Summary: A decline in the sense of smell can be one of the earliest indicators of Alzheimer’s disease. New research explains how immune cells in the brain mistakenly remove nerve fibers that connect the locus coeruleus and the olfactory bulb—two regions essential for detecting and processing odors.
This immune-driven pruning is triggered when hyperactive neurons display altered membrane signals, marking otherwise intact fibers for removal. By uncovering this mechanism, the study points to a pathway that could enable earlier diagnosis and intervention, potentially before memory and other cognitive symptoms appear.
Key Facts
- Immune error: Microglia, the brain’s immune cells, remove noradrenergic axons linking the locus coeruleus and olfactory bulb.
- Early warning: These changes happen before cognitive decline, making smell loss a promising early diagnostic signal.
- Treatment window: Detecting these changes early could allow timely use of amyloid-beta antibody therapies.
Source: DZNE
A reduced sense of smell can precede cognitive symptoms in Alzheimer’s disease. Researchers at the German Center for Neurodegenerative Diseases (DZNE) and Ludwig-Maximilians-Universität München (LMU) report that a misdirected immune response contributes to this olfactory decline by eliminating nerve fibers that carry modulatory signals to the olfactory bulb.
Published in Nature Communications, the study combines experiments in mouse models with analyses of human brain tissue and PET imaging. The results suggest a biological basis for early smell impairment and offer potential markers for earlier detection and treatment of Alzheimer’s disease.
The team found that microglia target the long noradrenergic axons that extend from neurons in the locus coeruleus—an area in the brainstem involved in arousal, attention, and sensory processing—and project to the olfactory bulb, which interprets scent information received from the nose.
“The locus coeruleus influences many physiological processes, including cerebral blood flow, sleep-wake cycles, and sensory perception—most relevant here, the sense of smell,” explains Dr. Lars Paeger of DZNE and LMU.
“Our data indicate that, early in Alzheimer’s disease, axons linking the locus coeruleus to the olfactory bulb undergo changes that cause microglia to treat them as defective. The immune cells then remove these fibers, degrading olfactory function.”
Changes in the neuronal membrane
The researchers identified a specific alteration in axonal membranes: phosphatidylserine, a lipid normally confined to the inner leaflet of the cell membrane, becomes exposed on the outside. Externalized phosphatidylserine is a well-known “eat-me” signal for microglia and is commonly involved in synaptic pruning—the removal of redundant or damaged neuronal connections.
“We believe this membrane shift is caused by hyperactivity of the affected neurons in the context of Alzheimer’s disease,” says Paeger. “These neurons show abnormal firing patterns that likely trigger the externalization of phosphatidylserine and subsequent microglial phagocytosis.”
Evidence from multiple approaches
The study integrates diverse lines of evidence: experiments in Alzheimer’s mouse models, post-mortem analyses of human olfactory bulb tissue, and TSPO-PET imaging that detects microglial activation in living patients with mild cognitive impairment or early Alzheimer’s disease. Across these approaches, the researchers observed early loss of locus coeruleus axons in the olfactory bulb alongside olfactory impairment.
“Olfactory deficits and related nerve damage in Alzheimer’s have been noted before, but their cause remained unclear,” says Prof. Dr. Jochen Herms, co-author and research group leader at DZNE and LMU. “Our findings implicate an immunological mechanism acting at an early stage of the disease.”
Implications for early diagnosis and treatment
New amyloid-beta antibody therapies for Alzheimer’s are most effective when applied early in the disease process. Detecting olfactory circuit damage before cognitive symptoms appear could identify patients who would benefit from early intervention.
“These results open a path toward earlier identification of individuals at risk for Alzheimer’s,” Herms notes. “Combined olfactory testing and neurocircuit imaging could flag candidates for confirmatory testing and timely therapeutic intervention, increasing the chances of treatment success.”
About this olfaction and Alzheimer’s disease research news
Author: Marcus Neitzert
Source: DZNE
Contact: Marcus Neitzert – DZNE
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease” by Lars Paeger et al. Nature Communications
Abstract
Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease
Alzheimer’s disease often begins with non-cognitive symptoms such as reduced smell, which can predict later cognitive decline. The locus coeruleus (LC), the brainstem source of noradrenaline that modulates olfactory processing, is affected early in the disease.
The study demonstrates an early and specific loss of noradrenergic input to the olfactory bulb that coincides with impaired olfaction in an Alzheimer’s mouse model, occurring before the appearance of amyloid plaques.
Mechanistically, olfactory bulb microglia recognize and phagocytose LC axons. Genetically reducing microglial phagocytosis preserves LC axons and maintains olfactory function in experimental models.
Prodromal Alzheimer’s patients show elevated TSPO-PET signals in the olfactory bulb, mirroring findings in AppNL-G-F mice. Post-mortem analysis of olfactory bulbs from early Alzheimer’s patients confirms early LC axon degeneration.
These results link early LC damage to decreased smell in Alzheimer’s disease and support the use of olfactory testing and neurocircuit imaging for earlier diagnosis and timely therapeutic intervention.