Alpha-synuclein seeding more frequent with persistent post-COVID smell loss

A pilot observational study found detectable alpha-synuclein seeding activity in olfactory-mucosa samples from 35.7% of people with persistent olfactory dysfunction following documented SARS-CoV-2 infection, compared with 15.1% of infected participants with normal olfaction and 11.9% of healthy controls. The analysis included 188 adults: 51 patients with Parkinson’s disease, 95 people with a history of PCR-confirmed COVID-19 and 42 healthy controls. Alpha-synuclein seeding-amplification-assay positivity was highest in the Parkinson’s disease group, appearing in 80.4% of participants and in 24.2% of the post-COVID cohort as a whole. The overall difference between all post-COVID participants and healthy controls was not statistically significant, but positivity was concentrated among those whose impaired smell persisted after infection.

Researchers classified the 95 post-COVID participants through objective olfactory testing and their clinical history. The COVID+OD group included 42 adults whose smell impairment had persisted for at least three months after infection. Each had scores below 13 out of 16 on both the Identification and Discrimination subtests of the Sniffin’ Sticks test, had no structural nasal pathology considered capable of explaining the dysfunction, and had no olfactory dysfunction that predated the infection. The COVID−OD group comprised 53 adults with no history or current olfactory dysfunction; each scored at least 13 on both subtests. Both groups required a documented, PCR-confirmed SARS-CoV-2 infection at least three months before inclusion and a negative antigen test at enrollment. Healthy controls reported normal olfaction, had no history of COVID-19 or relevant neurological disorders, and also had Identification and Discrimination scores of at least 13.

The biological measurement used an alpha-synuclein seeding-amplification assay, abbreviated aSyn-SAA, on olfactory-mucosa samples obtained by ear, nose and throat specialists. Swabs were collected medial to the middle nasal turbinate toward the superior nasal turbinate, refrigerated at 4 degrees Celsius and shipped on dry ice for processing at the University of Verona. In the assay, diluted tissue homogenate was combined with recombinant full-length human alpha-synuclein, a fluorescence-sensitive dye and small glass beads. Reactions were run in triplicate at 30 degrees Celsius, with periodic shaking and fluorescence measurement for up to 50 hours. A sample was classified as positive if at least two of three replicates crossed the prespecified fluorescence threshold. Samples with one positive replicate were reanalyzed and, if the pattern persisted, were classified as negative.

Among the 137 participants in the healthy-control and post-COVID groups, 28, or 20.4%, had detectable olfactory-mucosa alpha-synuclein seeding activity. Diagnostic group was associated with assay status in an overall chi-square test, with a small-to-medium effect size of Cramer’s V = 0.25. After correction for multiple comparisons, the COVID+OD group had a significantly higher positivity rate than both healthy controls and the COVID−OD group, with adjusted p values of 0.030 for each comparison. The COVID−OD and healthy-control groups did not differ significantly, with an adjusted p value of 0.65. In multivariable logistic regression, diagnostic group remained associated with positive assay status after adjustment for age and sex, whereas age and sex were not significant predictors. Participants with persistent post-COVID olfactory dysfunction had higher adjusted odds of positivity than either healthy controls or post-COVID participants without olfactory dysfunction.

The study did not conduct a formal power calculation because no suitable prevalence estimates were available for olfactory-mucosa assay positivity in post-COVID groups or healthy controls. Because consecutively recruited groups differed in age, the researchers also assembled a sensitivity cohort of 33 age- and sex-balanced participants per group. That balanced analysis repeated the clinical-outcome comparisons rather than explicitly repeating the seeding-status comparison. It reproduced the main clinical pattern: COVID+OD participants had lower Montreal Cognitive Assessment scores and higher Movement Disorder Society Unified Parkinson’s Disease Rating Scale total scores than healthy controls. Higher scores also remained evident in the Part I and Part III MDS-UPDRS components, while the group effect for Part II did not reach statistical significance in the reduced cohort.

Within the post-COVID cohort, olfactory performance was associated with alpha-synuclein seeding status. After adjustment for age and sex, participants with a positive olfactory-mucosa assay had lower odor Discrimination scores and lower odor Identification scores. The corresponding analyses produced p < 0.001 for discrimination and p = 0.007 for identification, with partial eta-squared values of 0.12 and 0.08. No statistically significant association was detected between seeding activity and MDS-UPDRS total or subcomponent scores, MoCA scores, or Innsbruck REM Sleep Behavior Disorder Inventory scores. The clearest clinical correlate measured in the study was therefore the degree of olfactory impairment, rather than parkinsonian symptoms, global cognitive performance or symptoms suggesting REM sleep behavior disorder.

Broader assessments also distinguished the COVID+OD group from healthy controls. COVID+OD participants had lower MoCA scores, with an adjusted post-hoc p value of 0.038, and higher MDS-UPDRS total scores, including p < 0.001 for the comparison with healthy controls and p = 0.015 for the comparison with COVID−OD participants. They also had higher scores in the MDS-UPDRS sections assessing non-motor experiences of daily living, motor experiences of daily living and the motor examination. The authors emphasized that the absolute motor scores were low and did not suggest clinically manifest parkinsonism. They further noted that the observed pattern was compatible with reports in which persistent post-COVID olfactory dysfunction co-occurred with fatigue, affective symptoms, sleep disturbance, psychomotor slowing and cognitive impairment, although those broader outcomes cannot be assigned a cause in this study.

The observations are consistent with the hypothesis that injury and inflammation involving the olfactory mucosa after SARS-CoV-2 infection may promote local alpha-synuclein misfolding or aggregation. The study notes that SARS-CoV-2 may reach the nervous system through olfactory routes and that experimental evidence cited by the authors indicates that viral neuroinvasion and inflammation can promote alpha-synuclein misfolding. Research on olfactory neurons from people with persistent post-COVID hyposmia has also identified ongoing inflammatory changes. Nevertheless, the present association does not establish a causal pathway. Alpha-synuclein seeding activity has been detected in olfactory mucosa in conditions associated with alpha-synuclein pathology, meaning the current data cannot distinguish a transient post-infectious molecular response from a possible early signature of synucleinopathy.

Several features constrain interpretation of the pilot results. The study was small and cross-sectional, and it did not longitudinally establish whether assay positivity persists, resolves, progresses or predicts Parkinson’s disease or another synucleininopathy. Recruiting healthy controls without prior SARS-CoV-2 exposure became increasingly difficult as infection exposure spread through the population. Some controls may have had unrecognized previous infections, an uncertainty compounded because nucleocapsid antibody testing, which can distinguish infection-related seroreactivity from vaccine-related immunity, was introduced only after healthy-control recruitment was completed. The differences in motor and cognitive scores could also reflect post-COVID sequelae, pre-existing prodromal neurodegenerative changes or an interaction between both processes. The findings indicate a cross-sectional association in a selected clinical sample, not a demonstrated increase in neurodegenerative risk. Prospective studies using serial olfactory-mucosa assays, dopaminergic imaging and additional fluid and tissue biomarkers would be required to determine the biological and prognostic meaning of a positive result.

Subject of Research: Pilot study of olfactory alpha-synuclein seeding activity after SARS-CoV-2 infection

Article Title: Prevalence of alpha-synuclein seeding activity in the Olfactory Mucosa following SARS-CoV-2 infection: results from a pilot study

Article References: Heim, B., Seppi, K., De Cleene, N., Bongianni, M., Bronzato, E., Cerejo, C., Jagusch, F., Kindl, P., Löffler-Ragg, J., Weiss, G., Gottfried, T., Schmutzhard, J., Zanusso, G., & Poewe, W. (2026). Prevalence of alpha-synuclein seeding activity in the Olfactory Mucosa following SARS-CoV-2 infection: results from a pilot study. Acta Neuropathologica, 152(1), Article 58. https://doi.org/10.1007/s00401-026-03104-4

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03104-4

Keywords: SARS-CoV-2, COVID-19, olfactory dysfunction, alpha-synuclein, seeding amplification assay, olfactory mucosa, Parkinson’s disease, neuroinflammation, smell loss, pilot study, Prevalence, seeding