Regular aerobic exercise training and aggressive control of blood pressure and cholesterol — alone or in combination — significantly improved cardiovascular health but did not lead to measurable cognitive benefit over 2 years.

Results of a randomized clinical trial of older adults at risk for Alzheimer’s disease (AD) showed that despite clear improvements in cardiovascular risk factors, there was no significant difference in global cognitive function among those who received aerobic exercise and intensive blood pressure and cholesterol lowering, alone or in combination, compared with usual care over 24 months.

“We improved the body, but not the brain,” study investigator Jeffrey Keller, PhD, who leads the Institute for Dementia Research and Prevention, Pennington Biomedical Research Center, Baton Rouge, Louisiana, said in a statement.

“Exercise and reduction of cardiovascular risk factors are the foundation of cardiovascular and brain health. However, the benefits of these interventions on cognitive function may take longer time to manifest than the 24-month trial period at a population level,” first author Rong Zhang, PhD, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, told Medscape Medical News.

The results of the Risk Reduction for Alzheimer’s Disease (rrAD) trial were published online on March 23 in JAMA Neurology.

Inconsistent Findings

Physical inactivity, hypertension, and high cholesterol are established modifiable cardiovascular risk factors for age-related cognitive decline and dementia. Some previous research has suggested that addressing these factors might help slow age-related cognitive changes. However, the evidence has been inconsistent.

The rrAD trial included 513 adults (mean age, 68 years; 63% women) who did not have dementia at the time of enrolment, but who were considered at an elevated risk due to hypertension, a family history of dementia and/or subjective cognitive decline.

Participants were randomly allocated to one of the four groups: aerobic exercise training, intensive pharmacologic reduction of vascular risk factors, a combination of both, or usual care.

The exercise program involved moderate-to-vigorous activity totaling about 160 min/wk, while the medical intervention aimed to lower systolic blood pressure below 130 mm Hg and reduce serum low-density lipoprotein (LDL) cholesterol with atorvastatin. A total of 443 participants completed 24-month visits, and 480 were included in the primary data analysis.

The primary outcome was change in global cognitive function at 24 months, measured using the Preclinical Alzheimer Cognitive Composite (PACC) score, which is weighted toward memory performance.

At 24 months, PACC scores increased modestly in all groups, but there were no statistically significant differences between interventions. PACC scores rose by 0.2 units in participants who did not receive exercise and by 0.3 units in those who did, a difference that was not statistically significant (P = .37). 

Similarly, PACC scores increased by 0.3 units in those who did not receive intensive vascular risk reduction and by 0.2 units in those who did, again with no meaningful difference between groups (P = .12).

Secondary cognitive measures, including tests focused on executive function, showed the same pattern of small improvements without group differences.

Contrary to FINGER, POINTER

Despite the lack of cognitive benefit, the pharmacologic interventions targeting blood pressure and LDL cholesterol produced the expected physiologic changes.

Systolic blood pressure was reduced by an average of 13 points with antihypertensive therapy — five points more than those not receiving antihypertensive therapy. Statin therapy led to a 24-point drop in LDL cholesterol compared with a drop of seven points for those not receiving a statin.

Results of the rrAD trial stand in contrast with findings from the FINGER and US POINTER trials, which showed that combined multi-component interventions of exercise, diet, cognitive training, and monitoring of vascular risk improved cognitive function in older adults.

Targeting only exercise and vascular risk factors may not be sufficient to influence cognition, and that more comprehensive interventions could be necessary to produce meaningful effects on brain health, the rrAD trialists noted in their paper.

Zhang said the “inconsistent findings between rrAD and FINGER and US POINTER is likely related to the differences in the trial interventions.”

The researchers also cautioned that the sample size required to assess group differences in changes in cognitive function over 24 months may have been underestimated based on previous studies. And the degree of separation in blood pressure and cholesterol levels between groups may have been insufficient to result in group differences in cognitive function.

In addition, although participants had a family history of dementia and/or self-reported subjective cognitive decline, neither imaging nor blood-based biomarkers were used to stratify or enrich the study sample, which could have reduced the ability to detect intervention effects.

“Given the demonstrated effects of these interventions on cardiovascular health, longer-term trials are needed to determine their efficacy in mitigating age-related cognitive decline and dementia prevention,” the researchers concluded.

Too Late in the Game?

In a linked editorial, neurologists Holly Elser, MD, PhD, with Hospital of the University of Pennsylvania, Philadelphia, and Jonathan Graff-Radford, MD, with Mayo Clinic College of Medicine, Rochester, Minnesota, highlight another potential factor in the null effect seen in the rrAD trial.

The best available evidence suggests that lifestyle factors — like high LDL cholesterol, physical inactivity, diabetes, and hypertension — are most likely to influence dementia risk in midlife, they noted.

Therefore, “it may be difficult to observe meaningful changes in cognitive function when interventions are delivered in late life and participants are followed up for a limited time period,” they added.

Elser and Graff-Radford also echoed the authors pointed about a lack of biomarker data.

“Biomarker enrichment strategies using imaging or blood-based markers may further enhance clinical trial efficiency by selecting individuals at greatest risk of decline, thereby increasing the likelihood of detecting meaningful intervention effects,” they wrote.

This study was funded by a grant from the US National Institutes of Health, with additional funding from the Josephine Hughes Sterling Foundation. The authors had no relevant disclosures. Elser is associate editor of JAMA Neurology. Graff-Radford reported receiving grants as a site investigator for trials from Cognition Therapeutics and Eisai; and personal fees from serving as a faculty member for IMPACT AD.