Evidence for alpha-synuclein aggregation in older individuals with hyposmia: a cross-sectional study

Background Synuclein pathology in neurodegenerative diseases, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), begins years before motor or cognitive symptoms arise. Alpha-Synuclein seed amplification assays (alpha-syn SAA) may detect aggregated synuclein before symptoms occur. Methods Data from the Parkinson Associated Risk Syndrome Study (PARS) have shown that individuals with hyposmia, without motor or cognitive symptoms, are enriched for dopamine transporter imaging (DAT) deficit and are at high risk to develop clinical parkinsonism or related synucleinopathies. alpha-syn aggregates in CSF were measured in 100 PARS participants using alpha-syn SAA. Findings CSF alpha-syn SAA was positive in 48% (34/71) of hyposmic compared to 4% (1/25) of normosmic PARS participants (relative risk, 11.97; 95% CI, 1.73-82.95). Among alpha-syn SAA positive hyposmics 65% remained without a DAT deficit for up to four years follow-up. alpha-syn SAA positive hyposmics were at higher risk of having DAT deficit (12 of 34) compared to alpha-syn SAA negative hyposmics (4 of 37; relative risk, 3.26; 95% CI, 1.16-9.16), and 7 of 12 alpha-syn SAA positive hyposmics with DAT deficit developed symptoms consistent with synucleinopathy. Interpretation Approximately fifty percent of PARS participants with hyposmia, easily detected using simple, widely available tests, have synuclein pathology detected by alpha-syn SAA. Approximately, one third (12 of 34) alpha-syn SAA positive hyposmic individuals also demonstrate DAT deficit. This study suggests a framework to investigate screening paradigms for synuclein pathology that could lead to design of therapeutic prevention studies in individuals without symptoms. Copyright (c) 2025 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).