Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease
Alzheimer's disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before appearance of amyloid plaques. Mechanistically, OB microglia recognize and phagocytose LC axons. Reducing phagocytosis genetically preserves LC axons and olfaction. Prodromal AD patients display elevated TSPO-PET signals in the OB, similarly to App<sup>NL-G-F</sup> mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Our findings reveal a mechanism linking early LC damage to hyposmia in AD, suggesting olfactory testing and neurocircuit imaging for early diagnosis and enable timely therapeutic intervention for Alzheimer's disease.
Authors
- Lars Paeger (ORCID: https://orcid.org/0000-0001-8716-3483)
- Guo Jun Liu (ORCID: https://orcid.org/0000-0002-4278-8372)
- Robert Perneczky (ORCID: https://orcid.org/0000-0003-1981-7435)
- Gerda Mitteregger-Kretzschmar
- Richard B. Banati (ORCID: https://orcid.org/0000-0003-3558-597X)
- Selim Guersel
- Boris‐Stephan Rauchmann (ORCID: https://orcid.org/0000-0003-4547-6240)
- Jonas J. Neher (ORCID: https://orcid.org/0000-0003-1346-8924)
- Jessica Wagner (ORCID: https://orcid.org/0000-0003-2587-3310)
- Katharina Ochs
- Ryan J. Middleton (ORCID: https://orcid.org/0000-0001-8024-7772)
- Gloria Biechele (ORCID: https://orcid.org/0009-0008-5161-9571)
- Matthias Brendel (ORCID: https://orcid.org/0000-0002-9247-2843)
- Sabina Tahirović (ORCID: https://orcid.org/0000-0003-4403-9559)
- Paul Feyen
- Felix L. Struebing (ORCID: https://orcid.org/0000-0002-9436-6294)
- Yuan Shi (ORCID: https://orcid.org/0000-0001-6135-1830)
- Karin Wind-Mark (ORCID: https://orcid.org/0000-0002-5461-1873)
- Katerina Karali
- Carolin Meyer (ORCID: https://orcid.org/0000-0002-1498-4827)
- Carolin Kurz (ORCID: https://orcid.org/0000-0003-4299-6240)
- Jochen Herms (ORCID: https://orcid.org/0000-0002-6201-1042)
- Thomas Koeglsperger (ORCID: https://orcid.org/0000-0001-6101-0323)
- S Rumpf (ORCID: https://orcid.org/0000-0003-0301-2579)
- Nicolas Landgraf
- Danilo Prtvar (ORCID: https://orcid.org/0009-0004-8251-1441)
- Johanna Gentz
- Yannik Tillmann
- Meike Schweiger
- Theresa Niedermeier
Institutions
- The University of Sydney (AU)
- Australian Nuclear Science and Technology Organisation (AU)
- German Center for Neurodegenerative Diseases (DE)
- LMU Klinikum (DE)
- Munich Cluster for Systems Neurology (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Imperial College London (GB)
- Ludwig-Maximilians-Universität München (DE)
- University of Sheffield (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-08
- DOI
- https://doi.org/10.1038/s41467-025-62500-8
- Citations
- 10
- Primary Topic
- Olfactory and Sensory Function Studies
- Type
- article
- Field-Weighted Citation Impact
- 14.65