APOE-ε4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology
- PMID: 37700353
- PMCID: PMC10496176
- DOI: 10.1186/s40478-023-01626-6
APOE-ε4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology
Abstract
Lewy body (LB) pathology commonly occurs in individuals with Alzheimer's disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer's Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB-), sole LB pathology (AD-LB+), or no pathology (AD-LB-). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD-LB-), and compared the AD+LB+ to AD+LB- groups. APOE-ε4 was significantly associated with risk of AD+LB- and AD+LB+ compared to AD-LB-. However, APOE-ε4 was not associated with risk of AD-LB+ compared to AD-LB- or risk of AD+LB+ compared to AD+LB-. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.
Keywords: APOE-ε4; Alzheimer’s disease pathology; BIN1; Co-pathology; GWAS; Genetic risk; Lewy body pathology.
© 2023. BioMed Central Ltd., part of Springer Nature.
Conflict of interest statement
The authors declare that they have no competing interests.
Figures
Update of
-
APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.medRxiv [Preprint]. 2023 Jul 20:2023.04.21.23288938. doi: 10.1101/2023.04.21.23288938. medRxiv. 2023. Update in: Acta Neuropathol Commun. 2023 Sep 12;11(1):149. doi: 10.1186/s40478-023-01626-6. PMID: 37503074 Free PMC article. Updated. Preprint.
Similar articles
-
APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.medRxiv [Preprint]. 2023 Jul 20:2023.04.21.23288938. doi: 10.1101/2023.04.21.23288938. medRxiv. 2023. Update in: Acta Neuropathol Commun. 2023 Sep 12;11(1):149. doi: 10.1186/s40478-023-01626-6. PMID: 37503074 Free PMC article. Updated. Preprint.
-
Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.PLoS Genet. 2011 Feb;7(2):e1001308. doi: 10.1371/journal.pgen.1001308. Epub 2011 Feb 17. PLoS Genet. 2011. PMID: 21379329 Free PMC article.
-
APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology.Neurology. 2018 Sep 18;91(12):e1182-e1195. doi: 10.1212/WNL.0000000000006212. Epub 2018 Aug 24. Neurology. 2018. PMID: 30143564 Free PMC article.
-
The Mechanistic Role of Bridging Integrator 1 (BIN1) in Alzheimer's Disease.Cell Mol Neurobiol. 2021 Oct;41(7):1431-1440. doi: 10.1007/s10571-020-00926-y. Epub 2020 Jul 27. Cell Mol Neurobiol. 2021. PMID: 32719966 Review.
-
Genetics of Alzheimer's disease: new evidences for an old hypothesis?Curr Opin Genet Dev. 2011 Jun;21(3):295-301. doi: 10.1016/j.gde.2011.02.002. Epub 2011 Mar 1. Curr Opin Genet Dev. 2011. PMID: 21371880 Review.
Cited by
-
Parkinson's Disease and Dementia with Lewy Bodies: One and the Same.J Parkinsons Dis. 2024;14(3):383-397. doi: 10.3233/JPD-240002. J Parkinsons Dis. 2024. PMID: 38640172 Free PMC article. Review.
-
Apolipoprotein E Gene in α-Synucleinopathies: A Narrative Review.Int J Mol Sci. 2024 Feb 1;25(3):1795. doi: 10.3390/ijms25031795. Int J Mol Sci. 2024. PMID: 38339074 Free PMC article. Review.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous