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Objectives: Cardiovascular conditions like hypercholesterolemia and hypertension increase the risk for Alzheimer's Disease (AD). Thus, certain AD risk profiles may benefit from optimized multi- medication therapies including for example cholesterol-lowering and antihypertensive drugs. We previously showed that the drugs most frequently prescribed in older patients in Sweden are compounds from cardiovascular drug classes such as antithrombotic agents, lipid modifying agents, ACE inhibitors, selective calcium channel blockers and are used in combination. In this study we aim to investigate the effects of two multiple-drug regimens in the APPNL-G-F knock-in (APP KI) mouse model of AD and explore whether this could affect the disease progression at early stages. Methods: APP KI mice were fed for 2 months with a control or multi-medication diet (including anti- hypertensive, lipid lowering and psychotropic drugs, in two different combinations) based on the most used medications by older adults in Sweden. In addition to the multi-medication regimens, mice were also tested for specific monotherapies from the compounds used in combination. Animals were assessed for locomotion, cognition, and anxiety-like behavior. Brain tissues were collected for molecular biology experiments, while blood was analyzed by GC/LC-MS to measure serum metabolomics. Results: We found that multi-medication therapies in AD mice differentially affected essential functions such as locomotion, and distinct types of memory. APP KI male mice treated with combination#1 exhibited a rescue of cognitive deficits compared to controls, which we didn´t observe in females. These findings positively correlate with the significant reduction of cortical Aβ plaques observed in treated APP KI males. Conversely, combination#2 didn´t exert a positive effect on cognitive abilities. Monotherapy treatments induced different effects on functional and cognitive outcomes depending on sex, partially explaining the results observed in polypharmacy groups. Discussion: We show that multi-medication therapies comprising cardiovascular drugs like statins and β-blockers or ACE inhibitors may impact the progression of AD pathophysiology depending on sex and multiple-drug combination, suggesting some synergic effects deriving from the multi- medication rather than the administration of single compounds. The outcomes from this study can provide knowledge for designing more individualized therapies in aging and AD, taking sex and gender into special consideration.