Paez_2026_J.Alzheimers.Dis.Rep_10_25424823251387281

BACKGROUND: The aging global population faces significant challenges from Alzheimer's disease (AD). Metabolomics offers a non-invasive, cost-effective diagnostic alternative. Researchers identified significant variations in the level of salivary and urinary metabolites between AD patients and cognitively healthy controls. However, it's unclear whether differences in metabolites between AD patients and healthy controls are due to the disease or medications. OBJECTIVE: This study aims to investigate the impact of common AD medications (cholinesterase inhibitors) and hypertension medications (ARBs) on the AD patient metabolome. METHODS: A retrospective metabolomics analysis was conducted to elucidate whether observed metabolic perturbations were attributable to AD pathology or polypharmacy, with a specific focus on cholinesterase inhibitors and ARBs. RESULTS: Linear models revealed that cholinesterase inhibitors did not significantly modulate potential urinary and salivary biomarkers for AD. However, these inhibitors were associated with significant changes in urinary metabolite concentrations, including increased isovaleric acid and L-leucine and decreased formate and L-histidine (q = 0.027 for all). Analysis of ARB treatment revealed significantly reduced urinary tryptophan levels (q = 0.001) in AD patients and increased salivary acetone and isopropyl alcohol concentrations (q = 0.028) across all groups. Further analysis of saliva metabolite ratios revealed notable differences in asymmetric arginine methylation between the AD group and the control group (q = 0.021). Additionally, variations in citrate synthesis were observed between the mild cognitive impairment group and the control group on ARBs (q = 0.024). CONCLUSIONS: Our research confirms that distinct biomarker profiles characteristic of AD remain present regardless of cholinesterase inhibitor and ARB treatment, providing a foundation for future clinical studies and therapeutic development by providing better diagnostic tools.