Study Title
Effects of Exercise and Intensive Vascular Risk Reduction on Cognitive Function in Older Adults: A Randomized Clinical Trial
Background
Cognitive decline and dementia are major concerns as people age. Two common and modifiable risk factors for brain health are physical inactivity and vascular risk factors such as high blood pressure and elevated cholesterol. Previous research has shown that regular exercise may support brain function, and that better control of cardiovascular risk factors may also help protect cognition. However, it has remained unclear whether combining exercise training with intensive vascular risk reduction provides greater cognitive benefit than either approach alone.
This trial was designed to answer that question in older adults who were at increased risk for future cognitive decline because they had hypertension, a family history of dementia, and/or self-reported subjective cognitive decline. Subjective cognitive decline refers to a person’s own perception that memory or thinking is getting worse, even if standard testing has not yet shown dementia.
Study Design
This was a single-blind, multicenter randomized clinical trial with a 2×2 factorial design conducted at four clinical sites in the United States. A factorial design allows researchers to test two interventions at the same time and to see whether the combination works better than either intervention alone.
A total of 3,290 people were screened, and 513 older adults aged 60 to 85 years were randomized. Participants did not have dementia at baseline. They were assigned in a 1:1:1:1 ratio to one of four groups:
1. Aerobic exercise training only
2. Intensive vascular risk reduction only
3. Exercise plus intensive vascular risk reduction
4. Usual care
The study ran for 24 months. Enrollment began on February 2, 2017, and the final study visit took place on January 31, 2022. Data were analyzed from December 2022 through October 2024.
What the Interventions Involved
The exercise program focused on aerobic training, which generally means sustained physical activity that raises heart rate, such as brisk walking, cycling, or similar activities. Aerobic exercise is thought to benefit the brain by improving blood flow, reducing inflammation, and supporting cardiovascular fitness.
Intensive vascular risk reduction aimed to lower key cardiovascular risk factors more aggressively than usual routine care. The target was to reduce systolic blood pressure to below 130 mm Hg and lower low-density lipoprotein cholesterol (LDL-C) using atorvastatin. Atorvastatin is a widely used statin medication that helps lower cholesterol and reduce vascular risk.
Participants in the combined group received both exercise training and intensive vascular risk reduction.
Main Outcome Measures
The primary outcome was the change in global cognitive function from baseline to 24 months, measured by the Preclinical Alzheimer Cognitive Composite, or PACC. The PACC is a composite score designed to detect subtle changes in cognition, especially early changes that may occur before clear dementia develops.
Secondary outcomes included changes in the National Institutes of Health Toolbox Cognition Battery Fluid Cognition Composite score and individual test scores. The fluid cognition composite assesses abilities such as memory, processing speed, attention, and executive function—skills that are important for problem solving and adapting to new situations.
Results
Among the 513 randomized participants, the mean age was 68.7 years, and 63.0% were female. A total of 443 participants completed the 24-month visits, and 480 were included in the primary analysis.
Overall, all groups showed small improvements over time on cognitive testing, but the differences between intervention groups were not statistically significant.
For the primary outcome, there were no significant interactions between the intervention groups and the timing of visits. In practical terms, this means the pattern of cognitive change over 24 months did not differ meaningfully among the groups.
At 24 months:
– PACC scores increased by 0.2 units in the no-exercise group and by 0.3 units in the exercise group, with no significant difference between them.
– PACC scores increased by 0.3 units in the no-IRVR group and by 0.2 units in the IRVR group, again with no significant difference.
– Similar results were seen for the combined exercise and intensive risk reduction group compared with the other groups.
The secondary outcomes from the NIHTB-CB fluid composite and individual cognitive tests showed similar findings. Exercise, intensive vascular risk reduction, and the combination of both did not produce statistically significant cognitive advantages over usual care during the 24-month study period.
Interpretation
This trial provides important evidence that, in older adults at elevated risk for cognitive decline, a 2-year program of aerobic exercise, aggressive vascular risk reduction, or both together did not lead to measurable superiority in cognitive outcomes compared with usual care. This does not mean exercise or vascular risk control are unimportant. Both remain essential for overall health, and vascular risk management is well known to reduce the risk of stroke and other cardiovascular events.
Rather, the findings suggest that, for cognitive outcomes alone, these interventions may not produce large enough effects over 24 months to be detected in this setting, or that benefits may require longer follow-up, different participant selection, higher adherence, or additional combined lifestyle strategies. It is also possible that people in the usual care group were already receiving some level of risk management that reduced differences between groups.
Clinical Significance
The results are relevant for clinicians, researchers, and older adults concerned about memory loss or dementia prevention. The study reinforces several practical points:
– Regular exercise remains beneficial for heart, metabolic, and possibly brain health, even if this trial did not show a clear cognitive advantage over 24 months.
– Careful blood pressure and cholesterol control are important for reducing cardiovascular and stroke risk.
– Preventing cognitive decline likely requires a broader, long-term approach that may include sleep optimization, hearing care, diabetes management, smoking cessation, healthy diet, social engagement, and management of depression and other conditions.
– A negative or neutral trial result is still valuable because it helps refine future prevention strategies.
Limitations
As with any clinical trial, there are limitations to consider. First, the study population was specific: older adults with hypertension, family history of dementia, and/or subjective cognitive decline, but without dementia at baseline. The results may not apply to all older adults.
Second, cognitive decline often progresses slowly, and 24 months may be too short to detect large differences in some prevention studies. Third, adherence to exercise and medication targets can affect outcomes, and real-world participation may vary. Fourth, cognitive tests are useful but may not fully capture subtle day-to-day changes that matter to patients.
Bottom Line
In this multicenter randomized clinical trial, exercise, intensive vascular risk reduction with blood pressure and LDL cholesterol lowering, and the combination of both did not significantly improve cognitive function over 24 months in older adults at increased risk for dementia. The findings suggest that while these interventions are important for overall cardiovascular health, their short-to-medium term impact on cognition may be limited or more complex than expected.
Trial Registration
ClinicalTrials.gov Identifier: NCT02913664
Citation
Zhang R, Vidoni E, Vongpatanasin W, Kerwin DR, Cullum CM, Rossetti H, Stowe AM, Billinger SA, Gupta A, Hall T, Scheel N, Zhu DC, Hynan LS, Burns JM, Keller JN, Binder EF. Effects of Exercise and Intensive Vascular Risk Reduction on Cognitive Function in Older Adults: A Randomized Clinical Trial. JAMA Neurology. 2026;83(5):424-434. PMID: 41870419.
