Department of Neurology and Neurological Sciences, Stanford University, 290 Jane Stanford Way, E265, Stanford, CA, 94305-5090, USA.
Institut du Cerveau, Paris Brain Institute - ICM, Paris, France.
Acta Neuropathol Commun. 2023 Sep 12;11(1):149. doi: 10.1186/s40478-023-01626-6.
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 (ADLB), sole AD pathology (ADLB), sole LB pathology (ADLB), or no pathology (ADLB). 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 (ADLB), and compared the ADLB to ADLB groups. APOE-ε4 was significantly associated with risk of ADLB and ADLB compared to ADLB. However, APOE-ε4 was not associated with risk of ADLB compared to ADLB or risk of ADLB compared to ADLB. 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.
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导致 AD 病理学、LB 病理学或 AD-LB 共病。值得注意的是，APOE-ε4 是否独立于 AD 病理学影响 LB 病理学的风险仍存在争议。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 4985 名受试者分为 AD-LB 共病（ADLB）、单纯 AD 病理学（ADLB）、单纯 LB 病理学（ADLB）或无病理学（ADLB）。我们对每个疾病表型（NACC/Rush）进行了全基因组关联研究（GWAS）的荟萃分析，与对照组（ADLB）进行了比较，并将 APOE-ε4 与 ADLB 组进行了比较。APOE-ε4 与 ADLB 和 ADLB 相比，与 ADLB 的风险显著相关。然而，APOE-ε4 与 ADLB 相比，与 ADLB 的风险或 ADLB 相比，与 ADLB 的风险无关。BIN1 基因座的关联显示出定性相似的结果。这些结果表明，APOE-ε4 是 AD 病理学的风险因素，但当与 AD 病理学分离时，不是 LB 病理学的风险因素。BIN1 风险变异也存在同样的情况。这些发现，在迄今为止最大的 AD-LB 神经病理学 GWAS 中，区分了单纯和双重 AD-LB 病理学表型的遗传风险因素。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，可能提供更准确的疾病特异性多基因风险评分，因为后者可能受到未检测到的双重病理学和痴呆类型的临床误诊的混淆。
