Effect of Complement CR1 on Brain Amyloid Burden During Aging and Its Modification by APOE Genotype
Open accessAbstract
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 (11)C-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 (11)C-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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An important pathologic process in AD is activation of the innate immune system, with both astrocytosis and microgliosis.
“An important pathologic process in AD is activation of the innate immune system, with both astrocytosis and microgliosis [164].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [164]
The Introduction says the complement system has a role in AD pathogenesis, and the Discussion considers possible immune-mediated neuronal damage. Neither section says that AD involves both astrocytosis and microgliosis, so the source supports the immune-process aspect but not those specific features. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMicroglial expression of complement receptor CR1 has been linked to late-onset AD and may reflect microglial phagocytosis of synapses proposed to contribute to AD pathogenesis.
“microglial expression of the complement receptor CR1 has been linked to late-onset AD137,138 and may reflect the microglial phagocytosis of synapses that has been proposed to contribute to AD pathogenesis.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [137]
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- Authors
- Thambisetty, M., An, Y., Nalls, M., Sojkova, J., Swaminathan, S., Zhou, Y., Singleton, A. B., Wong, D. F., Ferrucci, L., Saykin, A. J., & Resnick, S. M.
- Affiliations
- National Institutes of Health (US)
- Indiana University Indianapolis (US)
- Johns Hopkins University (US)
- Corresponding author
- Thambisetty, Madhav
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 73
- Issue
- 5
- Pages
- 422-428
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3535537
- OpenAlex
- W2134105282
- Cited by
- 90
- References
- 37
- Citations by year
- 2025: 2 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 7 · 2016: 4 · 2015: 16 · 2014: 5 · 2013: 10
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institutes of Health (5u01ag024904-10, Z99 AG999999)
- National Institute on Aging (U01-AG-024904, N01-AG-32124, P30AG010129, P30AG010133, K01AG030514, R99 AG999999, U01AG032984, R01AG019771, RC2AG036535, ZIAAG000191, U24AG021886)
- National Cancer Institute (R01CA101318)
- 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
- brain amyloid burden, APOE ε4, Alzheimer's disease, aging, gene-gene interaction, amyloid-beta, Pittsburgh compound B PET, non-demented elderly, genetic risk variants
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alleles, Alzheimer Disease, Amyloid, Apolipoproteins E, Brain, Female, Gene Frequency, Genotype, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Radionuclide Imaging, Receptors, Complement 3b, Genetic Predisposition to Disease
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