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CR1 is associated with amyloid plaque burden and age‐related cognitive decline
Author(s) -
Chibnik Lori B.,
Shulman Joshua M.,
Leurgans Sue E.,
Schneider Julie A.,
Wilson Robert S.,
Tran Dong,
Aubin Cristin,
Buchman Aron S.,
Heward Christopher B.,
Myers Amanda J.,
Hardy John A.,
Huentelman Matthew J.,
Corneveaux Jason J.,
Reiman Eric M.,
Evans Denis A.,
Bennett David A.,
De Jager Philip L.
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22277
Subject(s) - neuropathology , cognitive decline , dementia , population , locus (genetics) , alzheimer's disease , cognition , psychology , medicine , oncology , gerontology , disease , neuroscience , biology , genetics , gene , environmental health
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. ANN NEUROL 2011