Transcriptomics-guided mechanistic mapping of phytotherapeutics for alzheimer’s disease

ABSTRACT Introduction Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic impairment. Current therapies offer only modest relief and fail to address the complex molecular mechanisms underlying disease progression. Transcriptomic advances now enable genome-wide identification of disease-associated genes and signaling networks, opening avenues for precise phytotherapeutics. This review evaluated transcriptomics-guided studies of medicinal plants, phytochemicals, and herbal formulations in AD, focusing on differentially expressed genes, molecular targets, signaling pathways, and neuroprotective mechanisms relevant to disease modification. Methods A PRISMA 2020-guided structured review was conducted using PubMed and Scopus. Original English-language studies evaluating medicinal plants or phytochemicals via transcriptomic and multi-omics approaches were included. Qualitative synthesis was performed due to methodological heterogeneity among studies. Results Only fourteen transcriptomics-based studies met eligibility criteria. Medicinal plants and phytochemicals were reported to modulate several AD-associated pathways, including NF-κB, PI3K/Akt, MAPK, AMPK, NLRP3 inflammasome, SIRT1/NRF2, CREB/BDNF, autophagy, mitophagy, oxidative stress, neuroinflammation, mitochondrial function, synaptic plasticity, and immune signaling. Integration with proteomics, metabolomics, network pharmacology, molecular docking, and machine learning improved mechanistic interpretation and generated hypotheses for candidate multitarget phytotherapeutics. As nearly every agent was studied only once, often without orthogonal confirmation, these findings remain hypothesis-generating rather than experimentally validated. Discussion Transcriptomics-guided mechanistic mapping provides a hypothesis-generating framework for prioritizing candidate multitarget phytotherapeutics for subsequent experimental testing in Alzheimer's disease. Future integration of multi-omics, functional validation, and clinically relevant human models will accelerate translation toward precision medicine and natural product-based disease-modifying therapies.