JAMA Neurol. 2026 Mar 23. doi: 10.1001/jamaneurol.2026.0359. Online ahead of print.
ABSTRACT
IMPORTANCE: Physical inactivity, hypertension, and hyperlipidemia are modifiable cardiovascular risk factors for age-related cognitive decline and dementia. It remains unknown whether exercise training combined with intensive pharmacological reduction of cardiovascular risk factors (IRVR) would have greater benefits on cognitive function than those of exercise or IRVR alone.
OBJECTIVE: To determine the effects of exercise, IRVR, and exercise combined with IRVR on cognitive function in older adults.
DESIGN, SETTING, AND PARTICIPANTS: This single-blind, multicenter randomized clinical trial with a 2 × 2 factorial design and duration of 24 months was conducted at 4 clinical sites in the US. Enrollment began on February 2, 2017; the final study visit was on January 31, 2022. After screening, older adults without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Data were analyzed from December 2022 through October 2024.
INTERVENTIONS: Participants were randomized with a 1:1:1:1 ratio to aerobic exercise training, IRVR (lowering of systolic blood pressure to <130 mm Hg and serum low-density lipoprotein cholesterol with atorvastatin), IRVR + exercise, and usual care.
MAIN OUTCOMES AND MEASURES: The primary outcome was change in global cognitive function at 24 months from baseline, assessed with the Preclinical Alzheimer Cognitive Composite (PACC) score. Secondary outcomes were changes in the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) fluid composite score and individual test scores.
RESULTS: A total of 3290 individuals were screened, and 513 older adults (aged 60-85 years) without dementia and with hypertension, family history of dementia, and/or self-reported subjective cognitive decline were randomized. Among 513 randomized participants (mean [SD] age, 68.7 [6.0] years; 323 female participants [63.0%]), 443 completed 24-month visits, and 480 were included in the primary data analysis. For the primary outcome, there were no statistically significant interactions between intervention groups and time of visits (P = .13). At 24 months, PACC scores increased by 0.2 units in the no-exercise group (95% CI, 0.1-0.3) and by 0.3 units in the exercise group (95% CI, 0.2-0.4), with no significant group differences (0.1 units; 95% CI, -0.1 to 0.2; P = .37). PACC scores also increased by 0.3 units in the no-IRVR group (95% CI, 0.2-0.4) and by 0.2 units in the IRVR group (95% CI, 0.1-0.3), with no significant group differences (0.1 units; 95% CI, -0.3 to 0.03; P = .12). Increases in the NIHTB-CB composite score and individual test scores with exercise or IRVR showed similar results.
CONCLUSIONS AND RELEVANCE: In this multicenter randomized clinical trial among older adults with family history of dementia and/or self-reported subjective cognitive decline, exercise, IRVR, or both did not result in statistically significant differences in improvements in cognitive function over 24 months.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02913664.
PMID:41870419 | DOI:10.1001/jamaneurol.2026.0359
