Neuropsychological And Plasma Biomarker Signatures Of Alzheimer’s Disease: A Catalan Multicenter Study

Author Block: Axel Rigol¹, Claudia Morante-Serra¹, Magda Castellví¹, Laura Mir¹, Miquel Massons Garcia¹, Jordi Sarto², Neus Falgàs^1,3, Guadalupe Fernandez-Villullas^1,3, Anna Antonell^1,3, Josep M Augé-Fradera⁴, Gerard Piñol-Ripoll⁵, Iolanda Riba⁵, Anna Carnés-Vendrell⁵, Marta Cullell⁵, Teresa Osuna⁶, Lorena Bajo⁷, Teresa Romero⁷, Eva Bonjoch⁷, Joan Bello⁸, Susana Fernández⁸, Marta Balagué⁸, Isabel Gómez-Ruiz⁸, Anuncia Boltes⁹, Claustre Pont-Sunyer⁹, Raquel Cuevas⁹, Sara Carrillo-Molina⁹, Laura Iglesias⁹, Teresa Maria Casadevall-Codina¹⁰, Lorena Grau-Guinea¹⁰, Fernando Jose-Espada¹⁰, Agnès Pérez-Millan^1,11, Raquel Sánchez-Valle^1,3, Mircea Balasa^1,3, Albert Lladó^1,3, Adrià Tort-Merino^1,3.

¹Alzheimer’s Disease and other Cognitive Disorders unit, Hospital Clínic de Barcelona, Fundació de Recerca Clínic Barcelona – Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain, ²Neurology Service, Hospital Universitari Santa Maria, Lleida, Spain, ³Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain, ⁴Department of Biochemistry and Molecular Genetics, Hospital Clínic de Barcelona, Barcelona, Spain, ⁵Hospital Universitari Santa Maria, Lleida, Spain, ⁶Hospital de Figueres, Figueres, Spain, ⁷Geriatria, Fundació Hospital de la Santa Creu de Vic, Vic, Spain, ⁸Neurology Service, Hospital Moisés Broggi-Consorci Sanitari Integral, Sant Joan Despí, Spain, ⁹Fundació Privada Hospital Asil de Granollers, Granollers, Spain, ¹⁰Hospital Sant Jaume de Calella, Calella, Spain, ¹¹eHealth Center, Faculty of Computer Science, Multimedia and Telecommunications, Universitat Oberta de Catalunya, Barcelona, Spain.

Background: Alzheimer’s disease (AD) and suspected non-neurodegenerative cognitive impairment (SND) frequently present with overlapping clinical profiles, challenging differential diagnosis. By leveraging data from six memory clinics across Catalonia, we aimed to characterize and compare the neuropsychological profiles of AD and SND, and to explore their associations with plasma p-tau217 and neurofilament light chain (NfL) concentrations.

Methods: We included 177 individuals who were classified into three groups according their clinical and CSF profile: AD (n=92), suspected non-neurodegenerative cognitive impairment (SND; n=40), and cognitively unimpaired controls (CU; n=45). Participants completed a comprehensive neuropsychological battery covering five major cognitive domains, AD CSF biomarkers and plasma biomarkers (p-tau217 and NfL). Baseline neuropsychological performance between AD and SND was compared using ANCOVAs adjusting for age and education. Linear regression models were performed to examine the associations between plasma biomarkers and cognitive performance. Each neuropsychological measure was used as the dependent variable in separate models, with plasma p-tau217 and NfL as independent variables. All models were adjusted for age and years of education. Longitudinal anaylses are on-going to evaluate how plasma biomarkers drive neuropsychological trajectories over time.

Results: Demographics, clinical and biomarker data are shown in Table 1. Compared to SND, the AD group showed poorer performance on verbal learning (F[1,130]=16.1,p<0.01) and encoding (F[1,130]=12.1,p<0.01) tasks, as well as in measures assessing free (F[1,130]=8.2,p<0.01) and cued (F[1,130]=7.8,p<0.01) delayed recall and visual memory (F[1,106]=10.2,p<0.01). Additionally, significant differences were found in favor of the SND group in visuoperceptive (F[1,130]=4.3,p<0.05) and visuospatial (F[1,130]=4.9,p<0.05) functions [Figure 1]. In SND and AD participants, plasma p-tau217 was negatively associated with learning and memory measures (β=-2.08 to -0.61,all p<0.05), auditory comprehension tasks (β=-4.78,p<0.05), visuoperceptive function (β=-3.65,p<0.01), and visual attention/processing speed (β=-2.26,p<0.05) [Figure 2]. NfL did not show any significant association.

Conclusion: Patients with AD exhibited the characteristic profile of episodic memory impairment, along with poorer visuoperceptive and visuospatial performance compared to those with SND. Higher plasma p-tau217 levels were associated with worse performance across multiple cognitive domains. These findings underscore the value of neuropsychological assessments and plasma p-tau217 for capturing disease-related cognitive decline and enhancing differential diagnosis between AD and SND in clinical practice.