Table_1_Repetitive Transcranial Magnetic Stimulation for Alzheimer’s Disease Based on Apolipoprotein E Genotyping: Protocol for a Randomized Controlled Study.DOC

To date, there is a shortage of effective treatment strategies for Alzheimer’s disease (AD), and although repetitive transcranial magnetic stimulation (rTMS) can improve AD cognitive function, there are obvious individual differences, which may be related to different apolipoprotein E (APOE) genotypes. As the risk and pathogenesis of AD varies greatly among different genotypes precise treatment strategies should be implemented depending upon genotype, which has not been proved by clinical studies. Apart from that, the published clinical studies are highly heterogeneous, and therefore, systematic and well-developed randomized controlled Trails (RCT) and demonstration of precise administration protocols are required. To verify this hypothesis, this project designed a RCT study, and randomly divided apoE4 carrier AD and non-carrier AD into high-frequency rTMS (HF-rTMS) or low-frequency rTMS (LF-rTMS) treatment groups. Specifically, 80 patients with AD, namely 48 APOE4 carriers and 32 non-APOE4 carriers will be included in the study. After that, based on different stimulation frequencies of rTMS, they will be divided into the HF-rTMS group and the LF-rTMS group, when patients with AD will be randomly assigned to different treatment groups. After AD patients are involved in the study, their memory, cognition, anxiety, depression and activities of daily living will be tested before and during 2 weeks of rTMS. Furthermore, peripheral blood will be collected before and after treatment to detect changes in pathological indexes via MSD platform (Meso Scale Discovery), while 32-channel EEG data will be also collected to detect and analyze changes in gamma oscillation. In addition, these patients will be followed up for 6 months and their neuropsychological scale was also evaluated every month. At present, our study has included 18 AD patients (10 APOE4 carriers; 8 non-carriers). Our study is still in progress. The grouping has not been unblinded. But the preliminary data demonstrated that non-carriers had better MoCA score improvement than APOE4 carriers. The results indicated that the two populations of AD patients should be treated differently. Thus, this project will provide direction for precision rTMS in AD and also promotes a shift in relevant treatment philosophy.
Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR2100041625].

目前，阿尔茨海默病（Alzheimer’s disease, AD）仍缺乏有效的治疗策略。尽管重复经颅磁刺激（repetitive transcranial magnetic stimulation, rTMS）可改善AD患者的认知功能，但个体差异显著，该差异可能与不同的载脂蛋白E（apolipoprotein E, APOE）基因型相关。由于不同基因型AD患者的发病风险与发病机制差异显著，因此应根据基因型制定精准治疗策略，但该观点尚未得到临床研究证实。此外，已发表的相关临床研究异质性极高，因此亟需开展系统性、设计完善的随机对照试验（randomized controlled trial, RCT），并验证精准治疗方案。
为验证该假说，本项目设计了一项RCT研究，将APOEε4携带者AD患者与非携带者AD患者随机分入高频rTMS（HF-rTMS）组或低频rTMS（LF-rTMS）治疗组。本研究拟纳入80例AD患者，其中48例为APOEε4携带者，32例为非携带者。随后，根据rTMS刺激频率的差异，将AD患者随机分配至HF-rTMS组与LF-rTMS组。AD患者入组后，将在rTMS治疗前及治疗2周疗程内，对其记忆、认知、焦虑、抑郁及日常生活活动能力进行评估。此外，将在治疗前后采集外周血样本，通过介尺度发现平台（Meso Scale Discovery, MSD）检测病理指标变化；同时采集32通道脑电图（electroencephalogram, EEG）数据，以检测并分析γ振荡的变化。另外，将对所有患者开展6个月随访，每月评估一次神经心理学量表。
目前本研究已纳入18例AD患者（其中APOEε4携带者10例，非携带者8例），研究仍在进行中，分组信息尚未揭盲。但初步数据显示，非携带者AD患者的蒙特利尔认知评估量表（Montreal Cognitive Assessment, MoCA）评分改善效果优于APOEε4携带者。该结果提示，两类AD患者应采取差异化治疗方案。因此，本项目将为AD患者的精准rTMS治疗提供方向，并推动相关治疗理念的革新。
临床试验注册：[www.ClinicalTrials.gov]，编号[ChiCTR2100041625]。