Noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease

Alzheimer’s disease (AD) is often accompanied by early non-cognitive symptoms, including olfactory deficits, such as hyposmia and anosmia ¹ . These have emerged as solid predictors of cognitive decline, but the underlying mechanisms of hyposmia in early AD remain elusive ² . Pathologically, one of the brain regions affected earliest is the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) and, a well-known neuromodulator of olfactory information processing ³ . Here we show that early and distinct loss of noradrenergic input to the olfactory bulb (OB) coincides with impaired olfaction in a mouse model of AD, even before pronounced appearance of extracellular amyloid plaques. Mechanistically, OB microglia detect externalized phosphatidylserine and MFG-E8 on hyperactive LC axons and subsequently initiate their clearance. Translocator protein 18 kDa (TSPO) knockout reduces phagocytosis, preserving LC axons and olfaction. Importantly, patients with prodromal AD display elevated TSPO-PET signals in the OB, similarly to APP ^NL-G-F mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Collectively, we uncover an underlying mechanism linking early LC system damage and hyposmia in AD. Our work may help to improve early diagnosis of AD by olfactory testing and neurocircuit analysis and consequently enable early intervention.