Biomarkers.

01/12/2025

Alzheimer's & dementia : the journal of the Alzheimer's Association

Authors: Marianna Rizzo, Charlotte E Teunissen, Frederic Brosseron, Sandra Kuhs, Gwendlyn Kollmorgen, Henrik Zetterberg, Kaj Blennow, Rejko Krüger, Sara B Gomes Fernandes, Dag Aarsland, Olga Borejko, Davit Chokoshvili, Wiesje M van der Flier, Afina W Lemstra, Betty M Tijms, Gabor C Petzold, Annika Spottke, Giovanni B Frisoni, Kathrin Brockmann, Thomas Gasser, Tormod Fladby, Marianne Wettergreen, Frank Jessen, Emrah Düzel, Günter U Höglinger, Claire Chevalier, Rajaraman Krishnan, Pieter Jelle Visser, Stephanie J B Vos

BACKGROUND: While evidence suggests complement system involvement in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), its association with disease biomarkers remains unclear. We investigated the relationship of complement factors with amyloid, tau, NfL, and α-synuclein in CSF in AD, DLB, PD, and controls.

METHOD: We included 321 individuals with AD, DLB, PD, and controls from 6 centers of the EPND study. CSF Aβ42/40, p-tau181, NfL, and α-syn were centrally measured using NeuroToolKit (Roche Diagnostics), and 14 CSF complement factors using Milliplex (Merck KGaA). Controls were defined as normal cognition and normal Aβ42/40, whereas AD as abnormal Aβ42/40 without meeting clinical criteria of DLB or PD. Linear regression models adjusted for age and sex were used. Associations were post-hoc compared between individuals with low(≤23), intermediate(24-27), and high(≥28) MMSE scores.

RESULT: Sample characteristics are presented in Table 1. Lower Aβ42/40 levels were associated with lower levels of 7 complement factors in controls and with higher C1q and C2 levels specifically in AD (Figure 1, Figure 2). No associations of Aβ42/40 with complement were found in DLB and PD. Higher p-tau181 levels were associated with increased levels of 7 complement factors in controls and 6 in AD, and showed fewer associations in DLB and PD. The strength of p-tau181 associations with complement was similar across groups. Higher NfL levels were widely associated with higher complement factor levels in controls (13) and AD (12), and less in PD (6) and DLB (4). Higher α-syn levels were broadly associated with higher complement factor levels in AD (13), controls (12), and DLB (12), but only minimally in PD (1). The strength of these NfL and α-syn associations with complement was not disease-specific. Conversely, compared to all groups, in PD higher α-syn levels were associated with lower C5, C5a, C9, factor-I and properdin levels. Individuals with intermediate MMSE scores largely drove the associations of α-syn with complement in AD. MMSE level did not clearly impact other associations.

CONCLUSION: CSF complement factors were associated with amyloid, tau, NfL, and α-synuclein, suggesting complement system involvement in several neurodegenerative diseases. Complement showed disease-specific associations with amyloid in AD and α-synuclein in PD.

PMID: 41453027