Individual Differences in the Effects of Physical Activity on Cognitive Function in People with Mild to Moderate Dementia

INTRODUCTION

There is an increasing interest in the potential of exercise as an intervention for cognitive decline in people with dementia. To date, the results from exercise studies are inconclusive [1,2], which may imply that physical activity is not a one-size-fits-all intervention. The effects of exercise may be moderated by patient characteristics, such as the ɛ4 allele of the gene Apolipoprotein E (APOE) and type of dementia. Previous studies with APOE ɛ4 status as moderator showed mixed results [3,4]. As for the type of dementia, the effect has not been investigated to date. We hypothesize that persons with vascular dementia would benefit most from aerobic exercise intervention as it improves vascular function and modifies key cardiometabolic risk factors [5]. Studies on these moderating effects are of great importance, as they can help determine who will benefit most from physical activity interventions and can help develop individualized training programs accordingly. The objective of this secondary analysis of a previously published randomized controlled trial (RCT) was to examine whether the effect of physical activity on cognitive function in persons with mild to moderate dementia is moderated by patient characteristics [6]. It was hypothesized that combined physical and cognitive exergame training would result in larger improvements in cognitive function than physical training alone. There is growing evidence for this in healthy older adults and in people with mild cognitive impairment, but this effect is less clear in persons with dementia [7]. In the RCT, an extensive neuropsychological test battery was administered to evaluate the cognitive domains of executive function, episodic memory, working memory, and processing speed, as we expected a differential effect of exercise interventions on these domains [6]. The main outcome was that both physical intervention groups (combined cognitive-physical training and aerobic training) improved equally on psychomotor speed, compared to an active control group.

METHODS

RESULTS

Fourteen participants (12%) did not complete the training and were excluded from the analyses. A full description of the reasons for drop-out has been provided previously [6]. Main reasons for drop-out were comorbid medical or physical problems and lack of motivation. There was no significant difference at baseline between the participants who completed the study and the participants who dropped-out in age, MMSE score, APOE genotype, and dementia type. For the cognitive domain scores, no differences were found, except for the domain of working memory in which the participants who dropped out performed significantly better at baseline than the participants who completed the study. In total 101 persons with dementia completed the study of whom 34 participated as controls. The participants from the two intervention groups (N = 67) were included in further analyses, 34 in the exergame group and 33 in the single aerobic group. The average age was 79.8 years, 54% were men, and 53.5% had Alzheimer’s disease. Four patients improved significantly on global cognition (4.5% responders). For the separate cognitive domains, 9 participants improved significantly on executive function (13.4%), 10 on processing speed (14.9%), 4 on episodic memory (6.0%), and 3 on working memory (4.5%).

The parameter estimates for all regression models are presented in Table 1. The regression model for global cognition did not show any significant relations. The regression model for episodic memory showed a significant negative relation between type of dementia and the RCI for episodic memory (RCI_mem), B = –0.53 (p = 0.024), indicating that the RCI_mem in people with Alzheimer’s disease is 0.53 units lower than the RCI_mem in people with other types of dementia. The regression model for working memory indicated two non-significant trends. First, there was a negative trend between APOE genotype and the RCI for working memory (RCI_wm), B = –0.39 (p = 0.053), implying that the RCI_wm in APOE ɛ4 carriers is 0.39 units lower than the RCI_wm in non-carriers. Second, we found a positive trend between age and the RCI_wm, B = 0.03 (p = 0.075), suggesting that when age increases with 1 unit, the RCI_wm increases with 0.03 units. The regression model for executive function showed a significant positive relation between the MMSE score and the RCI for executive function (RCI_exe), B = 0.13 (p = 0.017), indicating that when the MMSE score increases with 1 unit, the RCI_exe increases with 0.13 units. The regression model for processing speed showed a significant negative relation between the MMSE score and the RCI for processing speed (RCI_speed), B = –0.09 (p = 0.028), indicating that when the MMSE score increases with 1 unit, the RCI_speed decreases with 0.09 units. Second, the model showed a positive trend between age and the RCI for processing speed (RCI_speed), B = 0.03 (p = 0.095), suggesting that when age increases with 1 unit, the RCI_speed increases with 0.03 units.

DISCUSSION

In our study we found that only a minority of individuals with mild to moderate dementia showed significant and reliable improvements on global cognition (4.5%) or on any of the cognitive domains (4.5–14.9%) after a 12-week physical exercise intervention. Moreover, we found a smaller decline in episodic memory after the intervention in persons with non-Alzheimer disease compared to persons with Alzheimer’s disease. We did not find significant associations between APOE ɛ4 status and global cognitive change or change in any of the domains. We observed a positive relation between baseline MMSE score and post-treatment change in executive function, while we found a negative relation between baseline MMSE score and post-treatment change in processing speed. These findings indicate that persons with less severe cognitive impairment at baseline show less cognitive decline in executive function after the intervention, while in contrast (and counter-intuitively), persons with more severe cognitive impairment at baseline show less decline in processing speed after the intervention.

A strength of this study is the use of RCI analyses, which contributes to a more personalized approach as it can help gain insight into which persons with mild to moderate dementia will benefit most from physical activity interventions. There are also a number of limitations that need to be addressed. First, the fact that the RCI was not defined beforehand in our study protocol, but was added as post hoc analysis. Second, that we did not have one predefined primary outcome. Third, we only included the participants who completed the training and all measurements.

Overall, this study provides preliminary evidence that patient characteristics moderate the effect of physical activity on cognitive decline and that these effects differ per cognitive domain. Future research should focus on well-designed prospective studies with predefined RCI analyses to gain more insight into responder characteristics. These findings stress the need for a personalized approach when designing and analyzing interventions for persons with mild to moderate dementia to target those who benefit most from physical activity interventions.