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.
摘要:
路易体(LB)病理学通常发生在患有阿尔茨海默病(AD)病理学的个体中。然而,目前尚不清楚哪些遗传风险因素是AD病理的基础,LB病理学,或AD-LB共病。值得注意的是,APOE-ε4是否独立于AD病理影响LB病理的风险存在争议。我们调整了来自文献的标准,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共病(AD+LB+)。唯一的AD病理(AD+LB-),唯一的LB病理(AD-LB+),或无病理学(AD-LB-)。与对照组(AD-LB-)相比,我们对每个亚群(NACC/Rush)的每个疾病表型进行了全基因组关联研究(GWAS)的荟萃分析,并比较AD+LB+与AD+LB-组。与AD-LB-相比,APOE-ε4与AD+LB-和AD+LB+的风险显著相关。然而,与AD-LB-相比,APOE-ε4与AD-LB+的风险或与AD+LB+的风险无关。BIN1基因座处的关联显示出定性相似的结果。这些结果表明,APOE-ε4是AD病理的危险因素,但当与AD病理学分离时,不用于LB病理学。BIN1风险变体也是如此。这些发现,在迄今为止最大的AD-LB神经病理学GWAS中,区分单独和双重AD-LB病理表型的遗传风险因素.我们的GWAS荟萃分析汇总统计数据,来自基于死后病理评估的表型,与基于临床诊断的GWAS相比,可以提供更准确的疾病特异性多基因风险评分,这可能与未发现的痴呆型双重病理和临床误诊混淆。