O3‐09‐01: PROTECTIVE EFFECT OF PHYSICAL ACTIVITY ON LONGITUDINAL COGNITIVE DECLINE AND NEURODEGENERATION IN CLINICALLY NORMAL OLDER ADULTS WITH ELEVATED β‐AMYLOID BURDEN

In the absence of disease-modifying therapies for Alzheimer's disease (AD), there is a critical need to identify potentially modifiable risk factors that may delay the progression of AD. Here, we examined the protective effect of physical activity on subsequent cognitive decline and neurodegeneration in individuals with elevated β-amyloid (Aβ) burden. We examined longitudinal imaging and cognitive data from 182 clinically-normal older adults in the Harvard Aging Brain Study (mean age=73.4±6.2 years). Baseline physical activity was quantified with a pedometer (mean steps per day). Baseline Aβ burden was measured with 11-C Pittsburgh Compound-B positron emission tomography. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC; median follow-up=6.0±1.1 years). Neurodegeneration was assessed with longitudinal structural magnetic resonance imaging (2–4 scans per subject, median follow-up=4.5±1.3 years). Physical activity and Aβ were examined as interactive predictors of cognitive decline and gray matter volume loss in separate linear mixed models, adjusting for covariates. Since neurodegeneration has been closely associated with cognitive decline, we also assessed whether gray matter atrophy mediates the association between physical activity and cognitive decline. In models predicting PACC decline and gray matter volume loss, there was a significant interaction of physical activity with Aβ burden, whereby greater physical activity attenuated the negative impact of Aβ burden on cognitive decline (t =3.7; P<0.001; Figure 1) and neurodegeneration (t =3.2; P=0.002; Figure 2). Adjusting for vascular risk, as measured by the Framingham Risk Score, did not alter these associations. In these models, lower vascular risk was independently associated with slower Aβ-related cognitive decline (t =3.6; P<0.001) and neurodegeneration (t =2.5; P=0.01). Follow-up regional analyses suggested that, in individuals with elevated Aβ burden, greater physical activity was associated with slower cortical thinning in medial and lateral temporal, medial parietal regions, and insula (Figure 3). Finally, mediation analyses revealed both significant direct and gray matter volume-mediated effects of physical activity on PACC decline in the setting of elevated Aβ burden.