Population-scale subcellular proteomics reveals intracellular remodelling across the Alzheimer's disease-resilience spectrum

Jolly, H. A.; Seghers, P.; Balcomb, K.; Smith, A. J.; Pearson, L.; Agrawal, I.; Geary, B.; Bennett, D. A.; Wisniewski, T.; Fowler, S. L.; Drummond, E.; Crook, O. M.; Carlyle, B. C.

doi:10.64898/2026.08.20.746004

bioRxiv · 10.64898/2026.08.20.746004

Population-scale subcellular proteomics reveals intracellular remodelling across the Alzheimer's disease-resilience spectrum

Jolly, H. A.·Seghers, P.·Balcomb, K.·Smith, A. J.·Pearson, L.·Agrawal, I.·Geary, B.·Bennett, D. A.·Wisniewski, T.·Fowler, S. L.·Drummond, E.·Crook, O. M.·Carlyle, B. C.

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Abstract

Proteome-wide analyses of human tissue have transformed our understanding of disease, but provide limited insight into protein localisation, a functionally informative dimension of the proteome. In Alzheimer's disease, amyloid-{beta} and tau exhibit aberrant localisation, yet whether spatial reorganisation extends proteome-wide has remained inaccessible to abundance-based proteomics. Here, we develop comparative subcellular proteomics applied to dorsolateral prefrontal cortex from 75 individuals spanning the Alzheimer's disease-resilience spectrum, modelling protein localisation across disease. We identify 217 disease-associated localisation shifts enriched for endolysosomal function, intracellular trafficking, and RNA processing, and resolve tau proteoforms within insoluble aggregates. Our strongest localisation candidates show only modest differences in whole-tissue abundance, highlighting disease biology inaccessible to conventional proteomics. We validate co-localisation of CSNK1A1 with pathological tau and identify an unexpected neuronal localisation pattern for SCAI, a cancer-associated protein not previously characterised in human brain, highlighting the discovery potential of subcellular proteomics in tissue.

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Jolly, H. A., Seghers, P., Balcomb, K., Smith, A. J., Pearson, L., Agrawal, I., Geary, B., Bennett, D. A., Wisniewski, T., Fowler, S. L., Drummond, E., Crook, O. M., Carlyle, B. C.. 2026-08-21. Population-scale subcellular proteomics reveals intracellular remodelling across the Alzheimer's disease-resilience spectrum. https://doi.org/10.64898/2026.08.20.746004

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