{
  "abstract": "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biochemistry and Pharmacogenomics, Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Joanna Zdunek"
    },
    {
      "affs": [
        0
      ],
      "name": "Błażej Grodner",
      "orcid": "0000-0003-2184-6796"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5vp4a4wpnh3sw.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27209094",
  "fulltext_url": "https://europepmc.org/articles/PMC13705407",
  "id": "5vp4a4wpnh3sw",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/20/9094",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2736|Cholinesterase and Neurodegenerative Diseases"
    ]
  ],
  "openalex": "W7221790749",
  "pdf_url": "https://europepmc.org/articles/PMC13705407?pdf=render",
  "pmcid": "PMC13705407",
  "pmid": "42941873",
  "published": "2026-10-14",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/5vp4a4wpnh3sw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:55Z",
      "native_id": "10.3390/ijms27209094",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/20/9094"
    },
    {
      "first_seen": "2026-10-30T12:22:12Z",
      "native_id": "MED:42941873",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42941873"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2736|Cholinesterase and Neurodegenerative Diseases",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Peptides and Peptide Analogues Targeting Acetylcholinesterase-Associated Mechanisms in Alzheimer’s Disease and Dementias: Evidence Gaps, Design Strategies, and Translational Perspectives",
  "title_text": "Peptides and Peptide Analogues Targeting Acetylcholinesterase-Associated Mechanisms in Alzheimer’s Disease and Dementias: Evidence Gaps, Design Strategies, and Translational Perspectives",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:12Z",
  "url": "https://research.draconitic.com/paper/5vp4a4wpnh3sw",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}