Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome.
Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome.
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DOI：
10.1001/jamaneurol.2021.1893
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发表时间：
2021-08-01
期刊：
影响因子：
29
通讯作者：
Fortea J
中科院分区：
文献类型：
--
作者：
Bejanin A;Iulita MF;Vilaplana E;Carmona-Iragui M;Benejam B;Videla L;Barroeta I;Fernandez S;Altuna M;Pegueroles J;Montal V;Valldeneu S;Giménez S;González-Ortiz S;Muñoz L;Padilla C;Aranha MR;Estellés T;Illán-Gala I;Belbin O;Camacho V;Wilson LR;Annus T;Osorio RS;Videla S;Lehmann S;Holland AJ;Zetterberg H;Blennow K;Alcolea D;Clarimon J;Zaman SH;Blesa R;Lleó A;Fortea J
这项队列研究检查了阿尔茨海默病的症状和发病年龄;淀粉样蛋白，tau蛋白和神经变性生物标志物的变化;以及唐氏综合征成年人的大脑变化。载脂蛋白E（APOE）104等位基因与唐氏综合征阿尔茨海默病相关的临床和生物标志物变化有何关联？在这项对464例唐氏综合征成人患者的队列研究中，APOE β 4等位基因携带者既表现出阿尔茨海默病的早期临床症状，也表现出淀粉样蛋白（脑脊液Aβ1-42/1-40和淀粉样蛋白正电子发射断层扫描）、tau蛋白（血浆磷酸化tau 181）和神经变性（脑葡萄糖代谢低下和海马萎缩）生物标志物的早期变化。APOE β 4等位基因也改变了神经变性的地形。这项研究的结果表明，APOE β 4等位基因可以调节阿尔茨海默病的遗传形式，如唐氏综合征的临床表达和生物标志物。阿尔茨海默病（AD）是唐氏综合征（DS）患者死亡的主要原因。先前的研究表明，APOE β 4等位基因在DS痴呆发病的风险和年龄中起作用;然而，体内生物标志物的数据仍然很少。研究成人DS患者中APOE β 4等位基因与AD临床和多模式生物标志物的相关性。这项双中心队列研究招募了2009年6月1日至2020年2月28日期间在西班牙巴塞罗那和英国剑桥的DS成人。纳入的个体已进行了APOE基因分型，并具有至少1个临床或AD生物标志物测量结果; 2个个体因不存在21三体而被排除。参与者是APOE β 4等位基因携带者或非携带者。参与者接受了神经学和神经心理学评估。一部分受试者进行了生物标志物测量：脑脊液（CSF）中的Aβ1-42、Aβ1-40、磷酸化tau 181（pTau 181）和神经丝轻链（NfL）、血浆中的pTau 181和NfL;淀粉样蛋白正电子发射断层扫描（PET）;氟18标记的氟脱氧葡萄糖PET;和/或磁共振成像。比较APOE β 4等位基因携带者和非携带者症状发作时的年龄，并使用组内局部回归模型比较生物标志物与年龄的相关性。进行体素分析以评估灰质代谢和体积的地形差异。在纳入研究的464例DS成人中，97例（20.9%）为APOE β 4等位基因携带者，367例（79.1%）为非携带者。两组之间的年龄（中位数[四分位数间距]，45.9 [36.4-50.2]岁vs 43.7 [34.9-50.2]岁; P = 0.56）或性别（51名男性携带者[52.6%] vs 199名男性非携带者[54.2%]）无差异。与非携带者相比，APOE β 4等位基因携带者出现AD症状的年龄更小（平均[SD]年龄，50.7 [4.4]岁vs 52.7 [5.8]岁; P = 0.02），并且表现出更早的认知能力下降。局部估计的散点图平滑曲线进一步显示了生物标志物轨迹随年龄的组间差异，如非重叠CI所反映的。具体而言，携带者在40岁之前CSF Aβ1-42/Aβ1-40比值水平较低，淀粉样蛋白PET和血浆pTau 181较早升高，皮质代谢和海马体积较早丧失。在NfL生物标志物或CSF总tau和pTau 181中未发现差异。体素分析显示，APOE β 4等位基因携带者皮质下和顶枕结构的代谢较低，颞叶内侧体积较低。在这项研究中，APOE β 4等位基因与DS患者AD的早期临床和生物标志物变化相关。这些结果为APOE增加AD风险的机制提供了见解，强调了APOE基因型对未来DS临床试验的重要性。
This cohort study examines Alzheimer disease symptoms and age at onset; changes in amyloid, tau, and neurodegeneration biomarkers; and topography of brain changes in adults with Down syndrome. What is the association of the apolipoprotein E (APOE) ɛ4 allele with Alzheimer disease–related clinical and biomarker changes in Down syndrome? In this cohort study of 464 adults with Down syndrome, carriers of the APOE ɛ4 allele showed both earlier clinical symptoms of Alzheimer disease and earlier changes in amyloid (cerebrospinal fluid Aβ1-42/1-40 and amyloid positron emission tomography), tau (plasma phosphorylated tau 181), and neurodegeneration (cerebral glucose hypometabolism and hippocampal atrophy) biomarkers. The APOE ɛ4 allele also altered the topography of neurodegeneration. Results of this study suggest that the APOE ɛ4 allele can modulate both the clinical expression and the biomarkers of Alzheimer disease in a genetic form of the disease, such as in Down syndrome. Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce. To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS. This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers. Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18–labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume. Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers. In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.
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DOI：
10.1352/1944-7558-120.6.481
发表时间：
2015-11-01
影响因子：
2.1
作者：
Benejam, Bessy;Fortea, Juan;Videla, Sebastia
通讯作者：
Videla, Sebastia
影响因子：
5.3
作者：
Firth NC;Startin CM;Hithersay R;Hamburg S;Wijeratne PA;Mok KY;Hardy J;Alexander DC;LonDownS Consortium;Strydom A
通讯作者：
Strydom A
DOI：
10.1073/pnas.92.8.3586
发表时间：
1995-04-11
影响因子：
11.1
作者：
HYMAN, BT;WEST, HL;STANLEY, HE
通讯作者：
STANLEY, HE
DOI：
10.1002/dad2.12057
发表时间：
2020-01-01
影响因子：
5.3
作者：
Henson, Rachel L.;Doran, Eric;Fagan, Anne M.
通讯作者：
Fagan, Anne M.
影响因子：
120.7
作者：
Jansen, Willemijn J.;Ossenkoppele, Rik;Knol, Dirk L.;Tijms, Betty M.;Scheltens, Philip;Verhey, Frans R. J.;Visser, Pieter Jelle
通讯作者：
Visser, Pieter Jelle