Open Access

Carolin Kurz, Laura Carli, Selim Üstün Gürsel, Isabelle Schrurs, Alexander Jethwa, Margherita Carboni, Tobias Bittner, Sayuri Hortsch, Daniel Keeser, Matthias Brendel, Lena Burow, Jan Haeckert, Carolin A. M. Koriath, Maia Tatò, Julia Utecht, Boris Papazov, Estrella Morenas-Rodriguez, Oliver Pogarell, Carla Palleis, Endy Weidinger, Sophia Stoecklein, Johannes Levin, Günter Höglinger, Boris-Stephan Rauchmann, Robert Perneczky

• Background Blood-based biomarkers (BBBMs) could significantly facilitate the diagnosis of Alzheimer’s disease (AD) and non-AD dementia by providing less invasive alternatives to cerebrospinal fluid (CSF) and positron emission tomography (PET) imaging. Objective This study investigated how well the BBBMs—amyloid-β (Aβ) 1-42/1-40 ratio, phosphorylated tau181 (pTau181), apolipoprotein E4 (ApoE4), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)—reflect thorough clinical work-up validated by PET and CSF biomarkers in participants with AD (n = 27), Aβ-negative CBS (n = 26), and agematched healthy controls (HC) (n = 17). Methods Factor and correlation explored biomarker associations. Bayesian regression, backward selection regression, and ROC curve analysis were applied to identify optimal biomarker combinations and diagnostic cut-offs. Results In AD cases, pTau181 and ApoE4 levels were elevated, and the Aβ1-42/1-40 ratio was reduced. ROC analysis showedBackground Blood-based biomarkers (BBBMs) could significantly facilitate the diagnosis of Alzheimer’s disease (AD) and non-AD dementia by providing less invasive alternatives to cerebrospinal fluid (CSF) and positron emission tomography (PET) imaging. Objective This study investigated how well the BBBMs—amyloid-β (Aβ) 1-42/1-40 ratio, phosphorylated tau181 (pTau181), apolipoprotein E4 (ApoE4), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)—reflect thorough clinical work-up validated by PET and CSF biomarkers in participants with AD (n = 27), Aβ-negative CBS (n = 26), and agematched healthy controls (HC) (n = 17). Methods Factor and correlation explored biomarker associations. Bayesian regression, backward selection regression, and ROC curve analysis were applied to identify optimal biomarker combinations and diagnostic cut-offs. Results In AD cases, pTau181 and ApoE4 levels were elevated, and the Aβ1-42/1-40 ratio was reduced. ROC analysis showed high accuracy for pTau181, ApoE4 and Aβ1-42/1-40 in discriminating AD from HC, with a combination significantly improving performance. However, limited fold change, and high variability reduced the diagnostic applicability of Aβ1-42/1-40 ratio. Elevated NfL levels were the most reliable biomarker for CBS-Aβ(–) cases. GFAP showed limited discriminatory power due to overlapping levels, suggesting that it may not serve as a disease-specific biomarker but may be indicative of general neurodegeneration. Conclusions This study highlights the diagnostic utility of pTau181, ApoE4 and the Aβ1-42/1-40 ratio for AD and NfL in the CBS-Aβ(–) cases and emphasizes the added value of combined biomarker models for group differentiation. Prospective studies will help validate these findings and refine clinical thresholds.…