Summary: A loss of the sense of smell can be one of the first warning signs of Alzheimer’s disease, and new research suggests why. Scientists have discovered that microglia, the brain’s immune cells, mistakenly delete nerve fibers that connect the locus coeruleus and the olfactory bulb, two areas important for processing smell.
This immune-mediated pruning occurs when hyperactive neurons have altered membranes, marking them as defective even when they are not. By identifying this mechanism, the study opens an avenue that could allow for earlier diagnosis and treatment before cognitive symptoms appear.
Key data
- Immune system dysfunction: Microglia destroy nerve fibers that connect the locus coeruleus and the olfactory bulb.
- Early signal: These changes precede cognitive decline, making loss of smell a potential diagnostic tool.
- Treatment window: Results may allow earlier use of beta-amyloid antibody treatment.
Source: DZNE
A reduced sense of smell can be one of the first signs of Alzheimer’s disease, even before cognitive impairment sets in. A study by scientists from the German Center for Neurodegenerative Diseases (DZNE) and the Ludwig Maximilian University of Munich (LMU) sheds new light on this phenomenon and highlights the important role of the brain’s immune response, which apparently fatally attacks nerve fibers essential for olfactory perception.
The research, published in the journal Nature Communications, is based on observations in mice and humans, including brain tissue analyses and positron emission tomography (PET) scans. The findings could contribute to early diagnosis and therefore treatment.
The researchers concluded that these olfactory disorders arise when so-called microglial cells in the brain suppress connections between two regions of the brain, the olfactory bulb and the locus coeruleus.
The olfactory bulb, located in the forebrain, processes sensory information received from olfactory receptors in the nose. The locus coeruleus, a region of the brainstem, influences this process through long nerve fibers that emerge from neurons in the locus coeruleus and extend to the olfactory bulb.
“The locus coeruleus regulates various physiological mechanisms. These include, for example, cerebral blood flow, sleep-wake rhythms, and sensory processing. Dr. Lars Pager, a researcher at DZNE and LMU, points out that the sense of smell plays a critical role in understanding Alzheimer’s disease. His study demonstrates that, during the early stages of Alzheimer’s disease, changes occur in the nerve fibers that connect the locus coeruleus to the olfactory bulb, emphasizing a pivotal breakdown in neural processes as the condition initially emerges. These changes trigger a response from microglia, the brain’s immune cells, which recognize the damaged fibers.
As a result, the microglia begin to clear away the dysfunctional fibers, initiating a process of degradation. This early disruption in the communication between these brain regions is a key indicator of Alzheimer’s progression, as the brain’s immune system works to address the damage.
Membrane replacement
In particular, the team led by Dr. Lars Pegger, co-author of the current publication, and Prof. Dr. Jochen Herms found evidence of changes in the membrane structure of affected nerve fibers: Phosphatidylserine, a fatty acid normally found inside the nerve cell membrane, was pushed out.
“The presence of phosphatidylserine outside the cell membrane is known to be an alert signal for microglia. In the olfactory bulb, this phenomenon is usually associated with a process called synaptic pruning, which involves the removal of unnecessary or dysfunctional neuronal connections,” explains Paeger.
Our hypothesis posits that the structural alterations in the neuronal membrane are a consequence of hyperactivity in Alzheimer’s-affected neurons, which points to a state of pathological neural dysfunction.
A wide range of data
Pager and his team’s findings are grounded in a diverse set of observations, including studies on mice exhibiting Alzheimer’s-like symptoms, analysis of brain tissue from deceased Alzheimer’s patients, and PET scans of living individuals’ brains.
Olfactory dysfunction and damage to the associated nerves in Alzheimer’s have been a subject of ongoing research, but the exact causes behind these issues remain poorly understood, despite being widely discussed in the scientific community.
“Our results now point to an immunological mechanism as the cause of such impairments – and in particular, that such events already occur in the early stages of Alzheimer’s disease,” explains Joachim Herms, head of the research group at DZNE and LMU and member of the Munich Cluster of Excellence “SyNergy”.
Possibilities of early diagnosis
Recently, so-called beta-amyloid antibodies have become available for the treatment of Alzheimer’s disease. For this new therapy to be effective, it must be used in the early stages of the disease. This is where the results of the current research could prove important.
“Our discoveries might open the door to identifying individuals at risk of Alzheimer’s disease at an earlier stage.” They could then benefit from comprehensive testing to confirm the diagnosis before the onset of cognitive impairment. This would allow earlier intervention with anti-beta amyloid antibodies and increase the chances of a positive response,” explains Hormuz.
Abstract
Alzheimer’s disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which may predict later cognitive decline, but the mechanism remains unclear.
Pathologically, the brainstem’s locus coeruleus (LC), the primary source of the neurotransmitter noradrenaline (NA), which modulates the processing of olfactory information, is affected early.
Here, we demonstrate an early and significant loss of noradrenergic input to the olfactory bulb (OB) in an AD mouse model, prior to the appearance of amyloid plaques.
Mechanistically, frontal lobe microglia recognize phagocytic lymphoid cell axons. By reducing phagocytosis, lymphoid cell axons and the sense of smell are genetically preserved.
Patients in the prodromal stage of Alzheimer’s show elevated TSPO-PET signals in the frontal lobe, which mirrors the pattern observed in AppNL-GF mice. We also confirm early LC axon degeneration in the postmortem border lobes of early Alzheimer’s disease patients.
This study elucidates the pathological mechanisms that link initial lesions in the locus coeruleus (LC) to the development of olfactory deficits (hyposmia) in Alzheimer’s disease.This suggests that olfactory testing and neural circuit imaging are essential for early diagnosis and rapid therapeutic intervention in Alzheimer’s disease.
