Center for Computational Biology and Bioinformatics, Indiana Alzheimer Disease Center, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis.
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina.
JAMA Netw Open. 2019 Jul 3;2(7):e197978. doi: 10.1001/jamanetworkopen.2019.7978.
Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD.
To examine whether liver function markers are associated with cognitive dysfunction and the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD.
DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019.
Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables.
Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography.
Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], -0.465 [0.180]; P = .02 for memory composite score; β [SE], -0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], -0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], -0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers).
Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.
越来越多的证据表明，肝功能在阿尔茨海默病（AD）的病理生理学中起着重要作用。肝脏是一个主要的代谢中心；因此，研究肝功能与 AD、认知、神经影像学和 CSF 生物标志物之间的关联，将有助于提高对代谢功能障碍在 AD 中的作用的理解。
研究肝功能标志物是否与认知功能障碍以及 AD 的“A/T/N”（淀粉样蛋白、tau 和神经退行性变）生物标志物相关。
设计、地点和参与者：在这项队列研究中，从 2005 年 9 月 1 日至 2013 年 8 月 31 日，对 1581 名 AD 神经影像学倡议参与者进行了血清肝功能标志物的测量，同时还进行了认知测量、脑脊液（CSF）生物标志物、脑萎缩、脑葡萄糖代谢和淀粉样蛋白-β 积累。使用广义线性模型调整混杂变量和多重比较，评估肝功能标志物与 AD 相关的临床和 A/T/N 生物标志物之间的关联。统计分析于 2017 年 11 月 1 日至 2019 年 2 月 28 日进行。
AD 神经影像学倡议参与者的 5 种血清肝功能标志物（总胆红素、白蛋白、碱性磷酸酶、丙氨酸氨基转移酶和天冬氨酸氨基转移酶）被用作暴露因素。
主要结局包括 AD 的诊断、执行功能和记忆的综合评分、CSF 生物标志物、磁共振成像测量的脑萎缩、18F 氟脱氧葡萄糖（18F-FDG）正电子发射断层扫描测量的脑葡萄糖代谢和[18F]氟比替比正电子发射断层扫描测量的淀粉样蛋白-β 积累。
AD 神经影像学倡议（n=1581；697 名女性和 884 名男性；平均[SD]年龄，73.4[7.2]岁）包括 407 名认知正常的老年人、20 名有明显记忆问题的老年人、298 名早期轻度认知障碍患者、544 名晚期轻度认知障碍患者和 312 名 AD 患者。天冬氨酸氨基转移酶（AST）与丙氨酸氨基转移酶（ALT）比值升高和 ALT 水平降低与 AD 诊断相关（AST 与 ALT 比值：比值比，7.932[95%CI，1.673-37.617]；P=0.03；ALT：比值比，0.133[95%CI，0.042-0.422]；P=0.004）和认知表现不佳（AST 与 ALT 比值：β[SE]，-0.465[0.180]；P=0.02 用于记忆综合评分；β[SE]，-0.679[0.215]；P=0.006 用于执行功能综合评分；ALT：β[SE]，0.397[0.128]；P=0.006 用于记忆综合评分；β[SE]，0.637[0.152]；P<0.001 用于执行功能综合评分）。AST 与 ALT 比值升高与 CSF 淀粉样蛋白-β1-42 水平降低（β[SE]，-0.170[0.061]；P=0.04）和淀粉样蛋白-β 沉积增加（淀粉样蛋白生物标志物）、CSF 磷酸化 tau181 升高（β[SE]，0.175[0.055]；P=0.02）（tau 生物标志物）和 CSF 总 tau 水平升高（β[SE]，0.160[0.049]；P=0.02）和脑葡萄糖代谢减少（β[SE]，-0.123[0.042]；P=0.03）（神经退行性变生物标志物）相关。ALT 水平降低与淀粉样蛋白沉积增加（淀粉样蛋白生物标志物）和脑葡萄糖代谢减少（β[SE]，0.096[0.030]；P=0.02）以及脑萎缩（神经退行性变生物标志物）相关。
血清肝功能标志物与 AD 的认知表现和 A/T/N 生物标志物的一致关联突出了代谢紊乱在 AD 病理生理学中的作用。需要进一步的研究来确定这些关联是否代表因果关系或次要关系。肝脏酶在 AD 中的参与为新的诊断和治疗方法开辟了途径。
