APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.
APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.
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APOE - Δ 4 和 BIN1 会增加阿尔茨海默病病理学的风险，但不会增加路易体病理学的风险。
DOI：
10.1101/2023.04.21.23288938
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Greicius,MichaelD
中科院分区：
文献类型：
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作者：
Talyansky,Seth;Guen,YannLe;Kasireddy,Nandita;Belloy,MichaelE;Greicius,MichaelD
路易体 (LB) 病理通常发生在患有阿尔茨海默病 (AD) 病理的个体中。然而，目前尚不清楚哪些遗传风险因素是 AD 病理、LB 病理或 AD-LB 共同病理的基础。值得注意的是，APOE-ε4 是否独立于 AD 病理影响 LB 病理风险尚存在争议。我们采用文献中的标准，将来自国家阿尔茨海默病协调中心 (NACC) 和拉什大学医学中心的 4,985 名受试者分类为 AD-LB 共同病理 (AD+LB+)、单一 AD 病理 (AD+LB–)、单一 LB 病理 (AD–LB+) 或无病理 (AD–LB–)。我们对每个亚群 (NACC/Rush) 的全基因组关联研究 (GWAS) 与对照组 (AD–LB–) 进行了荟萃分析，并将 AD+LB+ 与 AD+LB– 组进行了比较。与 AD–LB– 相比，APOE-ε4 与 AD+LB– 和 AD+LB+ 的风险显着相关。然而，与 AD-LB- 相比，APOE-ε4 与 AD-LB+ 的风险无关，或者与 AD+LB- 相比，与 AD+LB+ 的风险无关。 BIN1 位点的关联表现出性质相似的结果。这些结果表明，APOE-ε4 是 AD 病理的危险因素，但当与 AD 病理分离时，则不是 LB 病理的危险因素。 BIN1 风险变体也是如此。这些发现是迄今为止最大的 AD-LB 神经病理学 GWAS 的结果，区分了单一和双重 AD-LB 病理表型的遗传危险因素。我们的 GWAS 荟萃分析汇总统计数据源自基于死后病理评估的表型，与基于临床诊断的 GWAS 相比，可能会提供更准确的疾病特异性多基因风险评分，而临床诊断可能会因未检测到的双重病理学和痴呆类型的临床误诊而混淆。
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, whetherAPOE-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 theBIN1locus exhibited qualitatively similar results. These results suggest thatAPOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds forBIN1risk 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.