A decreased sense of smell may be one of the earliest warning signs of Alzheimer’s disease, appearing before significant memory loss. A new study by scientists from DZNE and Ludwig Maximilians University Munich (LMU) provides new insights into why this happens. The study points to an important role for the brain’s immune system, showing that it can mistakenly attack nerve fibers essential for odor detection. Published in nature communicationsthe study combines evidence from mice and humans, including brain tissue analysis and so-called PET scans. These findings could help improve early detection and open the door to early treatment.
Researchers say odor-related problems occur when immune cells in the brain known as microglia begin to remove connections between two important areas: 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, located in the brainstem, helps regulate this process through long nerve fibers that extend to the olfactory bulb.
“The locus coeruleus controls a variety of physiological mechanisms, including, for example, cerebral blood flow, the sleep-wake cycle, and sensory processing. The latter is especially true for the sense of smell,” says Dr. Lars Pager, scientist at DZNE and LMU. “Our research suggests that early in Alzheimer’s disease, changes occur in the nerve fibers that connect the locus coeruleus and the olfactory bulb. These changes signal the microglia that the affected fibers are defective or redundant. As a result, the microglia degrade the nerve fibers.”
membrane changes
A team led by Dr Lars Pager and co-author Professor Jochen Helms identified specific changes in the membranes of these nerve fibers. They found that phosphatidylserine, a fatty molecule normally located inside neuron membranes, was moved to the outer surface.
“The presence of phosphatidylserine at lateral sites 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 believe that changes in membrane composition are caused by hyperactivity of neurons affected by Alzheimer’s disease, meaning that these neurons exhibit abnormal firing.”
Evidence from animal models, human tissue, and brain scans
This conclusion is supported by multiple lines of evidence. The researchers studied mice that exhibited Alzheimer’s disease-like features, examined brain tissue from deceased patients, and analyzed positron emission tomography (PET) scans of individuals with Alzheimer’s disease or mild cognitive impairment.
“The problem of smell in Alzheimer’s disease and the associated damage to the nerves has been discussed for some time, but its causes have been unknown until now. Our findings now point to an immunological mechanism as the cause of such dysfunction. In particular, they show that such events occur already in the early stages of Alzheimer’s disease,” says Joachim Helms, research group leader at DZNE and LMU and member of the Munich-based research group. “SyNergy” Cluster of Excellence.
Impact on early diagnosis and treatment
So-called amyloid beta antibodies have recently become available for the treatment of Alzheimer’s disease. For these treatments to work effectively, treatment must occur early in the disease process. This is where new discoveries can make a difference.
“Our findings could pave the way for early identification of patients at risk of developing Alzheimer’s disease, allowing them to undergo comprehensive testing to confirm the diagnosis before cognitive problems occur. This allows for early intervention with amyloid-beta antibodies, increasing the likelihood of a positive response,” Harms says.
