The ε4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid beta (Aβ) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit Aβ retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in the mice that express human APOE4 gene and overexpress Aβ (the E4FAD mice). Another goal of the study was to identify the potential pharmacogenetic differences in response to rapamycin between the E4FAD and E3FAD mice, the mice with human APOE ε3 allele. We used multi-modal MRI to measure in vivo cerebral blood flow (CBF), neurotransmitter levels, white matter integrity, water content, cerebrovascular reactivity (CVR) and somatosensory response; used behavioral assessments to determine cognitive function; used biochemistry assays to determine Aβ retention and blood-brain barrier (BBB) functions; and used metabolomics to identify brain metabolic changes. We found that in the E4FAD mice, rapamycin normalized bodyweight, restored CBF (especially in female), BBB activity for Aβ transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice. As the multi-modal MRI methods used in the study are readily to be used in humans and rapamycin is FDA-approved, our results may pave a way for future clinical testing of the pharmacogenetic responses in humans with different APOE alleles, and potentially using rapamycin to prevent AD for asymptomatic APOE4 carriers.

中文翻译：

---

APOE 基因型依赖性雷帕霉素药物遗传学反应可预防阿尔茨海默病。


载脂蛋白 (APOE4) 的 ε4 等位基因是阿尔茨海默病 (AD) 的最强遗传风险因素，阿尔茨海默病是最常见的痴呆症。认知功能正常的 APOE4 携带者在出现认知障碍之前几十年就已经出现了β淀粉样蛋白 (Aβ) 斑块以及脑血管、代谢和结构缺陷。能够抑制 Aβ 滞留并使大脑功能恢复正常的干预措施对于无症状 APOE4 携带者预防 AD 至关重要。该研究的一个主要目标是确定雷帕霉素 (Rapa) 的潜在用途，雷帕霉素是一种延长寿命的药物干预措施，可预防表达人类 APOE4 基因和过度表达 Aβ 的小鼠（E4FAD 小鼠）患 AD。该研究的另一个目标是确定 E4FAD 和 E3FAD 小鼠（携带人类 APOE ε3 等位基因的小鼠）对雷帕霉素反应的潜在药物遗传学差异。我们使用多模态 MRI 测量体内脑血流量（CBF）、神经递质水平、白质完整性、含水量、脑血管反应性（CVR）和体感反应；使用行为评估来确定认知功能；使用生物化学测定来确定 Aβ 保留和血脑屏障 (BBB) 功能；并使用代谢组学来识别大脑代谢变化。我们发现，在 E4FAD 小鼠中，雷帕霉素使体重正常化，恢复 CBF（尤其是雌性小鼠）、Aβ 转运的 BBB 活性、神经递质水平、神经元完整性和游离脂肪酸水平，并减少 Aβ 保留，而这些在 E3FAD 小鼠中未观察到。拉帕小鼠。相比之下，E3FAD-Rapa 小鼠的 CVR 反应较低，焦虑程度较低，大脑糖酵解减少，而 E4FAD-Rapa 小鼠则没有出现这些情况。 此外，雷帕霉素似乎使 E4FAD 小鼠的脂质相关代谢正常化，同时减缓了 E3FAD 小鼠的整体葡萄糖相关代谢。最后，雷帕霉素增强了 E3FAD 和 E4FAD 小鼠的总体含水量、白质中的水扩散和空间记忆，但不影响后爪刺激下的体感反应。我们的研究结果表明，雷帕霉素能够恢复年轻、无症状 E4FAD 小鼠的大脑功能并降低 AD 风险，并且 E3FAD 和 E4FAD 小鼠之间存在药物遗传学差异。由于该研究中使用的多模态 MRI 方法很容易用于人类，并且雷帕霉素已获得 FDA 批准，因此我们的结果可能为未来对具有不同 APOE 等位基因的人类药物遗传学反应进行临床测试铺平道路，并可能使用雷帕霉素预防无症状 APOE4 携带者的 AD。