Olfactory Dysfunction in Neurodegenerative Diseases

Olfactory dysfunction, often manifesting as reduced sensitivity to odours (hyposmia) or complete loss of smell (anosmia), is recognised as an early and pervasive non-motor feature of several neurodegenerative disorders, notably Parkinson’s disease and Alzheimer’s disease. In these proteinopathies, misfolded aggregates of α-synuclein or tau and amyloid-β accumulate in olfactory pathways, from the peripheral epithelium through the olfactory bulb to central olfactory cortices. Emerging evidence indicates that such pathology may propagate in a prion-like fashion, seeding adjacent regions and disrupting synaptic function. At the cellular level, alterations in neurotransmitter balance—particularly dopaminergic and GABAergic signalling in the olfactory bulb—contribute to circuit hyperactivity and impaired odour discrimination. Clinically, olfactory testing has shown promise both as a prodromal biomarker for risk stratification and as a tool to differentiate among parkinsonian syndromes. Understanding the mechanisms by which olfactory circuits become dysfunctional not only illuminates early disease processes but also opens avenues for intervention, with therapeutic modulation of local inhibitory networks emerging as a potential strategy. Across diverse populations and experimental models, olfactory deficits bear strong correlations with severity of nigrostriatal degeneration, cognitive decline, and broader network dysfunction, underlining their global significance and utility in both research and clinical practice.

Research from Nature Portfolio

A foundational study employing selective depletion of dopaminergic neurons in the substantia nigra revealed that olfactory deficits precede detectable motor impairment. In a murine model, partial loss of nigral dopamine cells induced pronounced hyposmia and odour discrimination deficits within one week, despite preserved gross motor function. Electrophysiological recordings from the olfactory bulb demonstrated heightened baseline oscillatory power across multiple frequency bands, coupled with attenuated odour-evoked beta-band excitation and high-gamma inhibition. Calcium imaging further showed exaggerated mitral cell responses to odours, implicating hyperactivity of principal output neurons in early sensory dysfunction. These findings underscore a functional link between midbrain dopaminergic degeneration and downstream olfactory circuit disruption, positioning abnormal mitral cell excitability as a key mediator of prodromal olfactory loss.

Olfactory Dysfunction in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in olfactory dysfunction in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Hyposmia: Reduced ability to detect or identify odours.

Olfactory bulb: The first central relay station for olfactory sensory neurons, containing mitral and tufted cells that transmit odour information.

Mitral cells: Principal excitatory neurons in the olfactory bulb that receive input from sensory neurons and project to olfactory cortices.

Dopaminergic neurons: Neurons that release dopamine, notably in the substantia nigra, whose loss underlies motor and non-motor Parkinsonian features.

GABAergic transmission: Inhibitory synaptic signalling mediated by gamma-aminobutyric acid, critical for balancing excitation in olfactory circuits.

Local field potential (LFP): The summed electrical activity of neuronal populations measured as oscillations, indicating circuit-level synchrony and processing.

References

1. The human olfactory system in two proteinopathies: Alzheimer’s and Parkinson’s diseases. Translational Neurodegeneration (2020).
2. Partial depletion of dopaminergic neurons in the substantia nigra impairs olfaction and alters neural activity in the olfactory bulb. Scientific Reports (2019).
3. Dopaminergic neurodegeneration in the substantia nigra is associated with olfactory dysfunction in mice models of Parkinson’s disease. Cell Death Discovery (2023).
4. Amelioration of olfactory dysfunction in a mouse model of Parkinson’s disease via enhancing GABAergic signaling. Cell & Bioscience (2023).