title: The relationship between complement factor C3, APOE ε4, amyloid and tau in Alzheimer's disease.
abstract: 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.
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Bonham
authors.affiliation: Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, 94143, CA, USA. jennifer.yokoyama@ucsf.edu.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA. rahul.desikan@ucsf.edu.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D000682:Amyloid / Q000134:cerebrospinal fluid; D000704:Analysis of Variance; D053327:Apolipoprotein E4 / Q000235:genetics*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000235:genetics; D015331:Cohort Studies; D003176:Complement C3 / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D010766:Phosphorylation; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D000682:Amyloid; D053327:Apolipoprotein E4; D015415:Biomarkers; D003176:Complement C3; C054369:MAPT protein, human; D016875:tau Proteins
keywords: APOE ε4; Alzheimer's disease; Amyloid; Aβ; CSF; Cerebrospinal fluid; Complement 3; phospho-tau; ptau