In the present study, 5 years of moderate-to-high intensity exercise in older adults was not significantly associated with cognition, although slightly higher cognitive scores and lower odds of MCI were observed in the ExComb group compared with the control group. Men in the ExComb group had significantly higher MoCA scores and lower odds of MCI than men in the control group, with no such effect in women, suggesting that the effect of exercise on cognition differs according to sex. Further, a change in \(V{\text{O}}_{{2{\text{peak}}}}\) was significantly associated with cognition. In particular, each 1-MET increase in \(V{\text{O}}_{{2{\text{peak}}}}\) was associated with higher MoCA scores and lower odds of MCI, whereas participants whose \(V{\text{O}}_{{2{\text{peak}}}}\) decreased had lower MoCA scores compared with participants whose \(V{\text{O}}_{{2{\text{peak}}}}\) remained stable, indicating that maintaining or improving \(V{\text{O}}_{{2{\text{peak}}}}\) is important for cognitive health in older age.

Exercise Effects on Cognition

To date, there is a lack of randomized controlled trials investigating the effect of exercise on the incidence of MCI in initially cognitively healthy older adults. In a large 24-month randomized controlled exercise trial, Sink et al. [36] found no differences in incident MCI between the exercise group and the health education group. In contrast, longitudinal observational studies have shown that moderate-to-vigorous physical activity is associated with a lower risk of incident cognitive impairment [37, 38]. This discrepancy is likely due to the need for studies to be long lasting to be able to detect incident cognitive impairment, something that is easier to achieve in observational studies. Unfortunately, given the lack of baseline assessments of MCI, we were unable to assess the incidence of new MCI cases in our study.

Although our overall results from a 5-year randomized controlled exercise trial provided limited effect sizes that did not reach statistical significance, they underscore a potential for the prevention of cognitive decline with weekly exercise at higher intensities in the general population of older adults. The population approach has been highlighted as the most crucial strategy in preventive healthcare [39], suggesting that although differences in health parameters in a study may be small at the individual level, they may play a more important role at the population-based level.

There are several plausible explanations as to why we did not observe a significant cognitive benefit of the 5-year exercise intervention. First, the assigned level and/or intensity of exercise may have been insufficient to produce a substantial group difference in global cognition or MCI in older adults, which is in line with previous findings [8, 36]. Further, it is worth noting that the control group in the Generation 100 Study had a high level of physical activity, and actually performed more HIIT exercise than the MICT group [40]. This likely influenced the lack of group differences in cognition in our study. Finally, individuals who dropped out from the study or declined to participate in the cognitive screening, and were thus not included in the analyses, may have had a different cognitive status than the included study participants. This may have led to a more cognitively homogenous sample, reducing individual and group differences in cognition.

Sex Differences

Although the overall effect of the exercise intervention on cognition was non-significant, our results provide novel evidence suggesting that the effect of moderate-to-high intensity aerobic exercise on cognition is more pronounced in men than in women. Men in the ExComb group had 36% lower odds of MCI, which is a smaller effect than in observational studies of physical activity and cognitive impairment [37, 38], but still can be of significance to public health given that approximately 5–10% of individuals with MCI will progress to dementia annually [41]. The differences in MoCA scores between men who exercised and men in the control group are, although statistically significant, of less clinical significance [42]. Our findings are contradictory to previous studies, which found greater cognitive benefits of exercise in women than in men [6, 43]. As there was no interaction effect of sex and change in \(V{\text{O}}_{{2{\text{peak}}}}\) on cognitive outcomes, and group differences in changes in \(V{\text{O}}_{{2{\text{peak}}}}\) in men was minimal, differences in changes in \(V{\text{O}}_{{2{\text{peak}}}}\) are unlikely to be the reason behind our findings. However, previous findings indicate higher prevalence and incidence rates of MCI in men [2, 44, 45]. Similarly, a higher proportion of men in our study were classified as having MCI at study end than women, which may have made it easier to uncover group differences in men. Additionally, several studies indicate higher resilience to age-related cognitive decline in women as opposed to men [46, 47]. As such, it is plausible that the differences in cognition observed between men in the intervention groups in our study are due to age-related cognitive decline in men in the control group, which was to some extent prevented in men in the exercise group. However, as we did not have baseline assessments of MoCA, we cannot be certain whether sex differences in the rate of age-related cognitive decline can explain the observed significant differences in men, but not in women. Thus, our conflicting results warrant further investigation of sex-dependent effects of exercise on cognition.

\(V{\text{O}}_{{2{\text{peak}}}}\)

The observed association between change in \(V{\text{O}}_{{2{\text{peak}}}}\) and cognition is in agreement with previous findings [13, 14, 16, 17], and with the CRF hypothesis [15]. The active control group [40] may explain why the associations between intervention group and MCI and cognitive function were marginal, whereas associations of change in \(V{\text{O}}_{{2{\text{peak}}}}\) and cognition were substantial and significant, regardless of group allocation. Indeed, although \(V{\text{O}}_{{2{\text{peak}}}}\) was significantly higher in the ExComb group than the control group at study end, we did not observe any significant group difference in change in \(V{\text{O}}_{{2{\text{peak}}}}\) from baseline to study end. This may explain why group allocation did not have a significant effect on cognition, whereas change in \(V{\text{O}}_{{2{\text{peak}}}}\) was independently associated with better cognition. Altogether, our results suggest that participating in exercise that improves or maintains CRF in older age is an effective strategy to ensure better brain health in older adults.

Strengths and Limitations

The strengths of our study include the large sample of older adults, the long intervention duration, high adherence to the intervention, and thorough health assessments, including repeated measurements of \(V{\text{O}}_{{2{\text{peak}}}}\) and detailed information on participants’ health status. The main limitation was the absence of MoCA assessments at baseline. This means that we cannot rule out the possibility of cognitively impaired participants at baseline, despite exclusion of individuals with dementia. Although a significantly uneven distribution is unlikely because of the thorough randomization process, we cannot rule out the possibility that an uneven distribution of cognitive function may have occurred at baseline. Hence, we could not assess how the exercise intervention affected change in cognitive status from baseline to study end. Another limitation was the active control group [40], which may have reduced group differences. It is difficult to obtain a suitable control group in randomized controlled exercise trials, as it is unethical to ask participants not to engage in any physical activity over a longer period. Volunteer bias [48] may have been present, as included participants were more active and more likely to report good health than non-participants [22]. Thus, the Generation 100 Study may not be representative of the general population of older adults. Adherence was assessed after 1, 3, and 5 years, and we do thus not have information on adherence between these timepoints. As adherence was measured using a questionnaire validated in young men, we cannot be sure that the questionnaire reflects the actual amount or intensity of exercise performed by the older adults in this study. Hence, we cannot rule out the possibility that some participants misinterpreted the questions, or that recent life events or cognitive changes may have caused recall bias [49]. Although the adherence criteria were set at a lower level than the prescribed exercise amount, data from the Generation 100 Study show that the participants on average exercised well above the minimum criteria [40]. Further, the power calculations in the original study were based on the primary outcome (mortality) [22] and did not take into account effect modification. The main analyses and the sex-stratified analyses were thus likely underpowered and must be interpreted with caution. Finally, we chose a different cut-off for MCI than in the original MoCA study [26], which may lower the validity of our results. However, mean MoCA scores in our study sample were below the recommended cut-off of 26 points, which supports previous findings that indicate that this cut-off is too high [29, 30].