Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype

Background: The rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in nondemented older individuals. Methods: We used ¹¹C-Pittsburgh Compound-B positron emission tomography to quantify brain amyloid burden in 57 nondemented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed ¹¹C-Pittsburgh Compound-B positron emission tomography data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset. Results: Risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE ε4 individuals showed significantly higher brain amyloid burden relative to APOE ε4 noncarriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample. Conclusions: Our findings suggest complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain Aβ in nondemented individuals at risk for AD and suggest that clinical outcomes of such treatments might be influenced by complex gene-gene interactions.