Alzheimer's disease is a progressive illness, and the earlier it is detected, the more its progression can be slowed. Recently, the diagnosis of this disease has advanced considerably, with, for example, blood tests that facilitate the detection of disease markers. However, other signs that are easier to detect could help tackle the disease early. This is particularly the case with loss of smell, which is common in people with this pathology.
A new study from the Center for Neurodegenerative Diseases in Munich, Germany, has revealed that the brain region that decodes information from the nose is one of the first victims of neurodegeneration. Their study, published on August 8, 2025, in the journal Nature Communications, shows that a loss of smell would allow for the early detection of people at risk of developing the disease, increasing the chances of treatment success.
The first brain region affected by the disease is involved in olfaction
The brain region in question is located in the locus coeruleus, a nucleus located within the brainstem, which connects the brain and spinal cord. This region is the origin of a large number of neurons that connect with the rest of the brain. It is therefore important in several processes, including the processing of sensory information. This region is also one of the first where an accumulation of modified tau proteins, one of the known causes of Alzheimer's disease. It could therefore be that this accumulation damages the neurons that leave this region, affecting the functions in which they are involved, such as smell.
To investigate this hypothesis, the researchers observed the brains of mice modified to develop symptoms similar to those of Alzheimer's disease in humans. Indeed, they were able to observe that the neurons starting from the locus coeruleus and connecting to the olfactory bulb (the region that processes sensory information from the nose) were damaged very early, when the mice were between one and two months old. It was particularly at the level of the axons, that is to say the nerve extensions of the neurons, that this damage was progressively visible: at two months, this affected 14 % of these fibers, 27 % at 3 months, and 33 % at 6 months. While this damage occurred much later in other regions of the brain, and was only visible from 6 months. This neuronal damage had consequences on the mice's sense of smell: while healthy mice were able to find food by following its smell, 60 % of the sick mice had difficulty doing so from the age of three months.
The immune system attacks these neurons very early in the disease
These lesions occurred in parallel with an increase in the number of microglia (immune cells in the brain) in the olfactory bulb. Upon closer examination, the researchers demonstrated that these microglia attack the axons of neurons originating from the locus coeruleus. The targeting of these neurons is due to a protein produced more in the diseased mice: MFG-E8, for milk fat globule-EGF factor 8 protein. This protein is found on the axons, and the microglia recognize them as a warning signal, triggering the attack. Our study suggests that, very early in Alzheimer's disease, there are changes within the nerve fibers that connect the locus coeruleus and the olfactory bulb, summarizes Lars Paeger, author of the study, in a press release. These alterations signal to microglia that these fibers are defective or superfluous. Consequently, the microglia destroy them.
These lesions were also observed in brain tissue from people who had died with Alzheimer's disease. And even in people who were not diagnosed, but who had high levels of modified tau proteins, and who were therefore probably at a very early stage of the disease. This discovery could allow early identification of patients at risk of developing Alzheimer's disease., explains Jochen Herms, co-author of the study. They could then do the necessary diagnostic tests to confirm and thus begin treatment before cognitive problems occur.”
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