Fading Sense of Smell May Signal Alzheimer’s Years Before Memory Loss
A weakening sense of smell could be one of the earliest warning signs of Alzheimer’s disease, emerging well before noticeable memory problems. Researchers from the German Center for Neurodegenerative Diseases (DZNE) and Ludwig Maximilian University of Munich (LMU) report new evidence suggesting that the brain’s immune system may be involved, mistakenly breaking down nerve fibers needed for normal odor perception. The findings, published in Nature Communications, draw on data from mouse studies, analyses of human brain tissue, and brain imaging.
The team focused on connections between two regions central to smell processing: the olfactory bulb and the locus coeruleus. The olfactory bulb, located in the forebrain, receives and processes signals originating from odor receptors in the nose. The locus coeruleus, located in the brainstem, helps regulate sensory processing through long nerve fibers that extend to the olfactory bulb.
According to the researchers, problems may begin when microglia—immune cells that act as the brain’s cleanup system—start removing these long nerve fibers and their connections. Dr. Lars Paeger of DZNE and LMU explained that early Alzheimer’s-related changes appear to affect the fibers linking the locus coeruleus to the olfactory bulb. These changes may cause microglia to interpret the fibers as damaged or unnecessary and then dismantle them.
The study also identified a specific change in the membrane of the affected nerve fibers. A fatty molecule called phosphatidylserine, which is normally found on the inner side of the neuronal membrane, was observed on the outer surface. This outward shift is widely known as an “eat-me” signal that prompts microglia to remove cellular material.
In the olfactory bulb, microglia commonly help fine-tune neural circuits through synaptic pruning, a normal process that removes weak or dysfunctional connections. In this case, however, the researchers suspect the signal is triggered by abnormal overactivity of neurons affected by Alzheimer’s, leading microglia to eliminate connections that are actually needed for healthy smell processing.
The conclusions are supported by several lines of evidence. The researchers examined mice with Alzheimer’s-like changes, analyzed brain tissue from deceased patients, and evaluated positron emission tomography (PET) scans from people diagnosed with Alzheimer’s or mild cognitive impairment.
Prof. Jochen Herms, a research group leader at DZNE and LMU, noted that smell impairment and damage to smell-related nerves have been discussed for years, but the underlying cause has remained unclear. The new results point to an immune-driven mechanism and suggest that these events may occur early in the course of the disease.
The findings could have implications for earlier diagnosis and treatment. Newer therapies using amyloid-beta antibodies are thought to be most effective when given early, before extensive brain damage occurs. If smell decline can help identify people at increased risk, it could prompt timely follow-up testing and potentially allow treatment to begin before cognitive symptoms become apparent.
