From the Psychiatric and Neurodevelopmental Genetics Unit (T.G., J.W.S.), Center for Genomic Medicine, Massachusetts General Hospital; Departments of Psychiatry (T.G., J.W.S.) and Neurology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (T.G., M.R.S.), Massachusetts General Hospital, Harvard Medical School, Charleston; School of Electrical and Computer Engineering and Nancy E. and Peter C. Meinig School of Biomedical Engineering (M.R.S.), Cornell University, Ithaca, NY; Center for Alzheimer Research and Treatment (R.A.S.), Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Department of Neurology and Neurological Sciences (E.C.M.), Stanford University School of Medicine, Palo Alto, CA.
Neurology. 2018 May 1;90(18):e1605-e1612. doi: 10.1212/WNL.0000000000005415. Epub 2018 Mar 28.
To investigate the effects of genetic risk of Alzheimer disease (AD) dementia in the context of β-amyloid (Aβ) accumulation.
We 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 ε4 status and PRS with longitudinal Aβ and cognitive and hippocampal volume measurements.
ε4 was strongly related to baseline Aβ, whereas only weak associations between PRS and baseline Aβ were present. ε4 was additionally related to greater memory decline and hippocampal atrophy in Aβ+ participants. When ε4 was controlled for, PRS was related to cognitive decline in Aβ+ participants. Finally, PRSs were associated with hippocampal atrophy in Aβ- participants and weakly associated with baseline hippocampal volume in Aβ+ participants.
Genetic risk factors of AD dementia demonstrate effects related to Aβ, as well as synergistic interactions with Aβ. The specific effect of faster cognitive decline in Aβ+ individuals with higher genetic risk may explain the large degree of heterogeneity in cognitive trajectories among Aβ+ individuals. Consideration of genetic variants in conjunction with baseline Aβ may improve enrichment strategies for clinical trials targeting Aβ+ individuals most at risk for imminent cognitive decline.
探讨在β-淀粉样蛋白（Aβ）积累的背景下，阿尔茨海默病（AD）痴呆的遗传风险的影响。
我们分析了 702 名参与者（221 名临床正常、367 名轻度认知障碍和 114 名 AD 痴呆）的数据，这些参与者具有遗传数据和可用的氟比他滨 PET。669 名参与者的一部分还进行了纵向 MRI 扫描，以评估海马体体积。多基因风险评分（PRS）是使用以前 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。我们检查了 ε4 状态和 PRS 与纵向 Aβ 以及认知和海马体体积测量之间的关系。
ε4 与基线 Aβ 有很强的关系，而 PRS 与基线 Aβ 之间仅存在微弱的关系。ε4 还与 Aβ+参与者的记忆衰退和海马体萎缩有关。当控制 ε4 时，PRS 与 Aβ+参与者的认知衰退有关。最后，PRS 与 Aβ-参与者的海马体萎缩有关，与 Aβ+参与者的基线海马体体积有微弱的关系。
AD 痴呆的遗传风险因素显示出与 Aβ 相关的作用，以及与 Aβ 的协同相互作用。在 Aβ+个体中，具有较高遗传风险的个体认知下降速度更快的特定效应可能解释了 Aβ+个体认知轨迹的高度异质性。考虑遗传变异与基线 Aβ 的结合可能会改善针对最有可能出现认知衰退的 Aβ+个体的临床试验的富集策略。
