APOE-ε4 and BIN1 increase risk of Alzheimer’s disease pathology but not specifically of Lewy body pathology

Acta Neuropathologica Communications

Research

Michael D. Greicius¹  Nandita Kasireddy¹  Michael E. Belloy¹  Seth Talyansky¹  Yann Le Guen² 

[1] Department of Neurology and Neurological Sciences, Stanford University, 290 Jane Stanford Way, E265, 94305-5090, Stanford, CA, USA;Department of Neurology and Neurological Sciences, Stanford University, 290 Jane Stanford Way, E265, 94305-5090, Stanford, CA, USA;Institut du Cerveau, Paris Brain Institute – ICM, Paris, France;

关键词: Lewy body pathology;    Alzheimer’s disease pathology;    Co-pathology;    GWAS;    Genetic risk;    APOE-ε;    BIN1;   

DOI  :  10.1186/s40478-023-01626-6

 received in 2023-04-25, accepted in 2023-07-22,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

【 图 表 】

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