A loss of smell can be one of the earliest warning signs of Alzheimer’s disease, but the reasons behind this sensory change have been unclear. Now, a study reveals that the problem may not lie in the nose or olfactory bulb itself, as previously thought.
Researchers At Germany's DZNE and Ludwig-Maximilians-Universität München (LMU) set out to investigate just why olfactory deficits (the loss of smell) often appear early in Alzheimer's disease (AD), long before memory loss or other symptoms. They focused on the locus coeruleus (LC), a lesser studied region of the brain.
"The locus coeruleus regulates a variety of physiological mechanisms," explained Dr. Lars Paeger, a scientist at DZNE and LMU. "These include, for example, cerebral blood flow, sleep-wake cycles, and sensory processing. The latter applies, in particular, also to the sense of smell."
Using a mouse model that mirrored early signs of AD-like pathology in the human brain, researchers homed in on the LC – a small region that sends out long projections (axons) to key areas across the brain, including the olfactory bulb, where smells are first processed. These axons don’t carry smell signals themselves; instead they release noradrenaline, a neurotransmitter that plays a key role in sensory tuning, attention and arousal.
The animals' brains had early-onset AD signs like amyloid-beta buildup and neuronal hyperactivity, but had not yet experienced widespread cell death – a hallmark of the disease as it progresses.
Using iDISCO+, a 3D brain-mapping technique, the researchers were able to visualize the LC–olfactory bulb circuit across the brain in great detail. They discovered that, in the mice, LC axons to the olfactory bulb had begun degenerating, even though the LC neurons themselves were still intact.
When they looked at these axons more closely, the researchers found abnormal expression of phosphatidylserine on the outside of the membrane. This then attracted microglia, the brain’s immune cells, which engulfed and removed the axons, disrupting olfactory signaling. Behavioral tests confirmed that the mice that had experienced this axon loss were less adept at detecting and discriminating between smells.
"Presence of phosphatidylserine at the outer site of the cell membrane is known to be an 'eat-me' signal for microglia," Paeger said. "In the olfactory bulb, this is usually associated with a process called synaptic pruning, which serves to remove unnecessary or dysfunctional neuronal connections. 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."
To see if the same mechanism might be happening in humans, the researchers examined post-mortem AD brain tissue. Here, they discovered similar signs of LC axon degeneration and microglial activity in the olfactory bulb region. Then, PET brain scans of individuals with early AD or mild cognitive impairment were examined, and they also revealed early disruptions in the LC–olfactory bulb pathway.
"Our study suggests that in early Alzheimer’s disease, changes occur in the nerve fibers linking the locus coeruleus to the olfactory bulb," Paeger said. "These alterations signal to the microglia that affected fibers are defective or superfluous. Consequently, the microglia break them down."
In addition to uncovering the mystery of this early symptom of neurodegeneration, the study paves the way for smell-based screening tools and preventative therapies that target early immune dysfunction – long before symptoms such as memory loss set in. It also reinforces the importance of understanding the role of the LC.
"Smell issues in Alzheimer's disease and damage to the associated nerves have been discussed for some time," said Joachim Herms, a research group leader at DZNE and LMU. "However, the causes were unclear. 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."
Much of the current treatment for AD relies on catching the disease as early as possible, before it does irreparable neuronal damage. In that sense, this research could be critical for more effective intervention.
"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," said Herms. "This would allow earlier intervention with amyloid-beta antibodies, increasing the probability of a positive response."
The study was published in the journal Nature Communications.
Source: DZNE
