This study investigates the long-term effects of metformin treatment on cognitive function in Alzheimer's disease (AD) model mice. Metformin, a primary anti-diabetic medication, has been proposed as a potential treatment for AD, but some studies suggest it may trigger or exacerbate AD pathology. The researchers administered metformin to both non-transgenic (NT) and transgenic 3xTg-AD mice over their lifespan, evaluating multiple cognitive domains using touchscreen operant chambers. They found that metformin enhanced attention, inhibitory control, and associative learning in younger NT mice but impaired memory retention and discrimination learning in older NT mice. In 3xTg-AD mice, metformin treatment exacerbated AD pathology, including increased levels of Aβ oligomers, plaques, phosphorylated tau, and GSK3β expression. Metformin also upregulated the AMPKα1-subunit and decreased synaptic markers in primary neurons. The study concludes that the repurposing of metformin for AD treatment should be carefully reconsidered due to its potential to impair cognition and exacerbate AD pathology.This study investigates the long-term effects of metformin treatment on cognitive function in Alzheimer's disease (AD) model mice. Metformin, a primary anti-diabetic medication, has been proposed as a potential treatment for AD, but some studies suggest it may trigger or exacerbate AD pathology. The researchers administered metformin to both non-transgenic (NT) and transgenic 3xTg-AD mice over their lifespan, evaluating multiple cognitive domains using touchscreen operant chambers. They found that metformin enhanced attention, inhibitory control, and associative learning in younger NT mice but impaired memory retention and discrimination learning in older NT mice. In 3xTg-AD mice, metformin treatment exacerbated AD pathology, including increased levels of Aβ oligomers, plaques, phosphorylated tau, and GSK3β expression. Metformin also upregulated the AMPKα1-subunit and decreased synaptic markers in primary neurons. The study concludes that the repurposing of metformin for AD treatment should be carefully reconsidered due to its potential to impair cognition and exacerbate AD pathology.