Higher physical activity levels mitigate synaptic protein loss and cognitive deterioration in aging and in Alzheimer's disease: a 10-year longitudinal study.

Synaptic degeneration is a hallmark of Alzheimer's disease (AD) and is closely linked to cognitive decline. Although physical activity (PA) can preserve synaptic integrity and cognitive function, its long-term effects during aging and AD progression remain poorly characterized. Here, we conducted a 10-year longitudinal study to investigate the effects of different PA levels on synaptic proteins and cognitive function during aging and in AD progression. The study included 231 cognitively normal older adults (preclinical AD, 116; controls, 115), who were stratified based on their PA intensity. Plasma was collected every 2 years to quantify four synaptic proteins (GAP43, neurogranin, SNAP25, and synaptotagmin 1) in neuron-derived extracellular vesicles (EVs), with concurrent cognitive assessments. The results indicated that all synaptic proteins declined over time, with a greater reduction in AD than in normal aging (P < 0.05). Synaptic protein levels did not differ between PA groups at baseline (P > 0.05), but at the 10-year follow-up, participants with higher PA had significantly greater synaptic protein levels than those with lower PA in both AD and controls (P < 0.05). Consistently, higher PA alleviated synaptic protein loss during aging (P < 0.05). Furthermore, higher PA was associated with slower cognitive decline in patients with preclinical AD (P < 0.05). Our study suggests that higher levels of PA may mitigate age- and AD-related synaptic deterioration, thereby contributing to cognitive resilience in late life.