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

Madhav Thambisetty, Yang An, Michael Nalls, Jitka Sojkova, Shanker Swaminathan, Yun Zhou, Andrew B. Singleton, Dean Foster Wong, Luigi Ferrucci, Andrew J. Saykin, Susan M. Resnick

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)422-428
Number of pages7
JournalBiological Psychiatry
Volume73
Issue number5
DOIs
StatePublished - Mar 1 2013

Fingerprint

Amyloid
Genotype
Alzheimer Disease
Brain
Neuroimaging
Alleles
Positron-Emission Tomography
Complement C4b
Complement 3b Receptors
Complement C3b
Baltimore
Genes
Single Nucleotide Polymorphism
Longitudinal Studies
Observation

Keywords

  • C-PiB PET
  • Alzheimer's disease
  • amyloid
  • APOE
  • CR1
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Thambisetty, M., An, Y., Nalls, M., Sojkova, J., Swaminathan, S., Zhou, Y., ... Resnick, S. M. (2013). Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. Biological Psychiatry, 73(5), 422-428. https://doi.org/10.1016/j.biopsych.2012.08.015

Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. / Thambisetty, Madhav; An, Yang; Nalls, Michael; Sojkova, Jitka; Swaminathan, Shanker; Zhou, Yun; Singleton, Andrew B.; Wong, Dean Foster; Ferrucci, Luigi; Saykin, Andrew J.; Resnick, Susan M.

In: Biological Psychiatry, Vol. 73, No. 5, 01.03.2013, p. 422-428.

Research output: Contribution to journalArticle

Thambisetty, M, An, Y, Nalls, M, Sojkova, J, Swaminathan, S, Zhou, Y, Singleton, AB, Wong, DF, Ferrucci, L, Saykin, AJ & Resnick, SM 2013, 'Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype', Biological Psychiatry, vol. 73, no. 5, pp. 422-428. https://doi.org/10.1016/j.biopsych.2012.08.015
Thambisetty, Madhav ; An, Yang ; Nalls, Michael ; Sojkova, Jitka ; Swaminathan, Shanker ; Zhou, Yun ; Singleton, Andrew B. ; Wong, Dean Foster ; Ferrucci, Luigi ; Saykin, Andrew J. ; Resnick, Susan M. / Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. In: Biological Psychiatry. 2013 ; Vol. 73, No. 5. pp. 422-428.
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abstract = "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.",
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AU - Swaminathan, Shanker

AU - Zhou, Yun

AU - Singleton, Andrew B.

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