APOE ε4 and late-life cognition: mediation by structural brain imaging markers.
APOE ε4 and late-life cognition: mediation by structural brain imaging markers.
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DOI：
10.1007/s10654-022-00864-7
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发表时间：
2022-06
影响因子：
13.6
通讯作者：
Blacker, Deborah
中科院分区：
文献类型：
--
作者：
Ma, Yuan;Sajeev, Gautam;VanderWeele, Tyler J.;Viswanathan, Anand;Sigurdsson, Sigurdur;Eiriksdottir, Gudny;Aspelund, Thor;Betensky, Rebecca A.;Grodstein, Francine;Hofman, Albert;Gudnason, Vilmundur;Launer, Lenore;Blacker, Deborah
载脂蛋白E等位基因4(ApoE-ε4)是认知功能减退和迟发性阿尔茨海默病的主要遗传危险因素。越来越多的证据表明，ε4携带者与成年后大脑结构的异常变化有关。为了更好地了解潜在的因果机制，我们在基于人群的年龄、基因/环境易感性-雷克雅未克研究中调查了ε4等位基因对认知的影响在多大程度上是由结构性脑成像标记物介导的。这项研究包括4527名参与者(基线年龄为76.3±5.4岁)，他们在基线时接受了脑磁共振成像评估(脑组织体积、白质病变体积、皮质下和皮质下梗塞以及脑微出血)和一系列神经心理测试。通过因果中介分析，量化ε-4对认知功能的中介作用。我们观察到，在ε-4载体对认知的总影响中，约有9%是由白质损伤体积介导的。当脑组织总体积与脑白质病变体积联合考虑时，这一比例增加到25%。在分离ε4纯合子和ε4杂合子的分析中，特别是ε4纯合子对整体认知的影响似乎部分是由脑微出血，特别是脑叶微出血介导的。没有证据表明皮质或皮质下梗塞对ε-4的影响起到了中介作用。本研究表明，ε-4对认知功能的影响部分通过脑白质损毁体积和脑组织总体积实现。这些发现提示脑小血管病变和神经退行性变在ε-4-认知关系中的联合作用。
The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik). This study included 4,527 participants (aged 76.3±5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship.
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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：
11.2
作者：
Bennett, David A.;Wilson, Robert S.;Boyle, Patricia A.;Buchman, Aron S.;Schneider, Julie A.
通讯作者：
Schneider, Julie A.
影响因子：
11
作者：
Bennett, DA;Schneider, JA;Arnold, SE
通讯作者：
Arnold, SE
影响因子：
29
作者：
Ringman, John M.;Sachs, Michael C.;Vinters, Harry V.
通讯作者：
Vinters, Harry V.
影响因子：
9.9
作者：
Knol MJ;Lu D;Traylor M;Adams HHH;Romero JRJ;Smith AV;Fornage M;Hofer E;Liu J;Hostettler IC;Luciano M;Trompet S;Giese AK;Hilal S;van den Akker EB;Vojinovic D;Li S;Sigurdsson S;van der Lee SJ;Jack CR Jr;Wilson D;Yilmaz P;Satizabal CL;Liewald DCM;van der Grond J;Chen C;Saba Y;van der Lugt A;Bastin ME;Windham BG;Cheng CY;Pirpamer L;Kantarci K;Himali JJ;Yang Q;Morris Z;Beiser AS;Tozer DJ;Vernooij MW;Amin N;Beekman M;Koh JY;Stott DJ;Houlden H;Schmidt R;Gottesman RF;MacKinnon AD;DeCarli C;Gudnason V;Deary IJ;van Duijn CM;Slagboom PE;Wong TY;Rost NS;Jukema JW;Mosley TH;Werring DJ;Schmidt H;Wardlaw JM;Ikram MA;Seshadri S;Launer LJ;Markus HS;Alzheimer's Disease Neuroimaging Initiative
通讯作者：
Alzheimer's Disease Neuroimaging Initiative