Serum β-synuclein predicts dementia conversion and mortality beyond amyloid-β and phospho-tau

Clicks: 14
ID: 333283
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Emerging

Ranked #404 of 455 articles by views in Brain research

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 455 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
Abstract 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 β-synuclein provides prognostic information independent of established amyloid-β (A; CSF Aβ42/Aβ40 ratio) and tau (T1; CSF pTau181) biomarkers has not been determined. 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−T1− controls (n = 97), A−T1+ PASSED (‘pTau and Aβ surge with subtle deterioration’, n = 65), and A + T1+ Alzheimer's disease (n = 97), with parallel analyses using Aβ40-normalised pTau181. Endpoints comprised dementia conversion (n = 185, median follow-up 4.1 years), all-cause mortality (n = 258, median 7.0 years), longitudinal MMSE trajectories (n = 185), and regional brain volumes (n = 137). Independence from CSF biomarkers was quantified through systematic effect attenuation analysis. Serum β-synuclein was selectively elevated in the Alzheimer's disease group (Cohen's d = 0.69 vs controls, P < 0.001) but not in PASSED individuals (P = 0.40), and was more strongly associated with CSF pTau181 (r = 0.36) than with the Aβ42/Aβ40 ratio (r = −0.20) across the cohort. Each standard deviation increase was associated with higher risk of dementia conversion (hazard ratio (HR) = 1.40; 95% CI: 1.11, 1.77; P = 0.005), faster cognitive decline (−0.11 SD/year, 95% CI: −0.18, −0.04, P = 0.002, corresponding to −0.20 MMSE points/year), and higher mortality (HR = 1.33; 95% CI: 1.07, 1.65; P = 0.010). For dementia conversion and mortality, adjustment for continuous CSF pTau181 and Aβ42/Aβ40 produced minimal attenuation (≤13%). Both associations were preserved under Aβ40-normalised T1 staging but not against continuous pTau181 normalised to CSF Aβ40. For cognitive decline, β-synuclein's effect remained significant after Aβ42/Aβ40 adjustment (25% attenuation; P = 0.007) but was substantially attenuated by pTau181 (58.5%; P = 0.186). Serum β-synuclein was associated with lower bilateral temporal lobe volume—the only lobar regions to survive hierarchical testing—with sub-regional involvement spanning the hippocampi, entorhinal cortex and parahippocampal gyrus, and explained 5.0–8.9% of unique variance beyond CSF biomarkers. Plasma glial fibrillary acidic protein (GFAP) showed a strong association with β-synuclein, estimated in the PASSED subgroup (β=0.34 per SD, P < 0.001). Serum β-synuclein provided prognostic information largely independent of CSF Aβ42/Aβ40 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.
Reference Key
openalex_W7223137451 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Eva-Maria Siegmann, Julian Schwarz, Laura Rudtke, Johannes Jablonowski, Dominique Cornelius Marterstock, Manuel Alexander Schmidt, Arnd Doerfler, Jana Kiesel, Neele Klement, Pauline Schulz, Piotr Lewczuk, Juan Manuel Maler, Johannes Kornhuber, Patrick Oeckl, Markus Otto
Are you one of these authors? Claim your profile
Journal Brain research
Year 2026
DOI
10.1093/brain/awag361
URL
https://doi.org/10.1093/brain/awag361
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.