The olfactory circuit is a critical neural pathway that processes smell information from the nasal cavity to higher cortical regions. This circuit is particularly relevant to neurodegenerative diseases because it is one of the earliest affected circuits in both Parkinson's disease and Alzheimer's disease[@doty2012].
The olfactory circuit begins in the olfactory epithelium located in the nasal cavity. Olfactory receptor neurons (ORNs) express specific odorant receptors and project their axons through the cribriform plate to the olfactory bulb.
The olfactory bulb is the first relay station where mitral and tufted cells process sensory input and send processed signals via the lateral olfactory tract.
The piriform cortex (also called the primary olfactory cortex) receives direct input from the olfactory bulb and projects to multiple limbic structures[@gottfried2010].
The olfactory circuit has unique anatomical connections to:
Olfactory dysfunction is one of the earliest and most common non-motor symptoms in Parkinson's disease, often predating motor symptoms by years[@braak2003]. Alpha-synuclein pathology (Lewy bodies) spreads along the olfactory circuit from the olfactory bulb to the anterior olfactory nucleus and piriform cortex.
Olfactory deficits occur early in Alzheimer's disease and correlate with tau pathology in the entorhinal cortex and hippocampus. The olfactory circuit provides a pathway for pathological protein spread[@wilson2011].
The olfactory circuit intersects with:
Understanding olfactory circuit dysfunction has led to:
The olfactory circuit plays a central role in the Braak staging hypothesis for Parkinson's disease progression:
The "body-first" versus "brain-first" PD subtypes differ in their initial propagation pattern through the olfactory system[@braak2003][@rey2018].
Detection of alpha-synuclein seeding activity in olfactory tissues (nasal brushing, olfactory bulb biopsy) offers a window into peripheral nervous system involvement in PD and related synucleinopathies[@crespo2018].
The olfactory circuit provides a non-invasive route for delivering neuroprotective agents to the CNS:
| Agent | Target | Stage |
|---|---|---|
| GDNF | Dopaminergic neurons | Preclinical |
| Exendin-4 (GLP-1) | Neuroprotection | Phase 2/3 |
| Thymosin alpha-1 | Neuroinflammation | Preclinical |
| Alpha-synuclein antibodies | Prion-like spread | Phase 1/2 |
Intranasal delivery bypasses the blood-brain barrier and can target the olfactory system directly, making it particularly relevant for PD and AD where the olfactory circuit is a site of early pathology[@pont2004].