Complement proteins C1q, C3, and Factor H are associated with early tau pathology and synaptic integrity in persons with pre‐symptomatic Alzheimer’s disease

Abstract Background The immune complement system is key to the elimination of redundant neural connections in the brain through a process called synaptic pruning. In neurodegenerative diseases such as Alzheimer's disease (AD), this system may result in excessive synapse loss, leading to brain atrophy and cognitive impairment. While increased cerebrospinal fluid (CSF) levels of complement proteins have been observed in patients with AD dementia, no studies have yet investigated the role of complement in the pre‐symptomatic phase of AD, nor throughout its progression. Method We used Luminex technology to assess complement protein levels in 566 CSF samples obtained over five years from 160 high‐risk asymptomatic subjects with familial history of AD [the PREVENT‐AD cohort; Breitner et al, 2016: JPAD 3,(4) 236]. Baseline complement levels were contrasted with CSF biomarkers of AD pathology (Aβ42, p(181) and total tau, NFL) and markers of synaptic dysfunction (GAP‐43, SYT1, SNAP‐25, ADAM22, ADAM23). Analyses were stratified by sex and ApoE4 carrier status. Currently pending are additional longitudinal analyses probing complement levels versus PET‐quantified cerebral amyloid and tau deposition, MRI volume of AD‐implicated structures, and cognitive ability (RBANS). Result Preliminary analyses revealed significant positive associations between complement proteins and p‐(181)tau (C1q: R 2 = .238, p < .0001; C3: R 2 = .041, p = .0099; C3b: R 2 = .027, p = .0384; Factor H: R 2 = .128, p < .0001) and total tau levels (C1q: R 2 = .247, p < .0001; C3: R 2 = .023, p = .0543; Factor H: R 2 = .128, p < .0001). Complement relationships with synaptic protein levels were more significant overall in females, which showed the following associations [GAP‐43 (C1q: R 2 = .389, p < .0001; Factor H: R 2 = .315, p = .0002); SNAP‐25 (C1q: R 2 = .367, p < .0001; C3: R 2 = .106, p = .0459; Factor H: R 2 = .278, p = .0072); SYT1 (C1q: R 2 = .316, p = .0002; Factor H: R 2 = .246, p = .0015)]. Conclusion There is a clear association between complement levels, tau pathology, and synaptic markers in the asymptomatic phase of AD, especially in women. Longitudinal and multimodal investigation is ongoing to further characterize these relationships.