Systems Biology and Machine Learning Identify RAB2A as a Potential Target for Ocimum basilicum L. Volatile Intervention in Alzheimer's Disease via the Nose‐to‐Brain Pathway

ABSTRACT

Overcoming blood–brain barrier delivery limitations remains a critical challenge in Alzheimer's disease (AD) prevention. Ocimum basilicum L. ( O. basilicum ) volatiles possess physicochemical properties potentially favorable for nose‐to‐brain delivery. This study investigated their potential molecular mechanisms in AD using systems biology and machine learning. Volatile compounds were screened using physicochemical criteria. Weighted gene co‐expression network analysis and three machine learning algorithms (LASSO, XGBoost, and Random Forest) were integrated with clinicopathological analysis, risk assessment, single‐cell RNA sequencing, and molecular docking were employed to investigate potential mechanisms. Nineteen volatiles with potential nose‐to‐brain delivery properties were identified. RAB2A emerged as a core candidate target, with expression positively correlated with Braak staging. Single‐cell analysis revealed predominant neuronal expression, while functional enrichment implicated synaptic vesicle transport, oxidative phosphorylation, and neuroinflammatory regulation. Molecular docking results showed that RAB2A had active binding affinity with compounds such as 1,8‐cineole, γ‐terpinene, menth‐4‐ene‐3‐one, anethole, and menth‐4‐ene. Regulatory network analysis further implicated upstream transcription factor CTCF and Golgi‐associated proteins BLZF1, GORASP2, and RAB1A. These findings identify RAB2A as a potential target of O. basilicum volatiles, suggesting possible modulation of synaptic function, oxidative stress, and neuroinflammation and providing a theoretical basis for investigating nose‐to‐brain interventions in AD.