Smell โฃLoss Linked to Early AlzheimerS Disease in New Study
LONDON – A newlyโ published study in Nature Communications identifies early loss of noradrenergic axonsโ in the olfactory bulb as aโข key driver of smell loss – a frequently observed,yet frequently enough underestimated,early symptom of Alzheimer’sโ disease. Researchers pinpointed increased microglial phagocytosis of these axons as the underlying mechanism, perhaps offering new avenues for earlier diagnosis and intervention.The โresearch, led by C.Meyer and colleagues andโค 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 โฃbulbs of these mice at two months of age. RNA sequencing analysis โshowedโ alteredโ geneโ expression in these microglia, โขwith several genes linked โคto synapse and plasticity, and a surprising limited role for phagocytosis-related genes – despite evidence of increased phagocytic activity demonstrated through in vitro โคand in vivo assays.
specifically, researchers observed increased phosphatidylserine (PS) externalisation and MFG-E8 decoration on locus coeruleus (LC) axons within the olfactory bulb, โmarking them for microglial clearance. This PS externalisation was โฃlinked to calcium-dependent hyperactivity in the โคLC neurons. Importantly, chemogenetic activation of LC neurons didโข not rescue olfactory behavior, highlighting the critical role of intact axonal structure.
The study โคdemonstrated that restricted overexpression of APP in the โLC was sufficient toโฃ induce olfactory bulb axon loss and hyposmiaโค (reduced sense of smell),establishing a causal link.Furthermore, increased TSPO signals were observed in the olfactoryโข bulbs of patients with prodromal Alzheimer’s disease, suggestingโข increased microglialโค density.
“The current study โhighlighted that theโ 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 improveโค early Alzheimer’s diagnosis and predictโฃ disease progression.