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

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.