CSF complement 3 and factor H are staging biomarkers in Alzheimer’s disease

Abstract

IntroductionCSF levels of established Alzheimer’s disease (AD) biomarkers remain stable despite disease progression, and non-amyloid non-tau biomarkers have the potential of informing disease stage and progression. We previously identified complement 3 (C3) to be decreased in AD dementia, but this change was not found by others in earlier AD stages. We hypothesized that levels of C3 and associated factor H (FH) can potentially distinguish between mild cognitive impairment (MCI) and dementia stages of AD, but we also found their levels to be influenced by age and disease status.ResultsWe developed a biochemical/bioinformatics pipeline to optimize the handling of complex interactions between variables in validating biochemical markers of disease. We used data from the Alzheimer’s Disease Neuro-imaging Initiative (ADNI, n = 230) to build parallel machine learning models, and objectively tested the models in a test cohort (n = 73) of MCI and mild AD patients independently recruited from Emory University. Whereas models incorporating age, gender, APOE ε4 status, and CSF amyloid and tau levels failed to reliably distinguish between MCI and mild AD in ADNI, introduction of CSF C3 and FH levels reproducibly improved the distinction between the two AD stages in ADNI (p < 0.05) and the Emory cohort (p = 0.014). Within each AD stage, the final model also distinguished between fast vs. slower decliners (p < 0.001 for MCI, p = 0.007 for mild AD), with lower C3 and FH levels associated with more advanced disease and faster progression.ConclusionsWe propose that CSF C3 and FH alterations may reflect stage-associated biomarker changes in AD, and can complement clinician diagnosis in diagnosing and staging AD using the publically available ADNI database as reference.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0277-8) contains supplementary material, which is available to authorized users.

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer’s disease

“…Its release and effects are thus complex, and IL-10 does not exist or act in isolation. Lower IL-10 levels in NC + may be interpreted as a failure in anti-inflammatory processes associated with onset of pathologic AD, or alternatively balanced anti- and proinflammatory responses in asymptomatic AD (e.g., we previously showed complement activation to accompany the MCI + to AD transition [ 18 ]). Similarly, higher IL-10 levels in AD than NC + and MCI + may represent exaggerated anti-inflammatory responses or appropriate IL-10 response to AD-related neuroinflammation.…”

“…However, successful replication of these markers' association with AD has been challenging. This may be due to many issues, including recruitment bias [ 18 ], processing artifacts when assays are performed by commercial vendors [ 19 ], and different antibodies, and few of them have been replicated across cohorts and assay platforms to undergo further standardization and application.…”

“…CSF is a ready source for simultaneously testing multiple markers reflecting AD core pathology, copathology (ischemia, Lewy bodies), neurodegeneration, common biological alterations (e.g., neuroinflammation), and unique exposures (e.g., environmental toxins) [ 20 ]. We previously sought to identify NANT biomarkers through single-center studies [ 12 , 14 , 19 ], and subsequently determined that some replication failures resulted from biases in recruitment, diagnosis, preanalytical handling, and analytical algorithms [ 18 ]. To validate the association between AD pathology, neurodegeneration, and the top NANT biomarkers, we adapted a round-robin design [ 21 ] involving subjects recruited from three Alzheimer’s disease centers, and collaboratively measured levels of nine analytes to correlate with AD biomarkers and clinical AD stages.…”

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

“…Additionally, CD57 that prevents MAC assembly is decreased in AD brain (181). CSF and plasma levels of certain complement proteins have been reported as promising biomarkers for AD diagnosis and progression (182)(183)(184)(185)(186). These observations suggest that activation of the complement system may contribute to the AD pathogenesis.…”

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in α-synuclein-based mouse models of Parkinson’s disease

“…Factor H (FH), the main regulator of this pathway, prevents formation and promotes the dissociation of C3 convertase enzyme (39,40). Several studies have suggested cerebrospinal fluid (CSF) C3 and FH levels could serve as biomarkers for AD and PD (41)(42)(43)(44). According to the alteration of FH expression in neurodegeneration, the expression level of FH was significantly increased in the postmortem brain of AD cases than in the normal elderly (ND) cases (45).…”