Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.
Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.
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DOI：
10.1093/braincomms/fcaa167
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发表时间：
2020
影响因子：
4.8
通讯作者：
Mill J
中科院分区：
文献类型：
--
作者：
Hannon E;Shireby GL;Brookes K;Attems J;Sims R;Cairns NJ;Love S;Thomas AJ;Morgan K;Francis PT;Mill J
阿尔茨海默病是一种高度可遗传的常见神经退行性疾病，其神经病理特征是β-淀粉样斑块和含有tau的神经纤维缠结积聚。除了与APOE基因座相关的公认风险外，在识别与阿尔茨海默病相关的其他遗传变异方面也取得了相当大的成功。了解遗传风险如何影响阿尔茨海默病的发展的主要挑战是临床和神经病理的异质性，以及伴随的高水平的共病。我们报告了一项多模式分析，将纵向临床和认知评估与神经病理数据相结合，作为痴呆症大脑研究的一部分，以了解阿尔茨海默病的遗传风险因素如何影响神经病理和临床表现的发展。这项研究包括693名痴呆症大脑研究队列中的捐赠者，包括遗传数据、半定量神经病理学测量、认知评估和既定的诊断标准。我们测试了APOE基因和阿尔茨海默病多基因风险评分(一种衡量遗传负担的量化指标)与存活率、阿尔茨海默病大脑四种常见神经病理特征(神经原纤维缠结、β-淀粉样斑块、路易小体和反式反应DNA结合蛋白43蛋白病)、临床状态(临床痴呆症评级)和认知表现(简易智力状态考试、蒙特利尔认知评估)的关系。在痴呆症研究队列中，载脂蛋白Eε4等位基因与大脑死亡的年轻年龄显著相关。我们对神经病理学的分析强调了APOEε4的两条独立途径，一条是β-淀粉样蛋白堆积与直肠病变的发展同时发生，另一条是独立于β-淀粉样变性的对直肠病变的直接影响。虽然我们也检测到载脂蛋白Eε4与痴呆状态和认知表现之间的关联，但这些都是由tautation调节的，强调它们是神经病理变化的结果。对多基因风险评分的分析确定了与直立性病变和β-淀粉样变性的关联，这似乎具有共同和独特的贡献，表明与阿尔茨海默病相关的不同基因变异在不同程度上影响神经病理的不同特征。综上所述，我们的结果为阿尔茨海默病的遗传风险如何影响痴呆的临床和病理特征提供了洞察力，增加了我们对APOE基因和其他遗传风险因素之间相互作用的理解。我们报告了一项多模式分析，分析了阿尔茨海默病的遗传风险因素如何影响痴呆研究(BDR)大脑中神经病理和临床表现的发展，强调了APOE与甲状旁腺病变和β-淀粉样变性的发展之间的共同路径，以及与直肠病变相关的独立路径。
Alzheimer’s disease is a highly heritable, common neurodegenerative disease characterized neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the APOE locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer’s disease. Major challenges in understanding how genetic risk influences the development of Alzheimer’s disease are clinical and neuropathological heterogeneity, and the high level of accompanying comorbidities. We report a multimodal analysis integrating longitudinal clinical and cognitive assessment with neuropathological data collected as part of the Brains for Dementia Research study to understand how genetic risk factors for Alzheimer’s disease influence the development of neuropathology and clinical performance. Six hundred and ninety-three donors in the Brains for Dementia Research cohort with genetic data, semi-quantitative neuropathology measurements, cognitive assessments and established diagnostic criteria were included in this study. We tested the association of APOE genotype and Alzheimer’s disease polygenic risk score—a quantitative measure of genetic burden—with survival, four common neuropathological features in Alzheimer’s disease brains (neurofibrillary tangles, β-amyloid plaques, Lewy bodies and transactive response DNA-binding protein 43 proteinopathy), clinical status (clinical dementia rating) and cognitive performance (Mini-Mental State Exam, Montreal Cognitive Assessment). The APOE ε4 allele was significantly associated with younger age of death in the Brains for Dementia Research cohort. Our analyses of neuropathology highlighted two independent pathways from APOE ε4, one where β-amyloid accumulation co-occurs with the development of tauopathy, and a second characterized by direct effects on tauopathy independent of β-amyloidosis. Although we also detected association between APOE ε4 and dementia status and cognitive performance, these were all mediated by tauopathy, highlighting that they are a consequence of the neuropathological changes. Analyses of polygenic risk score identified associations with tauopathy and β-amyloidosis, which appeared to have both shared and unique contributions, suggesting that different genetic variants associated with Alzheimer’s disease affect different features of neuropathology to different degrees. Taken together, our results provide insight into how genetic risk for Alzheimer’s disease influences both the clinical and pathological features of dementia, increasing our understanding about the interplay between APOE genotype and other genetic risk factors. We report a multimodal analysis profiling how genetic risk factors for Alzheimer’s disease influence the development of neuropathology and clinical performance in the Brains for Dementia Research (BDR) study, highlighting a shared pathway between APOE and the development of tauopathy and beta-amyloidosis and an independent pathway associated with tauopathy.
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影响因子：
11.2
作者：
Boyle PA;Yu L;Wilson RS;Leurgans SE;Schneider JA;Bennett DA
通讯作者：
Bennett DA
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
4.2
作者：
Blauwendraat C;Faghri F;Pihlstrom L;Geiger JT;Elbaz A;Lesage S;Corvol JC;May P;Nicolas A;Abramzon Y;Murphy NA;Gibbs JR;Ryten M;Ferrari R;Bras J;Guerreiro R;Williams J;Sims R;Lubbe S;Hernandez DG;Mok KY;Robak L;Campbell RH;Rogaeva E;Traynor BJ;Chia R;Chung SJ;International Parkinson's Disease Genomics Consortium (IPDGC), COURAGE-PD Consortium;Hardy JA;Brice A;Wood NW;Houlden H;Shulman JM;Morris HR;Gasser T;Krüger R;Heutink P;Sharma M;Simón-Sánchez J;Nalls MA;Singleton AB;Scholz SW
通讯作者：
Scholz SW
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
5.7
作者：
Corlier F;Hafzalla G;Faskowitz J;Kuller LH;Becker JT;Lopez OL;Thompson PM;Braskie MN
通讯作者：
Braskie MN