CR1 is associated with amyloid plaque burden and age-related cognitive decline

Lori B. Chibnik, Joshua M. Shulman, Sue E. Leurgans, Julie A. Schneider, Robert S. Wilson, Dong Tran, Cristin Aubin, Aron S. Buchman, Christopher B. Heward, Amanda J. Myers, John A. Hardy, Matthew J. Huentelman, Jason J. Corneveaux, Eric M. Reiman, Denis A. Evans, David A. Bennett, Philip L. De Jager

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Objective Recently, genome-wide association studies have identified 3 new susceptibility loci for Alzheimer's disease (AD), CLU, CR1, and PICALM. We leveraged available neuropsychological and autopsy data from 2 cohort studies to investigate whether these loci are associated with cognitive decline and AD neuropathology. Methods The Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) are longitudinal studies that enroll nondemented subjects and include annual clinical evaluations and brain donation at death. We evaluated CR1 (rs6656401), CLU (rs11136000), and PICALM (rs7110631) in 1,666 subjects. We evaluated associations between genotypes and rate of change in cognitive function as well as AD-related pathology. Lastly, we used pathway analysis to determine whether relationships between single nucleotide polymorphisms and cognitive decline are mediated through AD pathology. Results Among our study cohort, the mean years of follow-up were 7.8 for ROS and 4.3 for MAP. Only the CR1 locus was associated with both global cognitive decline (p = 0.011) and global AD pathology (p = 0.025). More specifically, the locus affects the deposition of neuritic amyloid plaque (p = 0.009). In a mediation analysis, controlling for amyloid pathology strongly attenuated the effect of the CR1 locus on cognitive decline. Interpretation We found that common variation at the CR1 locus has a broad impact on cognition and that this effect is largely mediated by an individual's amyloid plaque burden. We therefore highlight 1 functional consequence of the CR1 susceptibility allele and generalize the role of this locus to cognitive aging in the general population.

Original languageEnglish (US)
Pages (from-to)560-569
Number of pages10
JournalAnnals of neurology
Volume69
Issue number3
DOIs
StatePublished - Mar 2011

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Chibnik, L. B., Shulman, J. M., Leurgans, S. E., Schneider, J. A., Wilson, R. S., Tran, D., Aubin, C., Buchman, A. S., Heward, C. B., Myers, A. J., Hardy, J. A., Huentelman, M. J., Corneveaux, J. J., Reiman, E. M., Evans, D. A., Bennett, D. A., & De Jager, P. L. (2011). CR1 is associated with amyloid plaque burden and age-related cognitive decline. Annals of neurology, 69(3), 560-569. https://doi.org/10.1002/ana.22277