Non-core CSF Biomarkers Reveal Strong Associations With Core AD Biomarkers And Cognition In SCD And MCI:

Author Block:Isadora Lyrio Stabille1, Isadora Cristina Ribeiro1, Liara Rizzi2,1, Marjorie Cristina da Silva1, Raphael Fernandes Casseb3, Luis Eduardo Santos4, Ítalo Karmann Aventurato1, Ananssa Maíra dos Santos Silva4, Emanuel Rodrigues Guimarães1, Thaís Lopes Pinheiro4, Fernanda Guarino de Felice4,5, Marcio Luiz Figueredo Balthazar1. 

1Laboratory of Imaging and Biomarkers in Cognitive Disorders, School of Medical Sciences - FCM, State University of Campinas – UNICAMP, Campinas, Brazil, 2Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA, 3Laboratory of Neuroimaging - LNI, School of Medical Sciences - FCM, State University of Campinas – UNICAMP, Campinas, Brazil, 4D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil, 5Department of Biomedical and Molecular Sciences & Department of Psychiatry, Queen’s University, Kingston, ON, Canada.

Abstract:

Background: Alzheimer’s disease (AD) is characterized by a long preclinical and prodromal phase, during which molecular and synaptic alterations precede cognitive decline. While core AD cerebrospinal fluid (CSF) and plasma biomarkers are well established, increasing attention has been given to non-core CSF biomarkers reflecting neurodegeneration, synaptic dysfunction, and copathologies. Understanding their relationships with core biomarkers and cognitive performance in Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) may improve biological characterization in early AD.

Methods: This cross-sectional study included individuals with SCD or MCI. CSF non-core biomarkers related to neurodegeneration (neurofilament light chain), synaptic dysfunction (neurogranin, visinin-like protein 1), and copathologies (alpha-synuclein) were analyzed. Core biomarkers (Aβ42, Aβ40, total tau, p-tau181, p-tau217) were measured in plasma and/or CSF. Neuropsychological assessment included standardized tests. Group comparisons were adjusted for age and education. Associations were evaluated using MANCOVA and Spearman correlations.

Results: No significant differences in CSF non-core biomarker levels were observed between SCD and MCI. In the SCD group, strong positive correlations were observed between alpha-synuclein and VILIP-1 (rho = 0.857, p = 0.007), plasma p-tau181/total tau and VILIP-1 (rho = 0.788, p = 0.035), and CSF p-tau181/Aβ42 and alpha-synuclein (rho = 0.897, p = 0.003). Cognitive associations included a positive correlation between Trail Making Test A time and plasma Aβ42/Aβ40 (rho = 0.923, p = 0.001) and a negative correlation between RAVLT delayed recall and plasma p-tau181/total tau (rho = −0.712, p = 0.047). In the MCI group, markers of synaptic dysfunction showed strong intercorrelations, with neurogranin correlating positively with VILIP-1 (rho = 0.821, p = 0.001). Attention and executive performance showed negative correlations with neurogranin (rho = −0.538, p = 0.001), VILIP-1 (rho = −0.492, p = 0.001), and alpha-synuclein (rho = −0.421, p = 0.006). Amyloid/tau ratios were associated with plasma p-tau217 and memory performance, including plasma Aβ42/total tau with RAVLT A1-A5 (rho = 0.402, p = 0.004).

Conclusion: Although CSF non-core biomarker levels did not differ between SCD and MCI, stage-specific associations with core biomarkers and cognition suggest that non-core biomarkers provide complementary biological and clinically relevant information beyond core markers alonein prodromal AD.