Segmented Linear Mixed Model Analysis Reveals Association of the APOEɛ4 Allele with Faster Rate of Alzheimer's Disease Dementia Progression.
Segmented Linear Mixed Model Analysis Reveals Association of the APOEɛ4 Allele with Faster Rate of Alzheimer's Disease Dementia Progression.
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DOI：
10.3233/jad-210434
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
中科院分区：
文献类型：
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作者：
Chen XR;Shao Y;Sadowski MJ;Alzheimer’s Disease Neuroimaging Initiative
APOE β 4等位基因携带者出现迟发性阿尔茨海默病（AD）的风险增加，在较早的年龄表现出认知症状，并且更有可能从轻度认知障碍（MCI）转变为痴呆症，但尽管如此，目前仍不清楚β 4等位基因是否控制疾病进展的速度。确定AD的MCI和痴呆阶段期间，E14等位基因对认知下降和脑萎缩率的影响。选择分段线性混合模型对73例MCI、99例MCI/AD和39例MCI/AD参与者的认知和脑体积数据进行纵向建模，这些参与者在研究期间从MCI转变为AD痴呆。104携带者在MMSE、ADAS-11、CDR-SB和莫卡量表上表现出更快的下降，最后两项测量在痴呆过渡后显示出显著的104等位基因剂量效应，但在MCI期间没有。在年轻的参与者和女性中，104效应更为普遍。在向痴呆转变后，MCI携带者的整个大脑、海马、内嗅皮层、颞中回和脑室扩张的萎缩率也更快，但在MCI期间则没有。拥有E14等位基因与AD所致痴呆的更快进展相关。我们的观察结果支持这样的观点，即APOE基因型不仅控制AD的风险，而且还差异调节神经退行性疾病的进展机制。此外，我们的研究结果对AD临床试验设计具有重要意义。
APOEɛ4 allele carriers present with an increased risk for late-onset Alzheimer’s disease (AD), show cognitive symptoms at an earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ4 allele controls the rate of disease progression. To determine the effects of the ɛ4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ɛ3/ɛ3, 99 ɛ3/ɛ4, and 39 ɛ4/ɛ4 Alzheimer’s Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. ɛ4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ4 allele-dose effects after dementia transition but not during MCI. The ɛ4 effect was more prevalent in younger participants and in females. ɛ4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. Possession of the ɛ4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.