Conformation- and Timing-Resolved Effects of Natural Polyphenols on Amyloid-β: An Evidence-Graded Synthesis and Design Considerations

Natural polyphenols are routinely labeled as inhibitors of amyloid-β (Aβ) aggregation, yet many redirect or remodel selected assembly steps rather than suppressing them. Because Aβ occupies interconverting monomeric, oligomeric, protofibrillar and fibrillar states, apparent contradictions often reflect the starting state, treatment timing or endpoint rather than true discrepancies. A targeted, evidence-graded critical review integrates cell-free, cellular, animal and simulation studies across about 40 compound-class entries around the analytical unit chemotype × starting state × treatment timing, using oleuropein aglycone (OleA) as a case study and separating direct Aβ engagement from host-response, parent-compound, mixture and cross-amyloid evidence. Polyphenols can redistribute early ensembles, detoxify oligomers, remodel fibrils and promote clearance; activity tracks with aromatic recognition, hydrogen-bond topology, multivalency, glycosylation and oxidation state. Critically, a fall in the amyloid-dye signal does not establish reduced aggregate mass, toxicity or seeding. For OleA, direct evidence supports early redirection and late remodeling with reduced toxicity at supra-physiological excess. Anti-amyloid polyphenols should be evaluated as state-biased modulators. Well-supported conclusions require matched-timing experiments, orthogonal product accounting, toxicity and seeding on one preparation, and target engagement at achievable exposure. The review provides state-resolved evaluation standards and prioritized hypotheses, not validated design rules or evidence of clinical efficacy.