A diminishing smell sensitivity could signal the onset of Alzheimer's disease well before memory difficulties emerge, German scientists have discovered.
The latest findings, by researchers from DZNE and Ludwig-Maximilians-Universität München, help explain why olfactory problems develop during the disease's initial phases, revealing the crucial role of the brain's immune system.
Published in Nature Communications, the study examined both mouse models and human subjects, including brain tissue analysis and PET imaging.
The discoveries suggest that smell deterioration happens when the brain's defensive mechanisms inadvertently damage essential neural pathways responsible for processing scents.
Early intervention significantly improves the likelihood of successful treatment
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The research team discovered that brain immune cells known as microglia eliminate vital connections linking two key regions: the olfactory bulb in the forebrain and the locus coeruleus in the brainstem.
The olfactory bulb processes sensory data from nasal scent receptors, while the locus coeruleus sends lengthy nerve fibres to regulate this processing.
"The locus coeruleus regulates a variety of physiological mechanisms. These include, for example, cerebral blood flow, sleep-wake cycles, and sensory processing," explained Dr Lars Paeger from DZNE and LMU. "The latter applies, in particular, also to the sense of smell."
The study indicates that Alzheimer's-related changes in these connecting nerve fibres prompt microglia to identify them as damaged or redundant, leading to their destruction.
The research team identified specific alterations in the nerve fibre membranes that trigger this destructive process.
They found that phosphatidylserine, a fatty acid typically located inside neuronal membranes, had shifted to the exterior surface.
"Presence of phosphatidylserine at the outer site of the cell membrane is known to be an 'eat-me' signal for microglia," Dr Paeger notes.
This repositioning appears to result from excessive neuronal activity caused by Alzheimer's disease, with affected neurons displaying irregular firing patterns.
The membrane changes essentially mark healthy nerve connections for removal through a process normally used to eliminate unnecessary neural pathways.
Professor Joachim Herms from DZNE and LMU explained that although olfactory problems in Alzheimer's have been recognised previously, the underlying causes remained mysterious until now.
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Smell deterioration may happen when the brain's defensive mechanisms damage neural pathways
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The team's findings highlight an immunological mechanism responsible for these early-stage dysfunctions.
"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," Professor Herms states.
This breakthrough could enable clinicians to administer recently approved amyloid-beta antibody treatments at earlier stages, when they're most effective.
Early intervention significantly improves the likelihood of successful treatment outcomes.