Smell Loss Linked to Early AlzheimerS Disease in New Study
LONDON – A newly published study in Nature Communications identifies early loss of noradrenergic axons in the olfactory bulb as a key driver of smell loss – a frequently observed,yet frequently enough underestimated,early symptom of Alzheimer’s disease. Researchers pinpointed increased microglial phagocytosis of these axons as the underlying mechanism, perhaps offering new avenues for earlier diagnosis and intervention.The research, led by C.Meyer and colleagues and published today, https://doi.org/10.1038/s41467-025-62500-8, utilized the AppNL-G-F mouse model of Alzheimer’s disease. Findings revealed increased numbers of microglia cells in the olfactory bulbs of these mice at two months of age. RNA sequencing analysis showed altered gene expression in these microglia, with several genes linked to synapse and plasticity, and a surprising limited role for phagocytosis-related genes – despite evidence of increased phagocytic activity demonstrated through in vitro and in vivo assays.
specifically, researchers observed increased phosphatidylserine (PS) externalisation and MFG-E8 decoration on locus coeruleus (LC) axons within the olfactory bulb, marking them for microglial clearance. This PS externalisation was linked to calcium-dependent hyperactivity in the LC neurons. Importantly, chemogenetic activation of LC neurons did not rescue olfactory behavior, highlighting the critical role of intact axonal structure.
The study demonstrated that restricted overexpression of APP in the LC was sufficient to induce olfactory bulb axon loss and hyposmia (reduced sense of smell),establishing a causal link.Furthermore, increased TSPO signals were observed in the olfactory bulbs of patients with prodromal Alzheimer’s disease, suggesting increased microglial density.
“The current study highlighted that the underlying mechanism for hyposmia could be an underestimated sensory deficit in AD,” the authors conclude. They propose that combining olfactory testing with cerebrospinal fluid and blood biomarkers could improve early Alzheimer’s diagnosis and predict disease progression.