Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers

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; 1 mg/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.