Introduction: Alzheimer¿s disease (AD) is the most common neurodegenerative disease worldwide, characterized by progressive cognitive decline and, in advanced stages, marked motor impairments. These motor deficits are associated with muscle atrophy, mitochondrial dysfunction, and amyloid-ß (Aß) pathology affecting both motor brain areas and peripheral tissues, ultimately contributing to disability, fall risk, and reduced quality of life. Although physical exercise has been shown to confer cognitive and functional benefits in AD, to date, no studies have directly examined the relationship between motor performance and the underlying pathological mechanisms. This study introduces a novel approach by simultaneously addressing muscle pathology and mitochondrial alterations associated with motor decline. Methods: Twelve-month-old male triple-transgenic (3xTg-AD) and non-transgenic (Non-Tg) mice were assigned to sedentary or exercise groups (n¿=¿16 each group). The exercise protocol combined voluntary wheel running and forced treadmill training, 5¿days/week for 4¿months. Motor performance was evaluated using open-field, gait analysis, grip strength, and beam walking tests. Post-intervention, histological analyses evaluated Aß deposition and mitochondrial morphology, biochemical assays assessed mitochondrial function, and ELISA estimated Aß levels in the brain and muscle. Results: Physical exercise improved locomotion, balance, and strength in advanced stages of the disease, with modest benefits for memory. Histology showed reduced muscle atrophy and cortical amyloid, but not hippocampal. ELISA detected lower relative levels of Aß only in the brain. Exercise restored reduced muscle Complex I activity, increased brain Complex IV and ATPase in both tissues, and pronounced changes in mitochondrial morphology in muscle. Conclusion: This study provides the first evidence that physical exercise improves motor function and attenuates muscle and brain pathology in advanced stages of 3xTg-AD, supporting its potential as a complementary therapeutic strategy with translational relevance to humans.
