A declining sense of smell may be one of the earliest warning signs of Alzheimer’s disease, appearing even before noticeable memory problems. New research from scientists at DZNE and Ludwig-Maximilians-Universität München (LMU) offers fresh insight into why this happens. The study points to the brain’s immune system as a key player, showing that it may mistakenly attack nerve fibers that are essential for detecting odors. Published in Nature Communications, the research combines evidence from mice and humans, including brain tissue analysis and so-called PET scanning. These findings could help improve early detection and open the door to earlier treatment.
According to the researchers, smell-related problems arise when immune cells in the brain, known as “microglia,” begin removing connections between two important regions: the olfactory bulb and the locus coeruleus. The olfactory bulb, located in the forebrain, processes signals from scent receptors in the nose. The locus coeruleus, found in the brainstem, helps regulate this process through long nerve fibers that extend to the olfactory bulb.
“The locus coeruleus regulates a variety 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,” says Dr. Lars Paeger, a scientist at 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
The team, led by Dr. Lars Paeger and co-author Prof. Dr. Jochen Herms, identified specific changes in the membranes of these nerve fibers. They found that phosphatidylserine, a fatty molecule normally located on the inside 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,” explains Paeger. “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.”
Evidence From Animal Models, Human Tissue, and Brain Scans
The conclusions are supported by multiple lines of evidence. The researchers studied mice that show Alzheimer’s-like features, examined brain tissue from deceased patients, and analyzed positron emission tomography (PET) scans from 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 yet. 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.
Implications for Early Diagnosis and Treatment
So-called amyloid-beta antibodies have recently become available for the treatment of Alzheimer’s. For these therapies to work effectively, they must be given early in the disease process. This is where the new findings could make a difference.
“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.