplan, E. S.; Ariza, J.; Smith, K. A.; McMillen, D. A.; Chakka, A. B.; Goldy, J.; Melief, E. J.; Barta, S.; Oyama, A.; Ruiz, A.; Pom, C. A.; Ayala, A.; Bixby, M.; Huang, A.; Martin, N.; Cuevas, N. V.; Olsen, P.; Nagra, J.; Chakrabarty, R.; Tieu, M.; Cardenas, T.; Torkelson, A.; Bertagnolli, D.; Guzman, J.; Ferrer, R.; Waters, J.; Grabowski, T. J.; Crane, P. K.; Gatto, N. M.; Miller, J. A.; Hodg

doi:10.64898/2026.01.10.694705

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bioRxiv · 10.64898/2026.01.10.694705

The Caudate Nucleus Exhibits Distinct Pathology and Cell Type-Specific Responses Across Alzheimer's Disease

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Abstract

A{beta} presence in the caudate nucleus (Ca) partially defines Thal stage III in Alzheimers disease (AD), but little is known about ADs cellular impact on the region. Leveraging a public basal ganglia taxonomy of cellular populations, we generated a cellular resolution atlas of AD-associated pathological changes in Ca. Unlike cortex, we found that Ca AD pathology is dominated by two key features: phosphorylated tau (pTau)-containing neuropil threads enriched near oligodendrocytes in white matter tracts and amyloid-{beta} diffuse plaques enriched in gray matter. Although AD pathology in affected cortical regions results in neuronal loss, we find no AD-driven reductions in neuron proportions in Ca. However, there were observable changes in multiple cellular populations. Protoplasmic astrocytes and FLT1+/IL1B+ microglia increased in abundance with global pTau levels. We also observe gene expression changes in fast-spiking PTHLH-PVALB interneurons indicative of disrupted signaling pathways and altered intrinsic physiological properties. This work provides a cellular-resolution framework for understanding AD pathology in Ca.

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Kana, O. Z., Postupna, N., Agrawal, A., Long, B., Travaglini, K., Gabitto, M., Lai, H.-Y., Mahoney, J. T., Xiao, M., Bajwa, T., Hulsey-Vincent, H., Oyaizu, S. L., Mena, G. E., Hong, J., Gelfand, E. C., Kaplan, E. S., Ariza, J., Smith, K. A., McMillen, D. A., Chakka, A. B., Goldy, J., Melief, E. J., Barta, S., Oyama, A., Ruiz, A., Pom, C. A., Ayala, A., Bixby, M., Huang, A., Martin, N., Cuevas, N. V., Olsen, P., Nagra, J., Chakrabarty, R., Tieu, M., Cardenas, T., Torkelson, A., Bertagnolli, D., Guzman, J., Ferrer, R., Waters, J., Grabowski, T. J., Crane, P. K., Gatto, N. M., Miller, J. A., Hodg. 2026-01-10. The Caudate Nucleus Exhibits Distinct Pathology and Cell Type-Specific Responses Across Alzheimer's Disease. https://doi.org/10.64898/2026.01.10.694705

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