Mechanism for the protective effect of APOE ε2 against Alzheimer disease is linked to tau and the classical complement pathway

Abstract

AbstractBackgroundRecent reports suggest that the rare APOE Christchurch mutation and APOE2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the APOE2 protective effect linking to tau is largely unknown.MethodWe conducted a genome‐wide association study (GWAS) for AD among 2,120 APOE2 carriers from the Alzheimer Disease Genetics Consortium (ADGC), and prioritized by gene network analysis and methylation profiling of CpG sites in the locus using the Religious Orders Study and Memory and Aging Project (ROSMAP) data. We also performed differential gene expression analysis among APOE2/3 subjects in prefrontal cortex tissue from 44 AD and 75 control brains of the Framingham Heart Study (FHS), Boston University Alzheimer’s Disease Center (BUADC), and ROSMAP. We validated the relationships between protein levels of the top‐ranked genes and levels of tau and amyloid beta proteins in prefrontal cortex area of 193 FHS/BUADC brains.ResultOf the significant genetic associations with AD (P < 10−6), PPP2CB was the key node in APOE2‐related gene networks and contained the most significant CpG site (P = 5.2 × 10−4) located 2,814 bp upstream of the top‐ranked GWAS variant. The complement genes C4A and C4B were the top‐ranked differentially expressed genes (P < 2 × 10−4) with reduced expression in APOE2/3 controls compared in APOE2/3 cases or other carriers. Furthermore, the level of PPP2CB protein was significantly associated with increased levels of C4B protein (P = 8.2 × 10−7), and the C4A level was associated with increased pTau231/tTau ratio (P = 0.006). Protein levels of C4A, C4B, and PPP2CB were not associated with amyloid beta 42 (Aβ42) or pTau181/tTau ratio. We were unable to confirm previous reports on the role of C1q, since the C1q level was not associated with any of these phenotypes.ConclusionThis is the first to report the molecular link between a tau phosphatase and the classical complement pathway, especially C4, as a mechanism for the ε2 protective effect against AD. Our findings may lead to the development of novel therapeutic targets for AD by mimicking the neuroprotective effect of APOE2.