Background
Dementia is a syndrome characterized by progressive cognitive decline, motor deficits and/or behavioural problems, which increasingly affect the ability to perform activities of daily living [
1]. Alzheimer’s disease (AD) is the most common cause of dementia accounting for approximately 60-80% of the dementia cases, followed by vascular dementia [
1]. Older age is the strongest risk factor for dementia and due to the aging population the prevalence of dementia is increasing [
2]. There are over 9.9 million new cases of dementia each year and the number of persons with dementia is expected to reach 131.50 million in 2050 [
3]. Currently, there is no cure or an effective disease-modifying drug to treat dementia [
4]. Pharmacological treatment for AD and vascular dementia with acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) or memantine produce small benefits on cognitive and behavioural functioning [
5,
6]. However, the clinical relevance of these pharmacological treatments is controversial and these drugs can cause adverse events (e.g., anorexia, gastrointestinal problems, insomnia) in this vulnerable patient group [
6]. Therefore, we should focus on the development and implementation of non-pharmacological interventions as an alternative or add-on therapy. Physical activity seems to be an appealing option [
7,
8], as increased lifetime engagement in physical activity reduces the risk of dementia [
9] and recent research shows that older adults with dementia spend approximately two-third of the day being sedentary [
10].
Recent meta-analyses show positive effects of aerobic exercise interventions on cognitive function in cognitively healthy older adults, with the largest gains in executive-control processes [
11‐
14]. Executive function refers to higher-order cognitive processes that controls basic, underlying cognitive functions for non-routine, purposeful, goal-directed behaviour and is linked to prefrontal-parietal network activity [
15]. Several mechanisms have been identified that may explain this beneficial effect of aerobic exercise on cognitive function: (1) aerobic exercise in aging individuals may increase brain volume, in both grey and white matter, primarily located in the prefrontal and temporal cortices. These brain regions are important for executive control processes and episodic memory, respectively [
16,
17]; (2) aerobic exercise may increase the size of the anterior hippocampus, which may lead to improved memory performance [
18]; (3) aerobic exercise may enhance neurogenesis in the dentate gyrus of the hippocampus [
19]; (4) aerobic exercise may promote extensive cardiovascular changes in the peripheral and cerebral vasculature, such as enhanced angiogenesis [
20], and (5) aerobic exercise promotes cardiovascular fitness and therefore reduces peripheral vascular risk factors [
21]. Hence, aerobic exercise may have a positive effect on enhancing brain vitality and engagement in physical activity can reduce the risk of dementia-onset in healthy elderly [
9].
Several studies have investigated whether physical activity can slow the rate of cognitive decline in older adults with dementia. The results of these studies are mixed. A recently updated meta-analysis of the Cochrane library [
22] did not find evidence that physical activity slows cognitive decline in older adults with dementia. In contrast, a meta-analysis of Groot et al. [
23] found a beneficial effect of physical activity on cognitive function. This positive effect was independent of the frequency of the intervention and driven by interventions that included aerobic exercise [
23]. The opposing outcomes may be explained by the difference in the included studies. Groot et al. incorporated sixteen trials published up to 2015 in the analysis, while the Cochrane library incorporated nine trials and did not include studies after 2013 [
22,
23]. Specifically, the most recent studies, reviewed by Groot et al. [
23], showed a beneficial effect of physical activity on cognition [
24‐
26]. Moreover, both meta-analyses discuss the large variability in study population, exercise protocols and outcome measures that can complicate interpretation of the results [
22,
23].
Studies suggest that the neural and cognitive benefits, elicited by physical activity, can be further enhanced if exposure occurs in the context of a cognitively challenging environment [
27‐
29]. Experimental animal studies have shown that physical activity and environmental enrichment (a combination of complex inanimate and social stimulation [
30]) differently affect hippocampal neurogenesis, with physical activity influencing the proliferation of neural precursor cells and enriched environment exerting a survival promoting effect on newborn neurons [
27,
29]. The findings of previous studies on cognitive effects of single physical training versus combined cognitive-physical training in healthy older adults are in favour of a combined intervention [
31,
32]. These combined interventions also seem to positively influence cognition in persons with dementia, with significant effects found on executive function, attention and processing speed [
33]. These potential benefits of a combined cognitive-physical training need further investigation since the limited number and heterogeneity of the conducted studies [
33]. Moreover, there is a lack of comparison with single physical training interventions to identify the effectiveness of the different components of the intervention. Thus, methodologically high-quality combined cognitive-physical training compared with single physical training studies are needed.
Earlier studies indicate that the gene Apolipoprotein E (APOE) may be involved as a moderator in the effects of physical activity on cognition [
34,
35]. APOE is a cholesterol carrier that supports lipid transport and is involved in brain injury repair [
36]. The APOE gene is polymorphic with three major isoforms: ε2, ε3 and ε4 [
37]. Carrying the ε4 allele of APOE is the strongest genetic risk factor for developing AD and carrying the ε2 allele is protective [
2,
38]. Approximately 14% of the western population carries the ε4 allele and the estimated prevalence of APOE ε4 genotype amongst patients diagnosed with AD is 50% [
36,
39]. The risk of developing vascular dementia is also elevated in APOE ε4 carriers, although to a lesser extent [
40]. The moderating role of APOE ε4 in the effect of physical activity on cognition is still unknown. Some epidemiological data suggest that physical activity is more protective in APOE ε4 carriers compared to non-carriers with respect to incidence of dementia [
21]; cerebral amyloid deposition [
34]; cognitive function [
35,
41]; cognitive decline [
42] and memory-related brain activation [
35]. Other studies, however, suggest that physical activity is related to a lower incidence of dementia and higher level of cognitive functioning in APOE ε4 non-carriers [
43,
44]. In light of the ‘exercise-is-medicine’ paradigm, insight in APOE ε4 moderation may be relevant for the identification of people who will benefit most from physical activity and cognitive stimulation.
The proposed study will expand the scarce research on the cognitive effects of combined cognitive-aerobic training and single aerobic training in older adults with dementia. Furthermore, explorative data will be collected and analyzed to study the moderating effect of APOE status on cognitive and physical function effects.
Objectives and hypothesis
The primary objective is to study the effect of a 12-week combined cognitive-aerobic bicycle training on executive functioning, compared to a single aerobic bicycle training and an active control group (i.e. stretching and toning), in community-dwelling older adults with mild dementia. We hypothesize that both training regimes will have a positive effect on executive function, compared to the control intervention, with the largest effect in the combined cognitive-aerobic group.
Secondary objectives include investigating i) the effect of training on the cognitive domains of episodic memory, working memory and psychomotor speed, ii) the effect of the training regimes on physical functioning; iii) the effect of training on activities of daily living, mood, quality of life and frailty, and iv) whether the cognitive effects of training are modified by APOE ε4 carrier state.
Acknowledgments
This study is part of a collaborative research of a multidisciplinary experts consortium from the University Medical Center Groningen, University of Groningen and VU University Amsterdam, the Netherlands. The aim of the consortium is to determine how specific exercise protocols can counter the negative effects of physical inactivity on dementia progression.