Physical activity as a modifiable risk factor in preclinical Alzheimer's disease

Abstract

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.

Fig. 1. Associations of baseline physical activity with longitudinal Aβ, tau and cognition.

a, Linear mixed effects model revealed no association between baseline physical activity and longitudinal Aβ burden (β = −0.0006 [−0.01 to 0.01], P = 0.92; n = 241). b–d, By contrast, there were significant interactions between baseline physical activity and Aβ burden on longitudinal ITC tau burden (b), longitudinal cognition measured with PACC5 (c) and longitudinal functional decline measured with CDR-SOB scores (d). Individuals with high baseline physical activity and elevated Aβ (solid red line) showed slower ITC tau accumulation (β = −0.13 [−0.19 to −0.06], P < 0.001; n = 172) (b), slower PACC5 decline (β = 0.10 [0.05 to 0.16], P < 0.001; n = 296) (c) and slower CDR-SOB progression (β = −0.14 [−0.22 to −0.05], P = 0.001; n = 296) (d). Statistical significance was assessed using two-tailed t-tests, with P < 0.05 considered statistically significant without adjustment for multiple comparisons. Baseline physical activity (mean steps per day) and Aβ burden were modeled as continuous variables. To visualize the model results, the estimated trajectories based on representative levels of low versus high baseline physical activity and (for tau, PACC5 and CDR-SOB models) low versus high baseline Aβ burden are presented, with error bands representing 95% confidence intervals for the estimated trajectories. Low and high physical activity are represented by −1 and +1 s.d. relative to the mean (low, 2,800 steps per day; high, 8,700 steps per day). Low and high Aβ are represented, for illustration purposes, by the mean Aβ burden of Aβ-negative (PiB PVC-DVR = 1.17) and Aβ-positive (PiB PVC-DVR = 1.85) participants, respectively. The numbers of participants contributing longitudinal data to each 2.5-year segment for the respective statistical models are summarized in Extended Data Table 5.

Fig. 2. Tau accumulation mediated the associations between physical activity and cognitive/functional decline in preclinical AD.

a,b, Individual slopes for ITC tau, PACC5 (a) and CDR-SOB (b) were extracted from linear mixed effects models for moderated mediation analyses (n = 172; in participants who have both longitudinal tau and cognitive data). We modeled physical activity (mean steps per day) as predictor, ITC tau slope as mediator and PACC5 or CDR-SOB slopes as outcome. Both physical activity and Aβ burden were modeled as continuous variables in the mediation models. For the moderation analyses, low and high levels of Aβ burden were represented by the mean Aβ burden of Aβ-negative (PiB PVC-DVR = 1.17) and Aβ-positive (PiB PVC-DVR = 1.85) participants, respectively. Statistical testing was performed using a quasi-Bayesian Monte Carlo method based on 10,000 simulations to generate the estimates and 95% confidence intervals, with two-tailed P < 0.05 considered statistically significant without adjustment for multiple comparisons. Results demonstrated that at an elevated level of baseline Aβ burden, slower ITC tau accumulation fully mediated the association between higher physical activity and slower PACC5 decline (β = 0.59 [0.32 to 0.91], P < 0.001, 84% mediated) (a) and partially mediated the association between higher physical activity and slower CDR-SOB progression (β = −0.43 [−0.71 to −0.20], P < 0.001, 40% mediated) (b). In individuals with low baseline Aβ burden, there were no significant total or mediated effects of physical activity on PACC5 decline (total effect: β = 0.03 [−0.27 to 0.31], P = 0.85; mediated effect: β = −0.002 [−0.16 to 0.15], P = 0.98) or CDR-SOB progression (total effect: β = 0.05 [−0.28 to 0.37], P = 0.75; mediated effect: β = 0.001 [−0.11 to 0.12], P = 0.98). The error bars represent the 95% confidence intervals for the estimated mediated, direct and total effects.

Fig. 3. Physical activity levels and changes in tau and cognition in preclinical AD.

a–c, Using extracted slopes for ITC tau (n = 172) (a), PACC5 (b) and CDR-SOB (c) (PACC5 and CDR-SOB, n = 296), we examined the interactive effects of baseline physical activity level (ordinal) and Aβ burden (continuous) using linear regression models. Levels of physical activity (ordinal) were defined as inactive (≤3,000 steps), low activity (3,001–5,000 steps), moderate activity (5,001–7,500 steps) and active (≥7,501 steps). The number of individuals in each physical activity subgroup included in the tau, PACC5 and CDR-SOB analyses are summarized in Extended Data Table 1. Aβ burden was modeled as a continuous variable. For illustration purposes, low and high Aβ are represented by the mean Aβ burden of Aβ-negative (PiB PVC-DVR = 1.17) and Aβ-positive (PiB PVC-DVR = 1.85) participants, respectively. The error bars represent the 95% confidence intervals for the estimated effects of physical activity levels on tau and cognitive slopes at representative levels of low and high Aβ burden. Results demonstrate that in individuals with elevated baseline Aβ, even low levels of physical activity (3,001–5,000 steps) were associated with substantially slower rates of tau accumulation and cognitive decline compared to inactive individuals. There were further attenuations of tau accumulation and cognitive and functional decline at moderate activity (5,001–7,500 steps per day), with similar rates in the active group (≥7,501 steps per day).

Extended Data Fig. 1. Individual longitudinal Aβ, tau, PACC5 and CDR-SOB trajectories.

Individual trajectories of (a) global Aβ, (b) inferior temporal cortex (ITC) tau, (c) Preclinical Alzheimer’s Cognitive Composite-5 (PACC5) scores, and d) Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores from all participants are shown without adjustment for any covariates. To allow clear visualization of the individual trajectories, participants were plotted according to high versus low baseline Aβ burden in columns and physical activity (mean steps per day) in rows, defined by above and below the median values. The trajectories are color coded by baseline Aβ burden according to the color bar, with each line representing one participant. The number of participants represented in each facet is provided for reference. The time of baseline PiB PET was used as the study baseline (time = 0). Timing of the first tau PET scan varied across participants (2.2 ± 1.5 years), as tau PET was introduced mid-study when it became available. Aβ = beta-amyloid; DVR = distribution volume ratio; PVC = partial volume correction; PiB = Pittsburgh compound-B; SUVR = standardized uptake value ratio.

Extended Data Fig. 2. Interactive association between baseline physical activity and Aβ burden on initial ITC tau burden.

Linear regression model revealed a significant interaction between baseline physical activity and Aβ burden on initial inferior temporal cortex (ITC) tau burden (Physical activity*Aβ: β = -0.19 [-0.30 to -0.08], p = 0.001), adjusting for age, sex, years of education, and time interval between study baseline and first tau scan. There was no significant independent effect of physical activity on tau (Physical activity: β = -0.06 [-0.18 to 0.05], p = 0.28). Statistical significance was assessed using two-tailed t-tests, with p < 0.05 considered statistically significant without adjustment for multiple comparisons. Physical activity (mean steps per day) was square-root transformed prior to model entry to account for skewness with improvement in model fit (reduced BIC by 2.2). Non-transformed mean steps per day was used to plot the model result to enhance interpretability. Baseline Aβ burden was modeled as a continuous variable. To visualize the model results, the estimated ITC tau burden across the range of baseline physical activity at representative levels of low versus high baseline Aβ burden are presented. Error bands represent the 95% confidence intervals for the estimated tau burden. Low and high Aβ are represented, for illustration purposes, by the mean Aβ burden of Aβ-negative (PiB PVC-DVR 1.17) and Aβ-positive (PiB PVC-DVR 1.85) participants respectively. Aβ = beta-amyloid; DVR = distribution volume ratio; ITC = inferior temporal cortex; PVC = partial volume correction; SUVR = standardized uptake value ratio.

Extended Data Fig. 3. Interactive association between cross-sectional Aβ and initial ITC tau burdens on baseline physical activity.

Linear regression model revealed no significant interaction between cross-sectional Aβ and ITC tau burdens on baseline physical activity (Aβ*ITC tau: β = -0.04 [-0.15 to -0.07], p = 0.44), adjusting for age, sex, years of education, and time interval between study baseline and first tau scan. There were further no significant independent effects of Aβ or ITC tau on baseline physical activity (Aβ: β = 0.10 [-0.07 to 0.28], t = 1.16, p = 0.25; ITC tau: β = 0.01 [-0.21 to 0.22], p = 0.96). Statistical significance was assessed using two-tailed t-tests, with p < 0.05 considered statistically significant without adjustment for multiple comparisons. Physical activity (mean steps per day) was square-root transformed prior to model entry, but non-transformed mean steps per day was used to plot the model result to enhance interpretability. Baseline Aβ burden was modeled as a continuous variable. To visualize the model results, the estimated means steps per day across the range of initial ITC tau burden at representative levels of low versus high baseline Aβ burden are presented. Error bands represent the 95% confidence intervals for the estimated mean steps per day. Low and high Aβ are represented, for illustration purposes, by the mean Aβ burden of Aβ-negative (PiB PVC-DVR 1.17) and Aβ-positive (PiB PVC-DVR 1.85) participants respectively. Aβ = beta-amyloid; DVR = distribution volume ratio; ITC = inferior temporal cortex; PVC = partial volume correction; SUVR = standardized uptake value ratio.

Extended Data Fig. 4. Association between physical activity levels and baseline Aβ burden on longitudinal (a) PACC5 decline and (b) CDR-SOB progression.

Linear mixed effects models revealed interaction between baseline physical activity levels (ordinal) and Aβ burden (continuous) on longitudinal PACC5 decline and CDR-SOB progression. Using the inactive subgroup as reference, all higher levels of physical activity were associated with slower Aβ-related PACC5 decline and CDR-SOB progression, except the slower CDR-SOB progression in the low activity group did not reach statistical significance (Table 3). To visualize the model results, the estimated trajectories based on representative levels of low versus high baseline Aβ burden across physical activity levels are presented, with error bands representing 95% confidence intervals for the estimated trajectories. Low and high Aβ are represented, for illustration purposes, by the mean Aβ burden of Aβ-negative (PiB PVC-DVR 1.17) and Aβ-positive (PiB PVC-DVR 1.85) participants respectively, defined using the conventional Aβ-positivity threshold (PiB PVC-DVR of 1.324). The horizontal dotted line represents thresholds for cognitive impairment (-1.5 PACC5 z-score) and functional decline (1.5 points on CDR-SOB). The vertical dot-dash line represents median duration of cognitive follow-up (9 years). Aβ = β-amyloid; DVR = distribution volume ratio; PiB = Pittsburgh compound-B; PVC = partial volume corrected; SUVR = standardized uptake value ratio.

Extended Data Fig. 5

Participant flow chart.