Recent research indicates that a diminished sense of smell could serve as one of the earliest indicators of Alzheimer’s disease, potentially manifesting even before cognitive impairments become evident. This finding underscores the importance of identifying early signs to slow the progression of the disease, as previous studies have also pointed to changes in speech and gut bacteria as potential markers.
The study, published in Nature Communications, explores the neural mechanisms underlying this olfactory deficit. Researchers conducted a comprehensive analysis using positron emission tomography (PET) scans and brain tissue samples from both mice and humans. The results suggest that the immune response in the brain significantly contributes to the loss of smell associated with Alzheimer’s, leading to the degradation of neuronal fibers essential for odor perception.
According to Lars Paeger, a neurobiologist from the German Center for Neurodegenerative Diseases (DZNE) and Ludwig Maximilian University of Munich (LMU), specialized immune cells in the brain, known as microglia, are responsible for severing connections between the olfactory bulb and the locus coeruleus. The olfactory bulb is a structure in the forebrain that processes signals from scent receptors, while the locus coeruleus, located in the brainstem, influences the olfactory bulb and other areas of the brain through long nerve fibers.
“The locus coeruleus regulates a variety of physiological mechanisms,” Paeger explains. “These include cerebral blood flow, sleep-wake cycles, and sensory processing, particularly the sense of smell.”
The study reveals that early changes occur along the nerve fibers linking the locus coeruleus to the olfactory bulb in Alzheimer’s patients. Paeger notes, “These alterations signal to the microglia that affected fibers are defective or superfluous. Consequently, the microglia break them down.” This breakdown is linked to changes in neuronal membranes, specifically the movement of a fatty acid called phosphatidylserine from the inside to the outer layer of the membrane.
“The presence of phosphatidylserine at the outer site of the cell membrane is known to be an ‘eat-me’ signal for microglia,” Paeger says. This process, typically associated with synaptic pruning, aims to eliminate unnecessary or malfunctioning neuronal connections.
The repositioning of this fatty acid may indicate that Alzheimer’s disease alters nerve cell behavior, leading to abnormal firing patterns. “We assume the shift in membrane composition is triggered by hyperactivity of the affected neurons due to Alzheimer’s disease,” Paeger adds.
The research employed a multipronged approach, studying both live and deceased mice with Alzheimer’s characteristics, as well as post-mortem brain tissue from human patients. Joachim Herms, a neuroscientist from DZNE and LMU, stated, “Smell issues in Alzheimer’s disease and damage to the associated nerves have been discussed for some time. However, the causes were unclear. Our findings point to an immunological mechanism as the cause for such dysfunctions, especially arising in the early stages of Alzheimer’s disease.”
Understanding the loss of smell may provide essential insights for early diagnosis, enabling timely intervention. Herms emphasizes, “Our findings could pave the way for the early identification of patients at risk of developing Alzheimer’s, allowing them to undergo comprehensive testing to confirm the diagnosis before cognitive problems arise.”
Such early intervention could facilitate treatment with therapies, including amyloid-beta antibodies, potentially increasing the chances of a positive response. The implications of this research are significant, as they highlight the critical role of early detection in managing Alzheimer’s disease and improving patient outcomes.
