CR1 is associated with amyloid plaque burden and age‐related cognitive decline
Open accessAbstract
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
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Module m116 is enriched for genes near AD variants (p=0.0018 by INRICH) and mostly contains microglial genes.
“We also assessed whether any of the modules are enriched for genes found in the vicinity of AD variants (nearest genes, as previously reported4) and found one enriched module, m116, (p=0.0018 using the INRICH algorithm33) which mostly contains microglial genes (Table S6).”
From A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease (2018) · cites this paper as [33]
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- Authors
- 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.
- Affiliations
- Broad Institute (US)
- Rush University Medical Center (US)
- University of Miami (US)
- National Institutes of Health (US)
- Translational Genomics Research Institute (US)
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2011-03
- Volume
- 69
- Issue
- 3
- Pages
- 560-569
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC3066288
- OpenAlex
- W2168741270
- Cited by
- 174
- References
- 43
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 8 · 2018: 11 · 2017: 14 · 2016: 15 · 2015: 13 · 2014: 25 · 2013: 22 · 2012: 22
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Broad Institute
- Parkinson's UK (G-0907)
- National Institutes of Health (1k01ag024079-01a2)
- University of California, Irvine
- National Institute on Aging (P30-AG 10161, P30-AG-19610, R01AG023193, R01AG030146, P50‐AG16574, R01 AG30146, R01 AG15819, U01AG016976, K01-AG-024079, R01AG034504, R01-AG179917, K08AG034290, K01 AG024079-01A2, R01AG015819, P30AG010161, R01AG023173, P50 AG23173, P30AG019610, P30 AG010161-079004, P50AG016574)
- National Heart, Lung, and Blood Institute (UO1HL084744)
- National Institute of Allergy and Infectious Diseases (R01AI179917)
- National Institute of Neurological Disorders and Stroke (U24NS051872, R01NS059873, R01NS067305)
- NIH Blueprint for Neuroscience Research
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- complement receptor 1, Alzheimer's disease, amyloid plaques, age-related cognitive decline, clusterin, PICALM, genetic susceptibility loci, single nucleotide polymorphisms, mediation analysis, cognitive aging, neuropathology
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Analysis of Variance, Brain, Cognition Disorders, Female, Genotype, Humans, Longitudinal Studies, Male, Middle Aged, Receptors, Complement 3b, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Association Studies, Plaque, Amyloid
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