{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:39:39Z","timestamp":1792593579090,"version":"4.5.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Synaptic dysfunction is among the earliest pathological events in Alzheimer's disease and among the strongest neuropathological correlates of cognitive impairment, yet blood-based synaptic biomarkers are lacking. Whether serum \u03b2-synuclein provides prognostic information independent of established amyloid-\u03b2 (A; CSF A\u03b242\/A\u03b240 ratio) and tau (T1; CSF pTau181) biomarkers has not been determined.<\/jats:p>\n                  <jats:p>We studied 259 non-demented individuals with subjective or mild cognitive impairment from a single-centre memory clinic, classified by CSF biomarkers using externally validated cut-offs into A\u2212T1\u2212 controls (n\u2009=\u200997), A\u2212T1+ PASSED (\u2018pTau and A\u03b2 surge with subtle deterioration\u2019, n\u2009=\u200965), and A\u2009+\u2009T1+ Alzheimer's disease (n\u2009=\u200997), with parallel analyses using A\u03b240-normalised pTau181. Endpoints comprised dementia conversion (n\u2009=\u2009185, median follow-up 4.1 years), all-cause mortality (n\u2009=\u2009258, median 7.0 years), longitudinal MMSE trajectories (n\u2009=\u2009185), and regional brain volumes (n\u2009=\u2009137). Independence from CSF biomarkers was quantified through systematic effect attenuation analysis.<\/jats:p>\n                  <jats:p>Serum \u03b2-synuclein was selectively elevated in the Alzheimer's disease group (Cohen's d\u2009=\u20090.69 vs controls, P\u2009&amp;lt;\u20090.001) but not in PASSED individuals (P\u2009=\u20090.40), and was more strongly associated with CSF pTau181 (r\u2009=\u20090.36) than with the A\u03b242\/A\u03b240 ratio (r\u2009=\u2009\u22120.20) across the cohort. Each standard deviation increase was associated with higher risk of dementia conversion (hazard ratio (HR)\u2009=\u20091.40; 95% CI: 1.11, 1.77; P\u2009=\u20090.005), faster cognitive decline (\u22120.11 SD\/year, 95% CI: \u22120.18, \u22120.04, P\u2009=\u20090.002, corresponding to \u22120.20 MMSE points\/year), and higher mortality (HR\u2009=\u20091.33; 95% CI: 1.07, 1.65; P\u2009=\u20090.010). For dementia conversion and mortality, adjustment for continuous CSF pTau181 and A\u03b242\/A\u03b240 produced minimal attenuation (\u226413%). Both associations were preserved under A\u03b240-normalised T1 staging but not against continuous pTau181 normalised to CSF A\u03b240. For cognitive decline, \u03b2-synuclein's effect remained significant after A\u03b242\/A\u03b240 adjustment (25% attenuation; P\u2009=\u20090.007) but was substantially attenuated by pTau181 (58.5%; P\u2009=\u20090.186). Serum \u03b2-synuclein was associated with lower bilateral temporal lobe volume\u2014the only lobar regions to survive hierarchical testing\u2014with sub-regional involvement spanning the hippocampi, entorhinal cortex and parahippocampal gyrus, and explained 5.0\u20138.9% of unique variance beyond CSF biomarkers. Plasma glial fibrillary acidic protein (GFAP) showed a strong association with \u03b2-synuclein, estimated in the PASSED subgroup (\u03b2=0.34 per SD, P\u2009&amp;lt;\u20090.001).<\/jats:p>\n                  <jats:p>Serum \u03b2-synuclein provided prognostic information largely independent of CSF A\u03b242\/A\u03b240 across all endpoints and of pTau181 for survival outcomes, while sharing substantial prognostic variance with pTau181 for cognitive trajectory, supporting its candidacy as a blood-based synaptic complement to core Alzheimer's disease biomarkers.<\/jats:p>","DOI":"10.1093\/brain\/awag361","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:48:41Z","timestamp":1792590521000},"source":"Crossref","is-referenced-by-count":0,"title":["Serum \u03b2-synuclein predicts dementia conversion and mortality beyond amyloid-\u03b2 and phospho-tau"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2482-5851","authenticated-orcid":false,"given":"Timo Jan","family":"Oberstein","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rudtke","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Jablonowski","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique Cornelius","family":"Marterstock","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg , Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel Alexander","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg , Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnd","family":"Doerfler","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg , Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Kiesel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neele","family":"Klement","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Schulz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Lewczuk","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]},{"name":"Department of Neurodegeneration Diagnostics, Medical University of Bialystok , 15-267 Bia\u0142ystok ,","place":["Poland"]},{"name":"Department of Biochemical Diagnostics, University Hospital of Bialystok , 15-267 Bia\u0142ystok ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Manuel","family":"Maler","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Kornhuber","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU) , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-7023","authenticated-orcid":false,"given":"Patrick","family":"Oeckl","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) Ulm , Ulm 89081 ,","place":["Germany"]},{"name":"Department of Neurology, Ulm University Hospital , Ulm 89081 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Otto","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) Ulm , Ulm 89081 ,","place":["Germany"]},{"name":"Department of Neurology, Ulm University Hospital , Ulm 89081 ,","place":["Germany"]},{"name":"Department of Neurology, University clinic, Martin-Luther-University Halle-Wittenberg , 06120 Halle (Saale) ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,21]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag361\/72252697\/awag361.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag361\/72252697\/awag361.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:48:42Z","timestamp":1792590522000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag361\/8964972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,21]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag361","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,21]]},"article-number":"awag361"}}