Changes in Plasma Aβ42/40 Ratio and p-Tau181 in Amyloid-Positive Patients Treated with Sirolimus

Abstract Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) accumulation and tau protein pathology. The Aβ42/40 ratio serves as a key biomarker of amyloid burden, with lower ratios associated with disease progression. Similarly, elevated levels of phosphorylated tau at threonine 181 (p-Tau181) reflect tau pathology and correlate with early neurodegenerative changes in AD. While monoclonal antibodies targeting Aβ have shown efficacy in modifying these biomarkers, alternative therapeutic approaches such as mTOR inhibition remain underexplored in humans. Three amyloid-positive patients received sirolimus (7 mg/week) as an off-label use of an FDA approved drug, with an average treatment duration of 22 weeks. Plasma levels of Aβ42/40 and p-Tau181 were measured at baseline, mid-treatment and post-treatment. No concurrent plaque-modifying therapies were administered. All patients demonstrated increases in the Aβ42/40 ratio (range: + 19.4% to + 37.0%), while p-Tau181 levels decreased in two patients (−11.1% and −28.9%). The first biomarker changes, observed within 12 weeks, may reflect an early and potentially rapid effect. Sirolimus was well-tolerated with no reported side effects or clinical decline. These exploratory findings suggest that sirolimus may affect key plasma biomarkers associated with AD. Given its FDA approval and lower cost relative to monoclonal antibodies, sirolimus may warrant further clinical investigation as a potential disease-modifying approach. Further studies with controlled designs are required to determine whether these biomarker changes translate into clinical outcomes.