Rajanderan, Thevashree, Leuterio Picones, Kate Marian, Maharajan, Marikannan, Ali, Asgar, Sami, Farheen, Ali, Md Sajid, Hasnain, Md Saquib, Gopinath, Divya, and Ansari, Mohammed Tahir (2025) Mechanistic insights into the potential of cyclodextrins as therapeutic excipients in Alzheimer’s disease: a systematic review and meta-analysis. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 106. pp. 49-63.

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Abstract

Introduction Cyclodextrins (CDs) are increasingly recognized for their therapeutic potential in Alzheimer’s disease (AD), with evidence supporting their role in modulating amyloid-beta (Aβ) aggregation, tau phosphorylation, cholesterol homeostasis, and oxidative damage. However, the relative effectiveness of these mechanisms has not been evaluated systematically.

Methods A systematic review was conducted using PubMed, Scopus, and Web of Science databases from January 2010 to June 2025, following the PRISMA guidelines. Experimental in vitro and in vivo studies involving CDs in AD models were included. A random-effects model estimated pooled effect sizes (Hedges’ g), with subgroup and moderator analyses, to examine mechanistic contributions. Publication bias was assessed using funnel plots, Egger’s test, and Rosenthal’s Fail-safe N.

Results A total of 1,819 articles were selected, of which 11 met the inclusion criteria. Four studies were eligible for quantitative synthesis. Among the included studies, key themes emerged highlighting the therapeutic impact of CDs in improving Aβ clearance, modulating tau phosphorylation, restoring lipid and cholesterol homeostasis, and attenuating oxidative stress.The pooled random effects estimate (Hedges’ g = 4.26, SE = 0.75, 95% CI [1.87–6.66], p < 0.001; I² = 45.2%) indicated a significant overall therapeutic benefits of CD based interventions. Subgroup analysis was conducted to study the mechanism specific intervention, and the analysis revealed a stronger effect of CDs in studies targeting Aβ/tau/cholesterol pathways than in those targeting oxidative stress modulation. Minimal evidence of publication bias was observed.

Discussion CDs demonstrated enhanced therapeutic impact when targeting core AD mechanisms, such as Aβ aggregation and cholesterol dysregulation, supporting their role as mechanistically targeted modulators of neurodegeneration. However, the supplementary antioxidant effect of CDs through broad-spectrum oxidative stress modulation should not be overlooked, as this mechanism also contributes to potential therapeutic interventions for AD, particularly in rodent models. This underscores the value of mechanism-specific interventions in neurodegeneration and supports CDs as possible modulators of disease progression through targeted molecular engagement.

Conclusion CDs, particularly HP-β-CD, show promising evidence in AD when mechanistically targeted, warranting further translational research in disease-specific contexts. However, caution should be exercised in interpreting these findings due to the limited number of studies and the preclinical nature of the available evidence.

Item ID:	92162
Item Type:	Article (Research - C1)
ISSN:	1573-1111
Copyright Information:	© The Author(s), under exclusive licence to Springer Nature B.V. 2025
Date Deposited:	08 Jun 2026 23:52
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