Researchers Uncover “Eat-Me” Signal That Triggers Alzheimer’s First Symptom

Immune-driven nerve fiber damage may underlie early smell loss in Alzheimer’s, offering a new path for early diagnosis.

A diminishing sense of smell can appear as one of the earliest indicators of Alzheimer’s disease, often emerging before noticeable cognitive decline. Researchers from DZNE and Ludwig-Maximilians-Universität München (LMU) have uncovered new insights into this process, identifying a major role for the brain’s immune response.

Their findings suggest that immune activity mistakenly targets and destroys nerve fibers essential for odor perception. The study, reported in Nature Communications, draws on data from both mice and humans, including brain tissue analyses and PET imaging. This knowledge could support strategies for earlier diagnosis and intervention.

The team concluded that these smell-related impairments arise when microglia, the brain’s resident immune cells, strip away connections between two key regions: the olfactory bulb and the locus coeruleus. The olfactory bulb, situated in the forebrain, processes signals from the nose’s scent receptors. The locus coeruleus, part of the brainstem, influences this processing through long nerve fibers that extend into the olfactory bulb.

“The locus coeruleus regulates a variety of physiological mechanisms. These include, for example, cerebral blood flow, sleep-wake cycles, and sensory processing. The latter applies, in particular, also to the sense of smell,” explains Dr. Lars Paeger of DZNE and LMU.

“Our study suggests that in early Alzheimer’s disease, changes occur in the nerve fibers linking the locus coeruleus to the olfactory bulb. These alterations signal to the microglia that affected fibers are defective or superfluous. Consequently, the microglia break them down.”

Alterations in the membrane

Dr. Lars Paeger and Prof. Dr. Jochen Herms, a co-author of the study, found clear evidence of altered membrane composition in the affected nerve fibers. They observed that phosphatidylserine, a fatty acid normally located on the inner side of a neuron’s membrane, had shifted to the outer surface.

“Presence of phosphatidylserine at the outer site of the cell membrane is known to be an ‘eat-me’ signal for microglia. In the olfactory bulb, this is usually associated with a process called synaptic pruning, which serves to remove unnecessary or dysfunctional neuronal connections,” Paeger explains.

“In our situation, we assume that the shift in membrane composition is triggered by hyperactivity of the affected neurons due to Alzheimer’s disease. That is, these neurons exhibit abnormal firing.”

A wide range of data

The findings of Paeger and colleagues are based on a plethora of observations. These include studies on mice with features of Alzheimer’s disease, analysis of brain samples from deceased Alzheimer’s patients, and positron emission tomography (PET) scans of the brains of individuals with Alzheimer’s or mild cognitive impairment.

“Smell issues in Alzheimer’s disease and damage to the associated nerves have been discussed for some time. However, the causes were unclear until now. Now, our findings point to an immunological mechanism as cause for such dysfunctions – and, in particular, that such events already arise in the early stages of Alzheimer’s disease,” says Joachim Herms, a research group leader at DZNE and LMU as well as a member of the Munich-based “SyNergy” Cluster of Excellence.

Perspectives for early diagnosis

So-called amyloid-beta antibodies have recently become available for the treatment of Alzheimer’s. For this novel therapy to be effective, it needs to be applied at an early stage of the disease, and this is precisely where the current research could be significant.

“Our findings could pave the way for the early identification of patients at risk of developing Alzheimer’s, enabling them to undergo comprehensive testing to confirm the diagnosis before cognitive problems arise. This would allow earlier intervention with amyloid-beta antibodies, increasing the probability of a positive response,” says Herms.

Reference: “Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease” by Carolin Meyer, Theresa Niedermeier, Paul L. C. Feyen, Felix L. Strübing, Boris-Stephan Rauchmann, Katerina Karali, Johanna Gentz, Yannik E. Tillmann, Nicolas F. Landgraf, Svenja-Lotta Rumpf, Katharina Ochs, Karin Wind-Mark, Gloria Biechele, Jessica Wagner, Selim Guersel, Carolin I. Kurz, Meike Schweiger, Danilo Prtvar, Yuan Shi, Richard B. Banati, Guo-Jun Liu, Ryan J. Middleton, Gerda Mitteregger-Kretzschmar, Robert Perneczky, Thomas Koeglsperger, Jonas J. Neher, Sabina Tahirovic, Matthias Brendel, Jochen Herms and Lars Paeger, 8 August 2025, Nature Communications.
DOI: 10.1038/s41467-025-62500-8

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