This review outlines unique olfactory nerve features and argues that PD-related hyposmia more likely reflects systemic vulnerabilities in energy metabolism and neural network organization than solely peripheral alpha‑synuclein aggregation, noting that nasal seed‑amplification assays for…

By challenging simple propagation models and highlighting metabolism, network dysfunction, and limitations of nasal alpha‑syn biomarkers, the paper steers therapeutic discovery toward metabolic/neuroprotective strategies and multimodal biomarker approaches rather than focusing only on peripheral…

The olfactory nerve possesses unique anatomical features, including direct central nervous system (CNS) projection and continuous regeneration. Scientific advances have elucidated mechanisms such as combinatorial receptor coding and signal amplification. This review summarizes these foundations and examines olfactory dysfunction in COVID-19 and Parkinson's disease (PD). In COVID-19, evidence suggests that SARS-CoV-2 targets sustentacular cells rather than olfactory neurons, causing gene downregulation and parosmia attributed to incomplete peripheral filtering, while direct CNS invasion remains rare. In PD, olfactory loss is a prodromal feature. However, seed amplification assays reveal that alpha-synuclein aggregation in the nasal mucosa does not fully correlate with olfactory dysfunction, as reflected by differences between PD and Multiple System Atrophy. This, together with correlations with cardiac sympathetic denervation, challenges simple pathogen propagation hypotheses. We propose that PD-related hyposmia reflects a systemic vulnerability involving deficits in energy metabolism and neural network organization, rather than solely peripheral protein aggregation. Understanding these pathologies requires a multifaceted approach beyond anatomical lesions.