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Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting <jats:italic>GBA1<\/jats:italic>\u2010associated PD (<jats:italic>GBA1<\/jats:italic>\u2010PD) is a current challenge. We previously demonstrated that \u03b1\u2010synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross\u2010sectional study investigates an unexplored cohort of <jats:italic>GBA1<\/jats:italic>\u2010PD (<jats:italic>n<\/jats:italic>\u2009=\u200927) compared to 28 HC, and 36 iPD cases to (i) analyze \u03b1\u2010synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific <jats:italic>GBA1<\/jats:italic> mutations. PLA score discriminates <jats:italic>GBA1<\/jats:italic>\u2010PD from HC with sensitivity\u2009=\u200988.9% (95% CI 70.84\u201397.65), specificity\u2009=\u200988.5% (95% CI 69.85\u201397.55), and PPV\u2009=\u200988.9% (95% CI 73.24\u201395.90), AUC value\u2009=\u20090.927 (95% CI 0.859\u20130.996). No difference was found between <jats:italic>GBA1<\/jats:italic>\u2010PD patients and iPD, suggesting a common pathological pathway based on \u03b1\u2010synuclein oligomers. GCase score did not differ in <jats:italic>GBA1<\/jats:italic>\u2010PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in <jats:italic>GBA1<\/jats:italic>\u2010PD compared to iPD and HC (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001). Employing ROC curve to discriminate <jats:italic>GBA1<\/jats:italic>\u2010PD from iPD, we found an AUC value for synaptic density\u2009=\u20090.855 (95% CI 0.749\u20130.961) with sensitivity\u2009=\u200985.2% (95% CI 66.27%\u201395.81%), specificity\u2009=\u200977.1% (95% CI 59.86%\u201389.58%), and PPV\u2009=\u200974.19% (60.53%\u201384.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing <jats:italic>GBA1<\/jats:italic>\u2010PD from iPD and to their potential to stratify and monitor patients in the context of new pathway\u2010specific therapeutic options.<\/jats:p>","DOI":"10.1111\/bpa.13284","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T06:46:14Z","timestamp":1725259574000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Comparing <i>GBA1<\/i>\u2010Parkinson's disease and idiopathic Parkinson's disease: \u03b1\u2010Synuclein oligomers and synaptic density as biomarkers in the skin biopsy"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2944-8357","authenticated-orcid":false,"given":"Samanta","family":"Mazzetti","sequence":"first","affiliation":[{"name":"Department of Biosciences Universit\u00e0 degli Studi di Milano  Milan 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