Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer’s disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (nTotal = 2008, nPSP = 1037, nLBD-NP = 971) and Thal phase amyloid plaque scores (nTotal = 1786, nPSP = 1018, nLBD-NP = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46–4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = − 0.822, 95% CI − 1.439 to − 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = − 0.995, 95% CI − 1.773 to − 0.218, p = 0.012) than LBD-NP patients (ß = − 0.292, 95% CI − 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = − 0.638, 95% CI − 1.139 to − 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.

中文翻译：

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ABI3 和 PLCG2 错义变异与路易体病和进行性核上性麻痹的疾病风险和神经病理学的关联

错义变体 ABI3_rs616338-T 和 PLCG2_rs72824905-G 以前分别与阿尔茨海默病 (AD) 的风险升高或降低有关。尽管有报道称与其他神经退行性疾病有关，但在纯粹神经病理学诊断的队列中对这些变异的研究很少。此外，这些突变对神经退行性疾病病理的影响尚不清楚。在这项研究中，我们测试了 ABI3_rs616338-T 和 PLCG2_rs72824905-G 在尸检队列中对疾病风险的影响，该队列由 973 名神经病理学诊断为路易体病 (LBD-NP) 的患者和 1040 名进行性核上性麻痹 (PSP351) 的患者组成，与控件。根据 DLB 联盟标准，LBD-NP 患者被进一步分类为路易体临床痴呆的高、中和低可能性（DLB-CL）。我们还测试了与 Braak 神经原纤维 tau 缠结（nTotal = 2008，nPSP = 1037，nLBD-NP = 971）和 Thal 期淀粉样蛋白斑块评分（nTotal = 1786，nPSP = 1018，nLBD-NP = 768）的关联。此外，841 名 PSP 患者进行了定量的 tau 神经病理学测量，并针对遗传关联进行了评估。在我们的研究中，LBD-NP 或 PSP 与疾病风险没有统计学上的显着关联。LBD 中级疾病风险与 ABI3_rs616338-T 显着相关（OR = 2.65，95% CI 1.46–4.83，p = 0.001）。PLCG2_rs72824905-G 与较低的 Braak 分期相关（β = - 0.822，95% CI - 1.439 至 - 0.204，p = 0.009）。这种效应在 PSP 中比 LBD-NP 患者（β = - 0.995，95% CI - 1.773 至 - 0.218，p = 0.012）更明显（β = - 0.292，95% CI - 1.283 至 0.698，p = 0.563） . PLCG2_rs72824905-G 还显示与 PSP 中每种病变类型的定量 tau 病理学减少和总体 tau 负荷相关（β = - 0.638，95% CI - 1.139 至 - 0.136，p = 0.013）。这些发现支持 PLCG2_rs72824905-G 在抑制 tau 神经病理学中的作用。ABI3_rs616338-T 可能会特别影响 LBD-NP 中间类别的疾病风险，该类别由弥漫性新皮质或边缘 LB 患者组成，分别伴有中度或高度 AD 神经病理学。我们的研究为错义 PLCG2 变体提供了一种潜在的作用机制，并表明 ABI3 在不同的 LBD-NP 神经病理学类别中具有不同的疾病风险效应。这些发现支持 PLCG2_rs72824905-G 在抑制 tau 神经病理学中的作用。ABI3_rs616338-T 可能会特别影响 LBD-NP 中间类别的疾病风险，该类别由弥漫性新皮质或边缘 LB 患者组成，分别伴有中度或高度 AD 神经病理学。我们的研究为错义 PLCG2 变体提供了一种潜在的作用机制，并表明 ABI3 在不同的 LBD-NP 神经病理学类别中具有不同的疾病风险效应。这些发现支持 PLCG2_rs72824905-G 在抑制 tau 神经病理学中的作用。ABI3_rs616338-T 可能会特别影响 LBD-NP 中间类别的疾病风险，该类别由弥漫性新皮质或边缘 LB 患者组成，分别伴有中度或高度 AD 神经病理学。我们的研究为错义 PLCG2 变体提供了一种潜在的作用机制，并表明 ABI3 在不同的 LBD-NP 神经病理学类别中具有不同的疾病风险效应。