CSF proteins involved in neuroplasticity are associated with altered whole brain connectivity in prodromal AD

Background Individuals with prodromal Alzheimer’s Disease (AD) and higher gray matter connectivity measures show slower decline, suggesting resilience to AD. However, the precise biological processes underlying preserved brain connections remains unclear. Here, we studied this question using cerebrospinal fluid (CSF) proteomics. Method From the ADNI we selected 78 individuals with MCI and abnormal CSF amyloid (i.e., prodromal AD) and 34 with normal cognition and normal CSF amyloid levels for whom MRI and CSF proteomic data was available. For each T1 MRI scan we constructed gray matter networks using an automated pipeline (Tijms, Series et al. 2012) and calculated degree, connectivity density, clustering, path length and small‐world measures (i.e. gamma, lambda and small world coefficient). Linear models were used to test associations between each connectivity measure and CSF protein levels while correcting for age and gender. Proteins showing associations of p < 0.1 were selected to find groups of proteins that are associated with biological processes according to Gene Ontology (GO). Proteomic profiles for each connectivity measure were compared to investigate overlap. Finally, we tested for enrichment of potential upstream drivers with the Enrichr tool. Result In total, 115 proteins were associated with altered connectivity in prodromal AD subjects (figure 1). The majority of proteins (n = 93, 80%) showed higher levels with stronger (i.e., resilient) brain networks characterized by increased degree, connectivity density, clustering, path length, gamma, lambda or small world coefficient values. In controls, 80 of these 93 proteins showed an opposite relationship, with lower levels relating to higher values for these connectivity measures, which suggests that increased levels in prodromal AD may indicate a compensatory mechanism to maintain strong brain connectivity. According to a pathway analysis in GO, these proteins associated with stronger brain networks were mainly involved in neuroplasticity pathways. A subsequent Enrichr analysis suggested involvement of upstream divers SUZ12 and REST, which are known to regulate neuroplasticity processes. Conclusion We observed that higher CSF levels of neuroplasticity associated proteins were associated with higher brain connectivity values in prodromal AD, suggesting that plasticity mechanisms may play a role in resilience to AD pathology.