Lin Ai-Ling, Aware Chetan, Neher Caitlin, Hamdi Mohammad, Ericsson Aaron, Khegai Oleksandr, Patrie James, Kurt Mehmet, Govindarajan Maalavika, Woods Carter, Ivanich Kira, Beversdorf David, Cheng Jianlin, Balchandani Priti, Gonzales Mitzi, Altes Talissa
University of Missouri.
University of Washington.
Res Sq. 2025 Mar 19:rs.3.rs-6214340. doi: 10.21203/rs.3.rs-6214340/v1.
Rapamycin, known for its anti-aging properties, shows promise as a preventive strategy for Alzheimer's disease (AD) in APOE4 carriers-the highest-risk group for late-onset AD. Here we show that a 4-week open-label trial of low-dose Rapamycin (Sirolimus; 1mg/day) significantly improved cerebral blood flow (CBF) relative to baseline in cognitively normal APOE4 carriers (E4(+)) aged 45-65. It also reduced inflammatory cytokines, enhanced lipid metabolism, increased short-chain fatty acids (SCFA) and enriched gut microbiome composition linked to SCFA production. Conversely, non-carriers (E4(-)) displayed stable baseline-to-post-treatment CBF and SCFA and demonstrated different treatment-related patterns of metabolic and anti-inflammatory effects than E4(+). Serum amyloid A and tau remained unchanged for both groups. These findings suggest Rapamycin may counter early vascular and metabolic deficits in E4(+) individuals, with genotype-specific effects. By bridging anti-aging research and AD prevention, this study highlights a novel, safe, and precision-based approach to mitigating AD risk in APOE4 carriers.
雷帕霉素以其抗衰老特性而闻名，对于载脂蛋白E4（APOE4）携带者（晚发性阿尔茨海默病的最高风险群体）而言，有望成为一种预防阿尔茨海默病（AD）的策略。在此，我们表明，一项针对45至65岁认知正常的APOE4携带者（E4(+)）进行的为期4周的低剂量雷帕霉素（西罗莫司；1毫克/天）开放标签试验，相对于基线水平，显著改善了脑血流量（CBF）。该试验还降低了炎性细胞因子，增强了脂质代谢，增加了短链脂肪酸（SCFA），并丰富了与SCFA产生相关的肠道微生物群组成。相反，非携带者（E4(-)）的治疗前至治疗后CBF和SCFA保持稳定，并且表现出与E4(+)不同的与治疗相关的代谢和抗炎效应模式。两组的血清淀粉样蛋白A和tau蛋白均保持不变。这些发现表明，雷帕霉素可能会对抗E4(+)个体早期的血管和代谢缺陷，具有基因型特异性效应。通过将抗衰老研究与AD预防联系起来，本研究突出了一种减轻APOE4携带者AD风险的新颖、安全且基于精准医学的方法。
