Peptides and Peptide Analogues Targeting Acetylcholinesterase-Associated Mechanisms in Alzheimer’s Disease and Dementias: Evidence Gaps, Design Strategies, and Translational Perspectives

Alzheimer’s disease and related dementias involve interacting disturbances in amyloid-β, tau, neuroinflammation, oxidative stress, mitochondrial function, synaptic integrity, and cholinergic neurotransmission. Acetylcholinesterase, in addition to terminating cholinergic signalling through acetylcholine hydrolysis, participates in non-catalytic interactions associated with amyloid-β, providing a mechanistic rationale for multi-target therapeutic strategies. This critical narrative review evaluates natural acetylcholinesterase-inhibitory peptides, amyloid-targeting sequences, D-enantiomeric and retro-inverso analogues, endogenous and neuroprotective peptides, and selected peptidomimetic and multifunctional designs. The literature is considered according to an evidence hierarchy that distinguishes direct acetylcholinesterase/peripheral anionic site target engagement from independently demonstrated secondary mechanisms, cellular activity, central nervous system exposure, in vivo pharmacodynamics, and clinical efficacy. The reviewed evidence indicates that peptides and peptide-derived compounds offer substantial molecular recognition and structural adaptability and may, in principle, be engineered to combine selected cholinergic and disease-relevant functions. Importantly, no single candidate reviewed here has experimentally demonstrated all of the proposed cholinergic, anti-amyloid, anti-inflammatory, antioxidant, mitochondrial, and synaptoprotective activities simultaneously. However, neuroprotective, anti-amyloid, or cognitive effects alone do not establish direct acetylcholinesterase modulation, and many proposed multifunctional candidates lack experimental evidence of acetylcholinesterase/peripheral anionic site engagement. Overall, the available literature supports the feasibility of designing multifunctional peptide-based acetylcholinesterase-directed agents, but the evidence remains insufficient to establish a clinically validated class of multifunctional acetylcholinesterase modulators.