Multi-Omics and Structural Modeling for Identifying Phytochemical Modulators of Pathogenic Tau States: Integrative Discovery Pipeline of Tau-Targeting Phytochemicals Using SNP Biomarker Screening, Structural Modeling, and Network Pharmacology

Tau being a difficult target: intrinsically disordered, conformationally plastic, heavily post-translationally modified, and capable of adopting multiple fibrillar states in disease. Genetic variation within MAPT (e.g., coding SNPs at regulatory phosphorylation sites such as S262, S356) and splicing-related haplotypes modulates tau’s biochemistry and disease risk. Tau hyperphosphorylation, misfolding and aggregation drive axonal transport failure, synaptic loss, and neuronal death across tauopathies. Traditional ligand-screens using a single tau construct miss the broader landscape of proteoforms and patient-specific variants. Phytochemicals or Polyphenols (e.g., curcumin, EGCG, resveratrol), alkaloids (berberine, huperzine A), and terpenoids (ginkgolides) emerged as dominant scaffolds. Quantitative mapping revealed these compounds consistently attenuate tau phosphorylation at key epitopes (S262, S356, S396/S404), inhibit fibrillization, and restore microtubule stability through multitarget actions on GSK3β, CDK5, and PP2A pathways. In this systematic review and scientometric analysis, we identified and profiled 186 studies investigating phytochemicals with tau-modulating activity. Mining of MAPT variant data highlighted regulatory SNPs near phosphorylation sites S262 and S356 that modulate tau’s phosphorylation kinetics and aggregation propensity. Network pharmacology linked tau and its regulatory enzymes to central hubs including VEGFA, IL1B, ESR1, and APP, suggesting that efficacious phytochemicals confer combined tau-directed and anti-inflammatory or neurotrophic effects. AlphaFold-based structural modeling of wild-type and variant tau isoforms enabled molecular docking of 42 prioritized compounds. Top-ranked hits curcumin analogs, EGCG, and asiaticoside exhibited strong binding near the microtubule-binding domain with favorable CNS permeability and low predicted toxicity based on ADMET profiling. Together, these analyses delineate phytochemical scaffolds that combine direct biochemical modulation of pathogenic tau states with network-level neuroprotective activity. The integrated genetic–structural–systems framework presented here provides a rational basis for advancing multitarget phytochemicals as stratified therapeutics in tauopathies.