Study Reveals How Smell Loss May Be An Early Sign of Alzheimer’s

A reduced sense of smell can be an early indicator of Alzheimer’s, often appearing before noticeable cognitive deficits. Scientists at DZNE and Ludwig-Maximilians-Universität München (LMU) have conducted research that provides new insight into this phenomenon. They found that the immune response in the brain plays a critical role in this occurrence, since it appears to attack neuronal fibers essential for odor perception.

A loss of smell can be one of the first indicators of Alzheimer’s disease, although the causes of this sensory shift have remained unknown. According to a recent study, the issue might not be with the nose or the olfactory bulb itself as was previously believed. 

Researchers from Ludwig-Maximilians-Universität München (LMU) and Germany’s DZNE have shown why olfactory impairments, or the loss of smell, frequently appear early in Alzheimer’s disease, often before memory loss or other symptoms. They concentrated on a part of the brain that has received less attention: the locus coeruleus. 

The forebrain contains the olfactory bulb, which processes sensory data from the scent receptors of the nose. The locus coeruleus, a brainstem area, influences this processing via lengthy nerve fibers that originate in neurons in the locus coeruleus and stretch all the way to the olfactory bulb. 

According to Dr. Lars Paeger, a scientist at DZNE and LMU, the locus coeruleus regulates a number of physiological functions. These include, for instance, sleep-wake cycles, cerebral blood flow, and sensory processing. In particular, the latter also applies to the sense of smell. 

Researchers conclude that these olfactory dysfunctions occur because “microglia,” which are immune cells in the brain, break down connections between the locus coeruleus and the olfactory bulb.

According to Paeger, their research revealed that the nerve fibers connecting the locus coeruleus to the olfactory bulb may change in the early stages of Alzheimer’s. These changes indicate to the microglia that the damaged fibers are faulty or unnecessary. As a result, the microglia degrade them.

The findings, published in the journal Nature Communications, are based on observations made in mice and humans, including brain tissue analysis and so-called PET scanning [1]. This research could help in creating methods for early diagnosis and treatment.

Changes in the Membrane

The researchers discovered changes in the membrane composition of the impacted nerve fibers. A fatty acid that normally occurs inside a neuron’s membrane, phosphatidylserine, was found to have been moved to the outside of the affected nerve fibers, according to the team led by Dr. Lars Paeger and Prof. Dr. Jochen Herms, a co-author of the current publication. 

According to Paeger, the presence of phosphatidylserine at the outside of the cell membrane serves as a “eat-me” signal for microglia. This is typically linked to a procedure in the olfactory bulb known as synaptic pruning, which eliminates superfluous or dysfunctional neuronal connections. 

Paeger further explained, “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” [2].

A Broad Range of Data

The conclusions of Paeger and colleagues are based on a wide range of observations. These include positron emission tomography (PET) scans of the brains of people with Alzheimer’s or mild cognitive impairment, research on mice that exhibit symptoms of the disease, and examination of brain samples from Alzheimer’s patients who have passed away. 

Joachim Herms, a member of the Munich-based “SyNergy” Cluster of Excellence and a research group leader at DZNE and LMU, states that issues with smell in Alzheimer’s and damage to the associated nerves have been a topic of discussion for some time. The causes, however, were not yet known. 

Their research now suggests that immunological mechanisms are the source of these dysfunctions and that they occur early in Alzheimer’s disease. 

Prospects for Early Diagnosis

The treatment of Alzheimer’s disease now includes so-called amyloid-beta antibodies. This new treatment must be used early in the course of the illness to be effective, and this is where the current study may be helpful. 

Herms said their research may pave the way for the early detection of Alzheimer’s patients, allowing them to have thorough testing to confirm the diagnosis before cognitive issues occur. It would enable early treatment with amyloid-beta antibodies, increasing the likelihood of a favorable outcome. 

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References

1. Meyer, C., Niedermeier, T., Feyen, P.L., Strübing, F.L., Rauchmann, B.S., Karali, K., Gentz, J., Tillmann, Y.E., Landgraf, N.F., Rumpf, S.L. and Ochs, K., 2025. Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease. Nature Communications, 16(1), p.7338.
2. Insights into Smelling Problems Associated with Alzheimer’s. DZNE. Press Release. https://www.dzne.de/en/news/press-releases/press/insights-into-smelling-problems-associated-with-alzheimers/. Published Online: 15th August, 2025. Accessed: 27th October, 2025.
3. Immune Attack on Smell Pathways May Signal Early Alzheimer’s. Neuroscience news.com. https://neurosciencenews.com/microglia-olfaction-alzheimers-29580/. Published Online: 17th August, 2025. Accessed: 27th October, 2025.
4. Your nose could detect Alzheimer’s years before memory loss. Science Daily. https://www.sciencedaily.com/releases/2025/09/250901104643.htm. Published Online: 1st September, 2025. Accessed: 27th October, 2025.
5. Thompson, B. Scientists uncover how Alzheimer’s steals your sense of smell. New Atlas. https://newatlas.com/brain/alzheimers-dementia/smell-loss-early-alzheimers-disease/. Published Online: 18th August, 2025. Accessed: 27th October, 2025.