| Summary: | Therapeutic options for Alzheimer’s disease, the most common form of dementia, are currently restricted to palliative treatments. The glycosaminoglycan heparin, widely used as a clinical anticoagulant, has previously been shown to inhibit the Alzheimer’s disease-relevant β-secretase 1 (BACE1). Despite this, the deployment of pharmaceutical heparin for the treatment of Alzheimer’s disease is largely precluded by its potent anticoagulant activity. Furthermore, ongoing concerns regarding the use of mammalian-sourced heparins, primarily due to prion diseases and religious beliefs hinder the deployment of alternative heparin-based therapeutics. A marine-derived, heparan sulphate-containing glycosaminoglycan extract, isolated from the crab <i>Portunus pelagicus</i>, was identified to inhibit human BACE1 with comparable bioactivity to that of mammalian heparin (IC<sub>50</sub> = 1.85 μg mL<sup>−1</sup> (R<sup>2</sup> = 0.94) and 2.43 μg mL<sup>−1</sup> (R<sup>2</sup> = 0.93), respectively), while possessing highly attenuated anticoagulant activities. The results from several structural techniques suggest that the interactions between BACE1 and the extract from <i>P. pelagicus</i> are complex and distinct from those of heparin.
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