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bioRxiv · 10.64898/2026.08.26.747247

Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states

Garcia-Diaz Barriga, G.·Rosebrock, D.·Renner, H.·Meyer, I.·Penalosa-Ruiz, G.·Firulyova, M. M.·Simon, M.·Yang, T.·Serratto, G. M.·Zoppetti, F.·Müller, W.·Illarionova, A.·Heise, K.·Kuhn, R.·von der Kammer, H.·Zimmer, B.·Gruber-Schoffnegger, D.
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Abstract

Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.

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Garcia-Diaz Barriga, G., Rosebrock, D., Renner, H., Meyer, I., Penalosa-Ruiz, G., Firulyova, M. M., Simon, M., Yang, T., Serratto, G. M., Zoppetti, F., Müller, W., Illarionova, A., Heise, K., Kuhn, R., von der Kammer, H., Zimmer, B., Gruber-Schoffnegger, D.. 2026-09-01. Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states. https://doi.org/10.64898/2026.08.26.747247

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