Inflammation is becoming increasingly recognized as an important contributor to
Alzheimer's disease (AD) pathogenesis. As a part of the innate immune system, the
complement cascade enhances the body's ability to destroy and remove pathogens and has recently been shown to influence Alzheimer's associated
amyloid and tau pathology. However, little is known in humans about the effects of the
complement system and genetic modifiers of AD risk like the ε4 allele of apolioprotein E (
APOE ε4) on AD pathobiology. We evaluated cerebrospinal fluid (CSF)
protein levels from 267 individuals clinically diagnosed as cognitively normal,
mild cognitive impairment, and AD. Using linear models, we assessed the relationship between
APOE ε4 genotype, CSF
Complement 3 (C3), CSF
amyloid-β (
amyloid) and CSF hyperphosphorylated tau (ptau). We found a significant interaction between
APOE ε4 and CSF C3 on both CSF
amyloid and CSF ptau. We also found that CSF C3 is only associated with CSF ptau after accounting for CSF
amyloid. Our results support a conceptual model of the AD pathogenic cascade where a synergistic relationship between the
complement cascade (C3) and
APOE ε4 results in elevated Alzheimer's neurodegeneration and in turn,
amyloid further regulates the effect of the
complement cascade on downstream tau pathology.