Commonly prescribed multi-medication therapies exert sex-specific effects on Alzheimer's disease pathology and metabolomic profiles in AppNL-G-F mice: Implications for personalized therapeutics in aging

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-03-27 DOI:10.1002/alz.70081

Francesca Eroli, Kristina Johnell, Zeynep Acararicin, Christina Tsagkogianni, Stefania Zerial, Saverio Lancia, Maria Latorre-Leal, Vilma Alanko, Sarah N. Hilmer, Anna Matton, Jonas W. Wastesson, Angel Cedazo-Minguez, Silvia Maioli

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引用次数: 0

Abstract

INTRODUCTION

Polypharmacy is common among older adults and people with dementia. Multi-medication therapy poses risks of harm but also targets comorbidities and risk factors associated with dementia, offering therapeutic potential.

METHODS

We evaluated the effects of two polypharmacy regimens and monotherapies on male and female App^NL-G-F knock-in mice. We assessed functional, emotional, and cognitive outcomes;amyloid pathology; and serum metabolomics profiles.

RESULTS

A combination of metoprolol, simvastatin, aspirin, paracetamol, and citalopram improved memory, reduced amyloid burden and neuroinflammation, and modulated AD-associated metabolomic signatures in male mice, with negligible effects in female mice. Substituting two cardiovascular drugs impacted emotional domains but worsened memory, predominantly in female mice. In males, monotherapies could not explain the combination effects, suggesting drug synergy, whereas in female mice, certain monotherapy effects were lost when combined.

DISCUSSION

This study uncovers the sex-specific effects of polypharmacy in an AD model, identifying mechanisms and biomarkers that can guide gender-specific use of medicines in dementia prevention and management.

Highlights

Two polypharmacy combinations show sex-specific effects on AD pathology and serum metabolomic profiles.
Metoprolol+simvastatin+aspirin+paracetamol+citalopram improves memory and amyloid pathology in male mice.
Replacing metoprolol and simvastatin with enalapril and atorvastatin eliminates benefits in male mice and impairs memory in female mice.
Selected monotherapies produce sex-specific effects but only partially explain the outcomes of the combinations.
Metabolomic pathways in serum indicate possible mechanisms and biomarkers for evaluating the effectiveness and safety of personalized therapies in aging and dementia.

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.