The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies (DLB). In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2,466 DLB cases versus 2,928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for DLB in patients without APOE ε4 (p = 6.58 x 10⁻⁹, OR = 3.41, 95% CI = 2.25–5.17), but not with DLB with APOE ε4 (p = 0.034, OR = 1.87, 95%, 95% CI = 1.05–3.37). We then divided 495 neuropathologically examined DLB cases into three groups based on the extent of concomitant Alzheimer’s disease co-pathology: pure DLB (n = 88), DLB with intermediate Alzheimer’s disease co-pathology (DLB + iAD, n = 66), and DLB with high Alzheimer’s disease co-pathology (DLB + AD, n = 341). In each group, we tested the association of the APOE ε4 against the 2,928 neurologically healthy controls. Our examination found that APOE ε4 was associated with DLB + AD (p = 1.29x10⁻³², OR = 4.25, 95% CI = 3.35–5.39) and DLB + iAD (p = 0.0011, OR = 2.31, 95% CI = 1.40–3.83), but not with pure DLB (p = 0.31, OR = 0.75, 95% CI = 0.43–1.30). In conclusion, though deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure DLB, but rather implicate GBA as the main risk gene for the pure DLB subgroup.

中文翻译：

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路易体痴呆的遗传评估涉及不同的疾病亚组

APOE基因座与患阿尔茨海默病和路易体痴呆 (DLB)的风险密切相关。特别是， APOE ε4等位基因作为 α-突触核蛋白病理学推定驱动因素的作用是一个激烈争论的话题。在这里，我们对 2,466 例 DLB 病例与 2,928 例神经健康的老年对照进行了综合评估。使用APOE分层全基因组关联研究方法，我们发现GBA与不具有APOE ε4的患者的 DLB 风险相关（p  =  6.58 x 10 ^-9，OR = 3.41，95% CI = 2.25–5.17），但是不适用于具有APOE ε4的 DLB （p  =  0.034，OR = 1.87，95%，95% CI = 1.05–3.37）。然后，我们根据伴随阿尔茨海默病共同病理的程度将 495 例经过神经病理学检查的 DLB 病例分为三组：纯 DLB（n = 88）、具有中间阿尔茨海默病共同病理的 DLB（DLB + iAD，n = 66）和DLB 与阿尔茨海默病高度共存（DLB + AD，n = 341）。在每组中，我们测试了APOE ε4与 2,928 名神经系统健康对照者的关联。我们的检查发现APOE ε4与 DLB + AD ( p  =  1.29x10 ⁻³² , OR = 4.25, 95% CI = 3.35–5.39) 和 DLB + iAD ( p  =  0.0011, OR = 2.31, 95% CI = 1.40 )相关–3.83），但纯 DLB 则不然（p  =  0.31，OR = 0.75，95% CI = 0.43–1.30）。总之，虽然这些样本没有深入的临床数据，但我们的研究结果并不支持APOE ε4是纯 DLB 中 α-突触核蛋白病理学的独立驱动因素的观点，而是暗示GBA是纯 DLB 的主要风险基因子组。