Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition
Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition
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DOI：
10.1212/wnl.0000000000005415
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发表时间：
2018-05-01
期刊：
影响因子：
9.9
通讯作者：
Mormino, Elizabeth C.
中科院分区：
文献类型：
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作者：
Ge, Tian;Sabuncu, Mert R.;Mormino, Elizabeth C.
目的探讨阿尔茨海默病(AD)痴呆的遗传风险与β-淀粉样蛋白(Aβ)蓄积的关系。方法分析702例受试者(221例临床正常，367例轻度认知障碍，114例AD痴呆)的遗传资料和F-BET。另外，669名参与者还接受了纵向MRI扫描，以评估海马体体积。多基因风险分数(PRS)是根据先前AD痴呆的大规模全基因组关联研究的汇总统计数据来估计的。结果APOE epsilon 4与基线Aβ有很强的相关性，而Prs与基线Aβ只有微弱的相关性。此外，在Aβ+参与者中，apoE epsilon 4与更大的记忆力下降和海马区萎缩有关。当APOE epsilon 4被控制时，在Aβ+参与者中，prs与认知能力下降有关。结论AD痴呆的遗传危险因素存在与Aβ相关的效应，以及与Aβ之间的协同作用。在遗传风险较高的Aβ+个体中，认知衰退更快的具体影响可能解释了Aβ+个体在认知轨迹上的高度异质性。将遗传变异与基线Aβ结合起来考虑，可能会改善针对Aβ+个体的临床试验的丰富策略，这些个体面临即将到来的认知能力下降的风险。
ObjectiveTo investigate the effects of genetic risk of Alzheimer disease (AD) dementia in the context of beta-amyloid (A beta) accumulation.MethodsWe analyzed data from 702 participants (221 clinically normal, 367 with mild cognitive impairment, and 114 with AD dementia) with genetic data and florbetapir PET available. A subset of 669 participants additionally had longitudinal MRI scans to assess hippocampal volume. Polygenic risk scores (PRSs) were estimated with summary statistics from previous large-scale genome-wide association studies of AD dementia. We examined relationships between APOE epsilon 4 status and PRS with longitudinal A beta and cognitive and hippocampal volume measurements.ResultsAPOE epsilon 4 was strongly related to baseline A beta, whereas only weak associations between PRS and baseline A beta were present. APOE epsilon 4 was additionally related to greater memory decline and hippocampal atrophy in A beta+ participants. When APOE epsilon 4 was controlled for, PRS was related to cognitive decline in A beta+ participants. Finally, PRSs were associated with hippocampal atrophy in A beta- participants and weakly associated with baseline hippocampal volume in A beta+ participants.ConclusionsGenetic risk factors of AD dementia demonstrate effects related to A beta, as well as synergistic interactions with A beta. The specific effect of faster cognitive decline in A beta+ individuals with higher genetic risk may explain the large degree of heterogeneity in cognitive trajectories among A beta+ individuals. Consideration of genetic variants in conjunction with baseline A beta may improve enrichment strategies for clinical trials targeting A beta+ individuals most at risk for imminent cognitive decline.