Epidemiological research has consistently demonstrated a sizable difference in outcomes between those who are sedentary and those who conduct even a modest, low level of physical activity. More exercise is better, of course, but some researchers have have nonetheless focused on the degree to which small amounts of activity can be beneficial in older individuals. Here, for example, researchers show that relatively low levels of physical activity slow the progression towards outright Alzheimer's disease in patients with high levels of amyloid-β aggregation. The amyloid-β in and of itself causes only minor loss of cognitive function, but sets the stage for a later environment of inflammation and tau aggregation that causes much more severe damage to the brain and its function.
Physical inactivity is a recognized modifiable risk factor for Alzheimer's disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid.
Importantly, this beneficial association was not related to lower amyloid burden at baseline or longitudinally. Instead, higher physical activity was associated with slower amyloid-related inferior temporal tau accumulation, which significantly mediated the association with slower cognitive decline. Dose-response analyses further revealed a curvilinear relationship, where the associations with slower tau accumulation and cognitive decline reached a plateau at a moderate level of physical activity (5,001-7,500 steps per day), potentially offering a more approachable goal for older sedentary individuals.
Collectively, our findings support targeting physical inactivity as an intervention to modify the trajectory of preclinical AD in future prevention trials, and further suggest that preferentially enrolling sedentary individuals with elevated amyloid may maximize the likelihood of demonstrating a protective effect of physical activity on tau accumulation and cognitive and functional decline in early AD.
Link: https://doi.org/10.1038/s41591-025-03955-6
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