Association of APOE Genotypes and Chronic Traumatic Encephalopathy.
Association of APOE Genotypes and Chronic Traumatic Encephalopathy.
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DOI：
10.1001/jamaneurol.2022.1634
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发表时间：
2022-08-01
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影响因子：
29
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这项遗传关联研究检测了APOE基因型与慢性创伤性脑病神经病理学和相关内源性表型之间的关联。载脂蛋白E ε4和ε2与慢性创伤性脑病（CTE）神经病理学和相关内源性表型相关吗？在这项对364名因接触性运动或军事服务而重复头部撞击暴露的脑供体（294名患有和70名没有神经病理学证实的CTE）的遗传关联研究中，APOEε4与年龄超过65岁的患者中的CTE分期和背外侧额叶中的定量磷酸化tau负荷显著相关。CTE阶段的APOEε4相关性大小与踢足球超过7年相似;未观察到APOEε2相关性。APOEε4可能会增加重复头部撞击暴露的老年人CTE相关神经病理学和临床结局的风险。反复头部撞击（RHI）暴露是慢性创伤性脑病（CTE）的主要危险因素。然而，CTE的发生率和严重程度在具有相似RHI暴露的那些人之间差异很大。有限的证据表明，APOEε4等位基因可能赋予CTE的风险，但以前的研究规模较小，范围有限。探讨载脂蛋白E基因型与CTE神经病理及相关内表型的关系。这项横断面遗传关联研究分析了2008年2月至2019年8月来自退伍军人事务-波士顿大学-脑震荡遗产基金会脑库的脑捐赠者。所有捐赠者都有接触RHI的接触体育或军事服务。所有符合条件的供体均纳入研究。分析于二零二零年六月至二零二二年四月期间进行。一个或多个APOEε4或APOEε2等位基因。CTE神经病理状态、CTE分期（0-IV）、11个脑区（0-3）中的半定量磷酸化tau（p-tau）负荷、背外侧额叶中的定量p-tau负荷（对数转换的AT 8+像素计数/mm 2）和痴呆。在364名连续脑供体（100%男性; 53名[14.6%]自我认定为黑人，311名[85.4%]为白色;中位数[IQR]年龄为65 [47-77]岁）20岁或以上，有294名CTE患者和70名对照。在年龄大于65岁的供者中，APOEε4状态与CTE分期显著相关（比值比[OR]，2.34 [95% CI，1.30-4.20];错误发现率[FDR]-校正P = 0.01）和背外侧额叶定量p-tau负荷（β，1.39 [95% CI，0.83-1.94]; FDR校正P = 2.37 × 10−5）。APOEε4状态与痴呆之间无显著相关性（OR，2.64 [95%CI，1.06-6.61]; FDR校正P = 0.08）。在11个大脑区域中，观察到额叶和顶叶皮质、杏仁核和内嗅皮质中半定量p-tau负荷的显著相关性（OR范围，2.45-3.26）。在足球运动员中，CTE阶段的APOEε4关联大小与踢足球超过7年相似。在年龄较大的一半样本中，相关性明显更大。CTE状态无显著相关性。当排除阿尔茨海默病神经病理学诊断的供体时，相关性大小相似，并且减少，但在调整神经炎和弥漫性淀粉样斑块后仍然显着。未观察到APOEε2状态的相关性。模型根据死亡时的年龄和种族进行了调整。APOEε4可能增加RHI暴露老年人CTE相关神经病理学和临床结局的风险。需要进一步的工作，以验证这些调查结果在一个独立的样本。
This genetic association study tests the association between APOE genotype and chronic traumatic encephalopathy neuropathology and related endophenotypes. Are APOEε4 and ε2 associated with chronic traumatic encephalopathy (CTE) neuropathology and related endophenotypes? In this genetic association study of 364 brain donors with repetitive head impact exposure from contact sports or military service (294 with and 70 without neuropathologically confirmed CTE), APOEε4 was significantly associated with CTE stage and quantitative phosphorylated tau burden in the dorsolateral frontal lobe among those older than 65 years. The APOEε4 association size for CTE stage was similar to playing more than 7 years of football; no associations were observed for APOEε2. APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with repetitive head impact exposure. Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope. To test the association between APOE genotype and CTE neuropathology and related endophenotypes. This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs–Boston University–Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022. One or more APOEε4 or APOEε2 alleles. CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8+ pixel count per mm2), and dementia. Of 364 consecutive brain donors (100% male; 53 [14.6%] self-identified as Black and 311 [85.4%] as White; median [IQR] age, 65 [47-77] years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio [OR], 2.34 [95% CI, 1.30-4.20]; false discovery rate [FDR]–corrected P = .01) and quantitative p-tau burden in the dorsolateral frontal lobe (β, 1.39 [95% CI, 0.83-1.94]; FDR-corrected P = 2.37 × 10−5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 [95% CI, 1.06-6.61]; FDR-corrected P = .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race. APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.