Karssemeijer et al.

Alzheimer's Research & Therapy (2019) 11:3

https://doi.org/10.1186/s13195-018-0454-z

RESEARCH Open Access

The quest for synergy between physical

exercise and cognitive stimulation via
exergaming in people with dementia: a
randomized controlled trial
Esther G. A. Karssemeijer1,2, Justine A. Aaronson3, Willem J. R. Bossers4,5, Rogier Donders6,
Marcel G. M. Olde Rikkert1,2 and Roy P. C. Kessels2,3,7*

Abstract
Background: Exercise is often proposed as a non-pharmacological intervention to delay cognitive decline in
people with dementia, but evidence remains inconclusive. Previous studies suggest that combining physical
exercise with cognitive stimulation may be more successful in this respect. Exergaming is a promising
intervention in which physical exercise is combined with cognitively challenging tasks in a single session. The aim
of this study was to investigate the effect of exergame training and aerobic training on cognitive functioning in
older adults with dementia.
Methods: A three-armed randomized controlled trial (RCT) compared exergame training, aerobic training and an
active control intervention consisting of relaxation and flexibility exercises. Individuals with dementia were randomized
and individually trained three times a week during 12 weeks. Cognitive functioning was measured at baseline, after the
12-week intervention period and at 24-week follow-up by neuropsychological assessment. The domains of executive
function, episodic memory, working memory and psychomotor speed were evaluated. Test scores were converted into
standardized z-scores that were averaged per domain. Between-group differences were analysed with analysis of
covariance.
Results: Data from 115 people with dementia (mean (SD) age = 79.2 (6.9) years; mean (SD) MMSE score = 22.9
(3.4)) were analysed. There was a significant improvement in psychomotor speed in the aerobic and exergame groups
compared to the active control group (mean difference domain score (95% CI) aerobic versus control 0.370 (0.103–0.
637), p = 0.007; exergame versus control 0.326 (0.081–0.571), p = 0.009). The effect size was moderate (partial η2 = 0.102).
No significant differences between the intervention and control groups were found for executive functioning, episodic
memory and working memory.
(Continued on next page)

* Correspondence: [email protected]
2
Radboud University Medical Center, Radboudumc Alzheimer Center,
Nijmegen, the Netherlands
3
Radboud University Medical Center, Donders Institute for Brain Cognition
and Behaviour, Department of Medical Psychology, Nijmegen, the
Netherlands
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 2 of 13

(Continued from previous page)

Conclusions: To our knowledge, this is the first RCT evaluating the effects of exergame training and aerobic training
on cognitive functioning in people with dementia. We found that both exergame training and aerobic training
improve psychomotor speed, compared to an active control group. This finding may be clinically relevant as
psychomotor speed is an important predictor for functional decline. No effects were found on executive function,
episodic memory and working memory.
Trial registration: Netherlands Trial Register, NTR5581. Registered on 7 October 2015.
Keywords: Cognition, Dementia, Alzheimer disease, Exercise, Physical activity, Cognitive stimulation, Exergame,
Neuropsychological, Randomized controlled trial

Background cognitive and physical exercise training on different cog-

The increasing prevalence of dementia greatly impacts nitive domains in people with dementia.
healthcare and society, stressing the need for global action Recent advances in technology present the opportun-
[1]. Since there is no cure or effective disease-modifying ity to combine physical exercise with cognitively
drug to treat the most common types of dementia to date challenging tasks in a single session using exergames
[1], research should also focus on the development and [14]. Exergaming is defined by “physical exercise inter-
implementation of non-pharmacological interventions as actively combined with cognitive stimulation in a
an alternative or add-on therapy [2]. Previous research has virtual environment” [15]. Exergame training is a phys-
shown that physical exercise improves cognitive perform- ical–cognitive dual-task training, which requires the
ance in older adults without dementia [3], and that phys- mental flexibility to switch between concurrent tasks. Men-
ical inactivity during midlife attributes to the risk of tal flexibility is a core component of executive functioning,
dementia [4, 5]. However, research on cognitive effects of a set of higher-order cognitive processes also including
physical exercise in older adults with dementia has shown cognitive inhibition, planning and problem-solving [16].
heterogeneous results [6, 7]. It seems that physical exer- We therefore hypothesize that exergame training will spe-
cise alone may not be enough for older adults with de- cifically benefit executive functioning. Previous research
mentia to alter or slow down cognitive decline. Previous has already shown that exergames improve global cognitive
studies suggest that combining physical exercise with cog- function in healthy older adults and in a clinical population
nitive stimulation may be a more successful strategy [8, 9]. of patients with Parkinson’s disease, schizophrenia, mul-
Animal studies have shown that physical exercise can tiple sclerosis and MCI, compared to physical exercise
prime the hippocampus to increase neurogenesis elicited training alone [17]. Moreover, older adults were found to
by cognitive stimuli [10, 11]. Furthermore, physical exer- enjoy participation in exergames, which may facilitate
cise combined with environmental enrichment positively long-term activity participation [18]. There is also prelim-
affects hippocampal neurogenesis, possibly via separate inary evidence that exergames are a feasible and enjoyable
pathways, with physical exercise influencing the prolifer- intervention for people with dementia [19, 20]. To our
ation of neural precursor cells and environmental en- knowledge, no previous randomized controlled studies
richment fostering survival of newborn neurons [10]. In have investigated the effect of exergames on cognitive
line with this, a meta-analysis [12] showed significant functioning, more specifically on executive functioning, in
benefits of combined cognitive and physical interven- older adults with dementia.
tions on cognitive function in healthy older adults. Previous studies suggest that the gene apolipoprotein
These beneficial effects significantly exceeded the effects E (APOE) may be a moderator in the effects of exercise
of physical exercise training alone [12]. In addition, we on cognition [21, 22]. APOE is a cholesterol carrier and
recently performed a meta-analysis in older adults with is important for lipid transport and injury repair in the
mild cognitive impairment (MCI) or dementia which brain [23]. There are three alleles of APOE: ε2, ε3 and
showed that combined cognitive and physical exercise ε4. Carrying the ε4 allele of APOE is a risk factor for
interventions improve global cognitive performance [13]. Alzheimer’s disease (AD) and carrying the ε2 allele is
Thus, these studies illustrate the potential of combined protective for AD [1]. Results from cohort studies are
interventions in delaying disease progression in persons contradictory, reporting that physical exercise is both
with MCI or dementia. However, the superiority of com- protective for cognitive decline in APOE ε4 carriers [24,
bined interventions over single physical exercise and the 25] as well as lowering the risk of dementia in APOE ε4
effects on different cognitive domains in individuals with non-carriers [26]. Insight into this moderating relation-
dementia remain unknown. Hence, the aim of the ship may contribute to identify people who will benefit
current study is to investigate the effects of combined most from our exergame intervention.
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 3 of 13

The primary aim of the current study is to investigate screening visit. The study was conducted in community
the efficacy of a 12-week exergame training and aerobic centres in Nijmegen, the Netherlands. Participants were
training compared to a control group on executive func- randomly assigned to one of the intervention groups or
tioning in older adults with dementia. We hypothesize the control group by an independent statistician. The
that exergame training results in greater improvement minimization method [31] was used to balance groups
on executive functioning than aerobic training. Second- for gender, severity of cognitive impairment (MMSE ≥
ary aims are: to assess the feasibility of exergames; to 20 or < 20), use of medication for Alzheimer’s disease,
compare effects of exergame training with single aerobic training location and level of education. The Dutch
training on the cognitive domains of psychomotor speed, classification of education levels [32] was used to clas-
episodic memory and working memory; to measure the sify the educational attainment of participants as low
follow-up effects of exergame training and aerobic train- (levels 1–3), average (levels 4–5) or high (levels 6–7).
ing; and to determine whether the cognitive effects of
training are modified by the APOE ε4 carrier state. Interventions
The study included three arms: exergame training, aer-
Methods obic training and active control. Participants in each
Study design arm received three training sessions per week for 12
The current study was a 12-week single-blind randomized weeks. Training sessions were given on a one-on-one
controlled trial (RCT) with two experimental intervention basis, and trained students or research assistants super-
groups and one active control group. Participants were in- vised the participants. Adherence to the intervention
cluded from January 2016 to September 2017. The Med- was calculated by dividing the number of sessions the
ical Ethics Committee of Radboud University Medical participant followed by the total number of sessions
Center in Nijmegen, the Netherlands approved the re- that were offered.
search protocol, which was published previously [27]. The The exergame training consisted of a combined cogni-
study was conducted in compliance with Declaration of tive–aerobic bicycle training developed by Bike Labyrinth
Helsinki ethical standards. Participants all verbally (www.bikelabyrinth.com). The aerobic training compo-
agreed to participate in the study and gave written in- nent consisted of cycling on a stationary bike, 30–50 min
formed consent. The trial is registered at the Dutch per session. The aerobic exercise was tailored to an indi-
trial register (http://www.trialregister.nl) with identifi- vidual fitness level and health status, and aimed to achieve
cation number NTR5581. an intensity of 65–75% of heart rate reserve after 12 weeks
of training [27]. For participants on medication that atten-
Participants and study procedures uates heart rate (e.g. beta-blockers), the Borg Rating of
Participants were approached via the memory clinic of Perceived Exertion (RPE) [33] was used to ensure that the
Radboudumc Alzheimer Center, day care centres for intended training intensity was achieved. In addition, the
older adults with cognitive disorders, advertisement in stationary bike was connected to a video screen. Partici-
local newspapers and word of mouth. Eligibility criteria pants followed a route through a digital environment and
for inclusion were: clinically confirmed diagnosis of de- simultaneously performed cognitive tasks targeting re-
mentia following the DSM-IV criteria [28] (vascular, sponse inhibition, task switching and processing speed.
Alzheimer or mixed type) with a Mini Mental Status The exergame training consisted of seven different cog-
Examination (MMSE) [29] score ≥ 17; aged 60 years or nitive training levels. The difficulty of the cognitive
older; if using anti-dementia medication, a stable dose tasks increased per level to ensure that the training
for at least 3 months before the start of the trial; and remained cognitively challenging. The exergame train-
being capable of giving informed consent [30]. Exclu- ing and different training levels are described exten-
sion criteria were: co-morbidity that limited exercising, sively in our protocol paper [27].
including severe cardiovascular, musculoskeletal or The single aerobic exercise group consisted of cycling
neurological disease; diagnosis of a depression, bipolar on a stationary bike that was not connected to a video
disorder or psychotic disorder at the moment of inclu- screen. The aerobic training was identical to the exer-
sion; current drug or alcohol dependency; exercising game training already described. Participants in the ac-
more than five times per week for at least 30 min at a tive control group received training that consisted of
moderate intensity; wheelchair bound; and severe hear- relaxation and flexibility exercises with a duration of
ing or visual problems that could not be corrected with 30 min and the same frequency as the training regimes
the use of hearing aids/glasses. When participants were of the intervention groups. The exercises required min-
recruited by newspaper advertisement or word of imal muscle strength and aerobic capacity and were
mouth, we confirmed the dementia diagnosis by inves- easy to perform. The level of social engagement was
tigating their medical record before planning a similar to the intervention groups.
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 4 of 13

Outcomes effects, Bonferroni-corrected post-hoc tests were

Full assessments were carried out before training (T0), performed. To investigate follow-up effects of the inter-
after the 12-week training phase (T2) and 12 weeks vention for each cognitive domain, we used mixed-
thereafter at the 24-week follow-up (F1). Intermediate model ANCOVA. Variables included in the model wer-
measurements were performed after 6 weeks of training ecognitive domain z-scores at T2 and F1 as dependent
(T1). Trained research assistants with a background in variables, group as between-subject factors, time as
neuropsychology assessed cognitive performance using within-subject factors, and the corresponding baseline
a test battery that was described previously [27], and measure as covariates. Additionally, a time × group
they were blinded to group allocation. The primary out- interaction term was added as a fixed effect. To assess a
come measure was objective executive functioning, moderating effect of APOE ε4, an interaction term be-
which was measured by four neuropsychological tasks tween APOE ε4 and group was added separately as a
that were averaged into one domain score: a short form predictor.
of the Trail Making Test part B [34], the abbreviated If a participant had missing data because he/she
5-line Stroop Color Word Test interference score [35, was cognitively incapable to perform a certain test,
36], Letter Fluency [37, 38], and the Rule Shift Cards the worst possible score for this test was awarded.
Test [39]. All tests, except for letter fluency, were also Afterwards, the domain z-score was calculated. If
administered after 6 weeks (T1). Secondarily, the fol- there were missing data due to drop-out and the rea-
lowing cognitive domains were assessed: episodic mem- son for missingness was at random, missing data were
ory (Location Learning Test—Revised [40]), working substituted using the multiple imputation method.
memory (WAIS-III Digit Span [41] and WMS-III Characteristic variables of the sample, cognitive do-
Spatial Span [42]), and psychomotor speed (short form main scores at baseline and training group were in-
of Trail Making Test part A [34] and the abbreviated cluded in the imputation model. The following
Stroop Color Word Test parts I and II [35]). Only all imputation settings were used: automatic model set-
psychomotor speed tests were also performed after 6 ting, 15 iterations and 5 imputations. If a participant
weeks (T1). Tests were categorized into cognitive do- had missing data due to drop-out because of cognitive
mains a priori using the conventional classification de- decline, the criterion for missing at random was not
scribed by Lezak et al. [43]. In order to calculate fulfilled. Use of multiple imputation would in this case
domain scores, test scores were converted into z-scores have been inappropriate as violation of the missing at
based on the mean and standard deviation of the total random assumption biases the estimates [46]. We ex-
sample at baseline [44]. Subsequently, these individual pected that the cognitive decline would be larger in
test z-scores were averaged per domain. these participants than the mean decline in the entire
After inclusion, saliva samples were taken with buccal group, as it was their reason for drop-out. We decided
swabs for APOE genotyping. Samples were stored at − to use a single value imputation approach for these par-
20 °C and analysed using real-time polymerase chain re- ticipants, in which we replaced the missing values by a
action (PCR) [45]. This results in different APOE gene single value, in our case the greatest decline in the
phenotypes: three homozygous (ε2/ε2, ε3/ε3, ε4/ε4) and group. To prevent imputing non-realistic values, the
three heterozygous (ε2/ε3, ε2/ε4, ε3/ε4) [45]. lowest possible score was used as a cut-off score. We
performed additional sensitivity analyses to check
Statistical analysis whether this alternative method of dealing with missing
Socio-demographic and clinical characteristics at data influenced our results.
baseline were presented using descriptive statistics. All statistical analyses were performed as intention-to-
Feasibility measures (e.g. adherence to the exercise treat analyses, including all participants irrespective of
programme, measures of exercise intensity and rating adherence to intervention. Additionally, we performed
of the exercise sessions) were compared between the per-protocol analyses including only those participants
groups with one-way analysis of variance (ANOVA) who successfully completed the intervention period and
and independent-sample t test. all measurements. SPSS 22 was used for all analyses with
To assess the effect of training on cognitive perform- α set at 0.05.
ance in each domain (i.e. executive function, episodic
memory, working memory and psychomotor speed), Results
analysis of covariance (ANCOVA) was performed with Patient flow and sample characteristics
post-training cognitive domain z-scores as dependent In total, 307 participants were screened for eligibility
variables, baseline z-scores as covariates and group and 121 participants eventually enrolled in the study.
(exergame training, aerobic training and active control) Six participants refused to participate during baseline
as between-subject factors. To specify significant group measurements and the remaining 115 participants
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 5 of 13

Fig. 1 Flowchart of participants in study. ITT intention to treat, PP per protocol

were randomized. Fourteen participants did not Attendance, intensity and safety
complete the 12-week intervention (12%). The num- Table 2 presents the adherence per group; a trend was found
ber of drop-outs did not differ significantly between towards higher adherence in the exergame group compared
the groups (p = 0.930). The enrolment, allocation to the aerobic group (mean difference (95% CI) 6.85 (− 0.09
process and reasons for drop-out are presented in to 13.79), p = 0.053). Participants rated both exercise inter-
Fig. 1. Baseline characteristics for the randomized ventions and the active control group highly (see Table 2).
sample were well matched between the groups Training duration, training load, heart rate and rate of per-
(Table 1). The included participants had a mean (SD) ceived exertion did not differ between both intervention
age of 79.9 (6.5) years and a mean (SD) MMSE score groups. The mean training intensity was light in both inter-
of 22.4 (3.2). There were no differences in age, vention groups with an average of 41.8% (SD = 13.3) and
MMSE score and Katz index between the different 43.5% (SD = 18.2) of maximal heart rate in the exergame
dementia types (see Additional file 1). group and aerobic group respectively. For the exergame
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 6 of 13

Table 1 Baseline characteristics of the study population

Variable Exergame group (n = 38) Aerobic group (n = 38) Control group (n = 39)
Age (years), mean (SD) 79.0 (6.9) 80.9 (6.1) 79.8 (6.5)
Men, n (%) 20 (52.6) 21 (55.3) 21 (53.8)
Educational level, n (%)
Primary school education or lower 6 (15.8) 7 (18.4) 6 (15.4)
Secondary education or vocational training 23 (60.5) 22 (57.9) 22 (56.4)
Higher education 9 (23.7) 9 (23.7) 11 (28.2)
a
Mini Mental State Examination, mean (SD) 22.9 (3.4) 22.5 (3.1) 21.9 (3.1)
Aetiology of dementia, n (%)
Alzheimer’s disease 22 (57.9) 16 (42.1) 21 (53.8)
Vascular dementia 4 (10.5) 4 (10.5) 3 (7.7)
Mixed dementia (Alzheimer/vascular) 5 (13.2) 8 (21.1) 11 (28.2)
Not specified 7 (18.4) 10 (26.3) 4 (10.3)
APOE carrier state, n (%)
ε4/ε4 1 (2.7) 5 (13.2) 3 (7.9)
ε3/ε4 20 (54.1) 13 (34.2) 16 (42.1)
ε3/ε3 15 (40.5) 16 (42.1) 16 (42.1)
ε3/ε2 0 3 (7.9) 4 (7.9)
ε2/ε4 1 (2.7) 1 (2.6) 0
ε2/ε2 0 0 0
Duration since dementia diagnosis (months), mean (SD) 13.6 (19.9) 13.8 (12.3) 18.9 (22.4)
b
Functional Comorbidity Index, mean (SD) 2.5 (1.9) 2.4 (1.8) 2.2 (1.4)
Katz index,c mean (SD) 5.2 (3.3) 4.5 (3.0) 5.1 (2.9)
Number of medications used, mean (SD) 4.9 (2.9) 5.9 (3.8) 6.1 (3.7)
Use of beta-blockers, n (%) 16 (42.1) 17 (44.7) 14 (35.9)
Dementia drugs, n (%)
Rivastigmine 6 (15.8) 4 (10.5) 8 (20.5)
Donezepil 0 0 0
Galantamine 1 (2.6) 3 (7.9) 2 (5.1)
Memantine 0 1 (2.6) 0
SD standard deviation
a
Scores on the Mini-Mental State Examination range from 0 (severe impairment) to 30 (no impairment)
b
Theoretical range 0–18, higher score indicates more co-morbidities
c
Theoretical range 0–15, higher score indicates higher dependency in activities of daily living

training, the median (interquartile range) training level Missing data

after 6 weeks was 5.0 (4.3–5.8), and after 12 weeks 5.5 Missing data due to drop-out of participants was 0% at
(5.0–6.0). After 6 weeks, 25% of the participants T0, 8.7% at T1, 9.6% at T2 and 17.5% at F1. Reasons for
reached level 6 or 7, and 50% reached level 5. After 12 drop-out are described in Fig. 1. In a total of six cases,
weeks, 50% of the participants reached level 6 or 7, and the reason for drop-out was refused participation (five
40% reached level 5. This demonstrates that there were out of six at follow-up measurements). Reason for re-
no floor effects for the cognitive stimulation activity fusal was cognitive decline, which led to caregivers’ with-
and about half of the participants were able to complete drawal of consent. As explained in Methods, we used
the highest levels, thus showing that the exergame single-value imputation for substituting missing data not
training was feasible and that adequate skill acquisition at random, and performed additional sensitivity analyses
was present. No occurrence of serious adverse events to check whether this influenced our results. Data for
(e.g. events leading to death, hospital admission or per- the remaining eight drop-outs were missing at random
sistent disability) related to the exercise interventions and were substituted using multiple imputation, as ex-
were recorded. plained in Methods.
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 7 of 13

Table 2 Training characteristics of the study population

Variable Exergame group (n = 38) Aerobic group (n = 38) Control group (n = 39)
Adherence rate (%), mean (SD) 87.3 (13.6)* 81.1 (13.7)* 85.4 (12.9)
Duration training session (min), mean (SD) 32.6 (6.0) 30.5 (8.7) 30a
Training load (W), mean (SD) 53.7 (34.9) 51.2 (27.7) NA
Resting heart rate (beats/min), mean (SD) 79.4 (12.1) 77.9 (10.4) NA
Heart rate during training (beats/min), mean (SD) 105.5 (14.8) 103.9 (14.3) NA
Heart rate difference (beats/min), mean (SD) 26.1 (15.1) 26.0 (13.8) NA
b
Training intensity (% of maximal heart rate), mean (SD) 41.8 (13.3) 43.5 (18.2) NA
Rate of perceived exertion during training,c mean (SD) 13.1 (1.2) 12.8 (1.9) NA
Rating of training sessionsd (scale 1–5), Median (interquartile range) 5.0 (4.0–5.0) 5.0 (4.0–5.0) 5.0 (4.0–5.0)
Training level after 6 weeksd (scale 1–7), Median (interquartile range) 5.0 (4.3–5.8) NA NA
d
Training level after 12 weeks (scale 1–7), Median (interquartile range) 5.5 (5.0–6.0) NA NA
Differences between groups tested with one-way analysis of variance (three groups) or independent-sample t test (two groups), if data were normally distributed.
For post-hoc comparisons, Tukey honest significant difference test was performed. If data was not normally distributed, Kruskall Wallis test was performed.
NA not applicable, SD standard deviation
a
All training sessions lasted for 30 min, time has not been recorded
b
Training intensity only calculated for participants who do not use beta-blockers (n = 21 and n = 20 in the exergame group and the aerobic group respectively)
c
Theoretical range 6–20, where 6 indicates lowest intensity level and score 20 indicates highest intensity level
d
Data not normally distributed, therefore presented as median (interquartile range)
*A trend was found towards higher adherence in the exergame group compared to the aerobic group (mean difference (95% confidence interval) 6.85 (− 0.09 to
13.79), p = 0.053)

Intention-to-treat analysis (0.399 to – 0.398), p = 0.399). We did not find any

Figure 2 shows the performance on the four cognitive between-group differences in any of the other cognitive
domains at each time point per treatment arm. No sig- domains at follow-up. Sensitivity analysis pointed in the
nificant differences were found between the exergame same direction, with a maintenance effect in the aerobic
group, aerobic group and control group on executive group compared to controls (mean difference domain
functioning after 12 weeks of training. Since after 6 score (95% CI) aerobic versus control 0.267 (0.048–
weeks (T1) letter fluency was not administered as an 0.486)), and no follow-up effect in any of the other cog-
executive function test, we decided not to include T1 nitive domains. Moderator analysis showed that carry-
data in our analyses. Significant improvement on the ing APOE ε4 did not influence the relation between
secondary measure psychomotor speed was found for training and cognitive performance. z-scores of the dif-
both the aerobic and the exergame group compared to ferent cognitive domains per group and time point are
the controls after 12 weeks of training (mean difference presented in Additional file 2. Raw data of cognitive
domain score (95% CI) aerobic versus control 0.370 test scores are presented in Additional file 3.
(0.103–0.637), p = 0.007; exergame versus control 0.326
(0.081–0.571), p = 0.009). The size of the effect was Per-protocol analysis
moderate (partial η2 = 0.102). This effect was not yet n the per-protocol analyses, we excluded 14 participants who
present at the intermediate measurements after 6 weeks did not complete the 12-week intervention period. The
(see Fig. 2). No significant differences were found be- remaining 101 participants were included in this analysis.
tween the groups on the secondary measures of epi- The results of the per-protocol analyses were in line with the
sodic memory and working memory after the 12-week intention-to-treat analyses, with positive effects of exergame
intervention period. An additional sensitivity analysis and aerobic training on psychomotor speed compared to
yielded similar results, which shows that our findings controls (mean difference domain score (95% CI) aerobic
are robust. Follow-up analysis showed that the im- versus control 0.322 (0.038–0.607), p = 0.021; exergame ver-
provement in psychomotor speed was maintained for sus control 0.283 (0.002–0.563), p = 0.047). As in the
both the aerobic group and the exergame group com- intention-to-treat analyses, no significant between-group dif-
pared to the controls (mean difference domain score ferences were observed in the domains of executive function,
(95% CI) aerobic versus control 0.453 (0.185–0.722), p memory and working memory. At follow-up there were nine
= 0.001; exergame versus control 0.326 (0.070–0.604), additional drop-outs, which led to inclusion of 92 partici-
p = 0.014. There was no significant difference between pants in the follow-up analysis. We found that there was a
the exergame and aerobic group (mean difference do- trend for maintained improvement in psychomotor speed
main score (95% CI) exergame versus aerobic − 0.116 at 24-week follow-up in the aerobic group compared to
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 8 of 13

Fig. 2 Mean z-scores and standard errors of mean (SEM) at baseline, after 12 weeks and after 24 weeks for domains of executive function,
psychomotor speed, episodic memory and working memory. Arrows represent SEM. *Significant effect (p < 0.05) of exergame training and
aerobic training on psychomotor speed compared to controls after 12 weeks; §maintenance effect (p < 0.05) of aerobic and exergame training on
psychomotor speed at 24-week follow-up

the control group (mean difference domain score (95% ε4 carriership did not influence the relation between
CI) aerobic versus control 0.267 (0.048–0.486), p = 0.057). training and cognitive function. Finally, we demon-
No significant intervention effects were observed in any strated that a newly developed exergame that comprises
of the other domains. both physical and cognitive training elements is feasible
for people with dementia.
Discussion
To our knowledge, this is the first randomized con- Interpretation of results and comparison with previous
trolled trial to investigate the differential effect of exer- research
gaming versus aerobic training on cognitive functioning Contrary to our hypothesis, the current results did not
in people with dementia. We hypothesized that exer- show a larger effect of exergame training compared to
game training would result in greater improvement on aerobic training on cognitive functioning. Comparable
executive functioning than single aerobic training. Al- research on the differential effects of combined cogni-
though we did not find an effect of exergame training tive and physical training versus only cognitive or phys-
or aerobic exercise on executive function after 12 ical interventions in people with dementia is scarce.
weeks, we found that psychomotor speed improved in There is one previously published paper reporting that
both the exergame and the aerobic group compared to neither a 12-week combined cognitive–aerobic training
active controls. This effect was maintained at the nor aerobic training only improved global cognitive
24-week follow-up. We did not find an effect of both function in a smaller sample of 80 individuals with AD
intervention groups in the cognitive domains of epi- [47]. However, the type of intervention and used out-
sodic memory and working memory compared to the come measures are incomparable to the current study.
control group. Moderator analysis showed that APOE Research in individuals with MCI showed inconsistent
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 9 of 13

findings regarding the cognitive benefits of combined functions in this group. Executive functions include
interventions and its potential superiority compared to higher-order processes such as inhibitory control, men-
physical exercise or cognitive training alone [48]. In tal flexibility and planning, which are already affected
contrast, for older adults without cognitive impairment in the early stages of dementia [54, 55]. Assessment of
there is converging evidence that combined interven- executive function in people with dementia may conse-
tions (including exergames) are superior to physical or quently result in floor effects or missing data, which
cognitive training alone [48], with larger effect sizes for make it difficult to measure change over time.
interventions that are performed simultaneously com- In our study we found a moderate effect of exergame
pared to sequential interventions [12]. training and aerobic training on psychomotor speed
In healthy older adults, evidence for the efficacy of after a 12-week training period in people with demen-
physical exercise and combined cognitive and physical tia. This effect was not yet present after 6 weeks of
interventions on executive functions [12, 49], memory training. Firstly, this may imply that the improvement
[12, 49], working memory [12, 50] and attention [51] is due to the training and not due to non-specific treat-
have been well established. In our current study, both ment or practice effects. Secondly, this suggests that a
exergame and aerobic-only training did not positively longer training duration is necessary to improve psy-
affect executive functions, working memory or episodic chomotor speed. Although still under debate, there is
memory. This seems partly in line with previous re- some evidence that physical exercise leads to improved
search. A meta-analysis performed by our group [13] cognitive function through promotion of hippocampal
demonstrated positive effects of combined interventions neurogenesis [56], brain angiogenesis [57] and synaptic
on global cognitive function in older adults with MCI or plasticity [58] elicited by an increased expression of
dementia, but no effects in the domains of executive neurotrophic factors [59]. In cognitively healthy older
function and memory. In contrast, a recently published adults, physical exercise interventions have the largest
RCT showed that both a mentally challenging exergame gains on executive control processes, psychomotor
and a passive exergame improve executive functioning speed and attention [49, 51, 60, 61]. In people with de-
in people with MCI [52]. However, the more challenging mentia there is little research about the benefits for dif-
exergame only yielded significant effects after 6 months ferent cognitive domains. From a neurobiological
of training, while the passive exergame already produced perspective, however, we do not have an explanation
gains after 3 months [52]. A possible explanation for this for why exercise would only improve psychomotor
discrepancy is that participants in the mentally challen- speed, but not the other cognitive skills assessed. We
ging exergame group needed more time to master the hypothesize, that only finding an effect on psychomotor
intervention, which may have delayed triggering the syn- speed, and not on executive functioning, may be related
ergistic effects of the combined intervention [52]. This to domain-specific responsiveness of the selected out-
might also explain the negative findings in our study, come measures. Processing speed tests typically are
since a mentally challenging exergame was used for a continuous outcome measures without ceiling or floor
relative short intervention period of 12 weeks. effects that are highly sensitive [62], which may explain
There is evidence that the severity of neurocognitive the sensitivity to change even in a dementia sample. In
disorder has a moderating impact on the cognitive ef- contrast, tests that measured executive functioning re-
fects of combined cognitive and physical training [53]. sulted in floor effects in our dementia sample, which
An increase in the severity of neurocognitive disorder made it difficult to measure change over time. Alterna-
may lead to a decrease of the intervention effect [53]. tively, one could also hypothesize that mood may be a
This could be explained by a reduced structural brain mediating factor for improvement on speed measures,
capacity (e.g. reduced number of neurons and synapses) as previous research showed that exercise and exer-
in participants with more severe neurocognitive disorder, game training can reduce depressive symptoms in
which may lead to limited resources necessary for healthy older adults [63, 64]. The positive effect on psy-
training-induced gains [53]. Therefore, it may be more chomotor speed was consistent across the different
difficult to induce cognitive benefits in people with de- neuropsychological tests used to measure psychomotor
mentia compared to those with MCI or healthy older speed (short form of Trail Making Test part A and the
adults. Moreover, the complexity to obtain valid neuro- abbreviated Stroop Color Word Test parts I and II),
psychological outcomes that are sensitive to change in which shows that the effect was robust and reliable. Its
persons who already have severe cognitive deficits due moderate effect size is slightly larger than to the
to their dementia complicates the assessment of cogni- small-to-moderate effect sizes commonly found in
tive functioning in this group. Even though we carefully studies examining the effects of cholinesterase inhibi-
selected and adjusted tests for use in mild-to-moderate tors on cognitive function [65, 66]. Given that interven-
dementia, it is particularly challenging to assess executive tions to ameliorate cognitive decline of people with
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 10 of 13

dementia are scarce, this effect size may be clinically of mood, since this might be a potential mediating fac-
relevant. Poor processing speed is a predictor of func- tor for the improvement in processing speed measures.
tional decline in basic and instrumental activities of
daily living [67]. In addition, poor processing speed is Clinical relevance and feasibility
reported to be a predictor for incident dementia [68] Both exergame training and aerobic training improved
and was found to be associated with shorter survival psychomotor speed after 12 weeks, with a moderate ef-
among older adults in Japan [69]. Furthermore, late-life fect size. This finding may be clinically relevant as psy-
cognitive decline is attributable to slower processing speed chomotor speed is an important predictor for
[70]. Thus, the reported improvement in processing speed functional decline. In our study, exergame training was
may be clinically relevant. not superior to aerobic training. However, there was a
The mean training intensity was light in both inter- trend for higher adherence in the exergame group
vention groups, with an average of 41.8% (SD = 13.3) compared to the aerobic group. Additionally, trainers
and 43.5% (SD = 18.2) of maximal heart rate in the who individually guided the training sessions reported
exergame group and the aerobic group respectively. We that it was easier to motivate participants in the exer-
expected that improved cardiorespiratory fitness would game group and to increase duration of the training
be a requirement to improve cognitive function [51], sessions. This was confirmed by our finding that no
and therefore we aimed to achieve moderate exercise participants dropped out in the exergame group due to
intensity (e.g. 65–75% of maximal heart rate) during low motivation (see Fig. 1). Accordingly, exergaming
the training sessions. However, the exercise training seems to be an effective method to stimulate
was tailored to an individual fitness level and health long-term physical activity participation in people with
status, and most participants were not able to achieve a dementia.
moderate training intensity. The recently published De-
mentia and Physical Activity (DAPA) trial [71] showed Future directions
that moderate to high-intensity aerobic and strength Future studies should examine whether certain individ-
exercise training did not slow cognitive decline in ual characteristics (e.g. type of dementia) moderate the
people with mild to moderate dementia, and even effect of physical activity on cognition. Insight into
worsened cognitive impairment in those who complied these individual differences is important because it can
with the intervention, despite an improvement in phys- determine which people are most likely to benefit from
ical fitness. It is therefore unlikely that the light training physical activity. It can also help to personalize inter-
intensity in our study limited the beneficial effects of ventions, thereby stimulating physical activity. More-
exercise on cognitive functioning. over, additional studies are needed to explore the
optimal intervention design and dose–response for eli-
Strengths and limitations citing beneficial cognitive effects in people with demen-
The strengths of our study include the inclusion of a tia. Future intervention trials should include measures
relatively large sample of people with dementia, a high of psychomotor speed as these can reliably and validly
adherence rate, the use of a comprehensive neuro- be assessed in people with dementia and are closely re-
psychological assessment and follow-up measurement lated to everyday activities. Furthermore, studies should
for long-term maintenance effects. However, some limi- also focus on investigating neurophysiological mecha-
tations need to be taken into account when interpreting nisms that underlie the cognitive effects of exercise, for
our results. Firstly, only participants who were mobile example by including neuroimaging measures.
and motivated enrolled in our study, which may limit
the external validity of the current findings. Secondly, Conclusions
participants were not blinded to allocation, which is an Exergaming is a feasible and highly appreciated exercise
unavoidable limitation of exercise studies. Outcome method to engage older adults with dementia in phys-
assessors were masked for intervention allocation. ical exercise, mixed with cognitive stimulation. Both
Thirdly, although we used adapted versions of executive exergame training and aerobic training can improve
tests, making administration in people with dementia psychomotor speed, which may be clinically relevant as
more feasible, a floor performance was still found in a psychomotor speed is an important predictor for func-
number of individuals. This may have reduced the sen- tional decline. Although no effects were found on
sitivity to measure change over time, obscuring poten- executive function, episodic memory and working
tial positive results. Fourthly, the intervention period memory, the potential broad range of effects of exer-
was only 12 weeks, which may have been too short to games for older adults with dementia (e.g. physical
show beneficial effects of exergames on executive func- functioning, quality of life, activities in daily living)
tioning. Lastly, future studies should include measures should be studied in future RCTs.
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 11 of 13

Additional files Center Groningen, University of Groningen, Groningen, the Netherlands.

6
Radboud University Medical Center, Department for Health Evidence,
Nijmegen, the Netherlands. 7Center for Cognition, Donders Institute for Brain
Additional file 1: Baseline characteristics of study population presented
Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
separately for different types of dementia (DOCX 18 kb)
Additional file 2: z-scores of different cognitive domains per group and Received: 13 July 2018 Accepted: 27 November 2018
time point. (DOCX 18 kb)
Additional file 3: Data of cognitive tests for each intervention group.
(DOCX 21 kb)
References
1. Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H, et al.
Abbreviations Defeating Alzheimer’s disease and other dementias: a priority for European
AD: Alzheimer’s disease; APOE: Apolipoprotein E; MCI: Mild cognitive science and society. Lancet Neurol. 2016;15:455–532.
impairment; MMSE: Mini Mental State Examination; RCT: Randomized 2. Selkoe DJ. Preventing Alzheimer’s disease. Science. 2012;337:1488–92.
controlled trial 3. Northey JM, Cherbuin N, Pumpa KL, Smee DJ, Rattray B. Exercise
interventions for cognitive function in adults older than 50: a systematic
Acknowledgements review with meta-analysis. Br J Sports Med. 2018;52:154–60.
The authors would like thank all participants and their caregivers for 4. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary
participating in this study. They express gratitude towards all healthcare prevention of Alzheimer's disease: an analysis of population-based data.
professionals (e.g. case managers, physical therapists, geriatricians, general Lancet Neurol. 2014;13:788–94.
practitioners) who referred patients to participate in our study, in particular 5. Ashby-Mitchell K, Burns R, Shaw J, Anstey KJ. Proportion of dementia in
Betsie Lomme, Maria Lam and Margaritha Ibraguimova. The authors are Australia explained by common modifiable risk factors. Alzheimers Res Ther.
grateful to all community centres/care centres that provided space for 2017;9:11.
executing the research. They are indebted to the research assistants Lizzy 6. Forbes D, Forbes SC, Blake CM, Thiessen EJ, Forbes S. Exercise programs for
van der Horst, Maud van Dorst, Anke Megens, Josette Westhoff and Willem people with dementia. Cochrane Database Syst Rev. 2015;14:CD006489.
Eikelboom for their assistance during recruitment, data acquisition and 7. Groot C, Hooghiemstra AM, Raijmakers PGHM, van Berckel BNM, Scheltens
training of the participants. They are also grateful to all students from P, Scherder EJA, et al. The effect of physical activity on cognitive function in
medicine, physiotherapy, applied psychology and biomedical sciences for patients with dementia: a meta-analysis of randomized control trials. Ageing
guiding the participants during the training period. The authors would also Res Rev. 2016;25:13–23.
like to thank Ella Keijzer and Job de Reus from Bike Labyrinth for developing 8. Fabel K, Wolf SA, Ehninger D, Babu H, Leal-Galicia P, Kempermann G.
the exergame used in our study and their support solving technical issues. Additive effects of physical exercise and environmental enrichment on
adult hippocampal neurogenesis in mice. Front Neurosci. 2009;3:50.
Funding 9. Law LL, Barnett F, Yau MK, Gray MA. Effects of combined cognitive and
The project is funded by the Netherlands Organisation for Health, Research exercise interventions on cognition in older adults with and without
and Development (ZonMw) (grant number 733050303). ZonMw did not cognitive impairment: a systematic review. Ageing Res Rev. 2014;15:61–75.
contribute to the study design or writing the manuscript. 10. Olson AK, Eadie BD, Ernst C, Christie BR. Environmental enrichment and
voluntary exercise massively increase neurogenesis in the adult
Availability of data and materials hippocampus via dissociable pathways. Hippocampus. 2006;16:250–60.
The datasets of the current study are available from the corresponding author 11. Van Praag H. Neurogenesis and exercise: past and future directions.
on reasonable request. NeuroMolecular Med. 2008;10:128–40.
12. Zhu X, Yin S, Lang M, He R, Li J. The more the better? A meta-analysis on
Authors’ contributions effects of combined cognitive and physical intervention on cognition in
MOR, WB, EK, JA and RK devised and designed the study. EK contributed to healthy older adults. Ageing Res Rev. 2016;31:67–79.
data collection. EK, RD, JA and RK performed and interpreted statistical 13. Karssemeijer EGA, Aaronson JA, Bossers WJR, Smits T, Olde Rikkert MGM,
analysis. EK drafted the first manuscript. All authors edited, read and Kessels RPC. Positive effects of combined cognitive and physical exercise
approved the final version of the manuscript. training on cognitive function in older adults with mild cognitive
impairment or dementia: a meta-analysis. Ageing Res Rev. 2017;40:75–83.
Ethics approval and consent to participate 14. Manera V, Ben-Sadoun G, Aalbers T, Agopyan H, Askenazy F, Benoit M, et al.
The study protocol has been approved by the Medical Ethical Committee of Recommendations for the use of serious games in neurodegenerative
Radboud University Medical Center, the Netherlands (Ref No. NL52581.091.15/2015– disorders: 2016 Delphi Panel. Front Psychol. 2017;8:1243.
1857). Written informed consent to participate is obtained from all participants. 15. van Santen J, Dröes R-M, Holstege M, Henkemans OB, van Rijn A, de Vries R,
et al. Effects of exergaming in people with dementia: results of a systematic
Consent for publication literature review. J Alzheimers Dis. 2018;63:741–60.
Not applicable. 16. Logie RH, Cocchini G, Delia Sala S, Baddeley AD. Is there a specific executive
capacity for dual task coordination? Evidence from Alzheimer's disease.
Competing interests Neuropsychology. 2004;18:504.
RK is co-author of the Location Learning Test—Revised and receives royalties 17. Stanmore E, Stubbs B, Vancampfort D, de Bruin ED, Firth J. The effect of
from its publisher Hogrefe. active video games on cognitive functioning in clinical and non-clinical
populations: a meta-analysis of randomized controlled trials. Neurosci
Biobehav Rev. 2017;78:34–43.
Publisher’s Note 18. Moholdt T, Weie S, Chorianopoulos K, Wang AI, Hagen K. Exergaming can
Springer Nature remains neutral with regard to jurisdictional claims in be an innovative way of enjoyable high-intensity interval training. BMJ
published maps and institutional affiliations. Open Sport Exerc Med. 2017;3:e000258.
19. Meekes W, Stanmore EK. Motivational determinants of exergame
Author details participation for older people in assisted living facilities: mixed-methods
1
Radboud University Medical Center, Donders Institute for Brain Cognition study. J Med Internet Res. 2017;19:e238.
and Behaviour, Department of Geriatric Medicine, Nijmegen, the Netherlands. 20. Colombo M, Marelli E, Vaccaro R, Valle E, Colombani S, Polesel E, et al.
2
Radboud University Medical Center, Radboudumc Alzheimer Center, Virtual reality for persons with dementia: an exergaming experience.
Nijmegen, the Netherlands. 3Radboud University Medical Center, Donders Gerontechnol. 2012;11:402–5.
Institute for Brain Cognition and Behaviour, Department of Medical 21. Head D, Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, et al.
Psychology, Nijmegen, the Netherlands. 4BeweegStrateeg, Groningen, the Exercise engagement as a moderator of the effects of APOE genotype on
Netherlands. 5Center for Human Movement Sciences, University Medical amyloid deposition. Arch Neurol. 2012;69:636–43.
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 12 of 13

22. Deeny SP, Poeppel D, Zimmerman JB, Roth SM, Brandauer J, Witkowski S, et 48. Bruderer-Hofstetter M, Rausch-Osthoff AK, Meichtry A, Munzer T,
al. Exercise, APOE, and working memory: MEG and behavioral evidence for Niedermann K. Effective multicomponent interventions in comparison to
benefit of exercise in epsilon4 carriers. Biol Psychol. 2008;78:179–87. active control and no interventions on physical capacity, cognitive function
23. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, and instrumental activities of daily living in elderly people with and without
mechanisms and therapy. Nat Rev Neurol. 2013;9:106–18. mild impaired cognition—a systematic review and network meta-analysis.
24. Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, et al. Ageing Res Rev. 2018;45:1–14.
Leisure-time physical activity at midlife and the risk of dementia and 49. Smith PJ, Blumenthal JA, Hoffman BM, Cooper H, Strauman TA, Welsh-Bohmer
Alzheimer's disease. Lancet Neurol. 2005;4:705–11. K, et al. Aerobic exercise and neurocognitive performance: a meta-analytic
25. Etnier JL, Caselli RJ, Reiman EM, Alexander GE, Sibley BA, Tessier D, et al. review of randomized controlled trials. Psychosom Med. 2010;72:239–52.
Cognitive performance in older women relative to ApoE-e4 genotype and 50. Rathore A, Lom B. The effects of chronic and acute physical activity on
aerobic fitness. Med Sci Sports Exerc. 2007;39:199–207. working memory performance in healthy participants: a systematic review
26. Podewils LJ, Guallar E, Kuller LH, Fried LP, Lopez OL, Carlson M, et al. with meta-analysis of randomized controlled trials. Syst Rev. 2017;6:124.
Physical activity, APOE genotype, and dementia risk: findings from the 51. Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L.
Cardiovascular Health Cognition Study. Am J Epidemiol. 2005;161:639–51. Physical activity and enhanced fitness to improve cognitive function in
27. Karssemeijer EGA, Bossers WJR, Aaronson JA, Kessels RPC, Olde Rikkert MGM. older people without known cognitive impairment. Cochrane Database
The effect of an interactive cycling training on cognitive functioning in Syst Rev. 2008;3:1–73.
older adults with mild dementia: study protocol for a randomized 52. Anderson-Hanley C, Barcelos NM, Zimmerman EA, Gillen RW, Dunnam
controlled trial. BMC Geriatr. 2017;17:73. M, Cohen BD, et al. The Aerobic and Cognitive Exercise Study (ACES)
28. American Psychiatric Association. Diagnostic and statistical manual of for community-dwelling older adults with or at-risk for mild cognitive
mental disorders, 4th edition (DSM-IV). Arlington: the American Psychiatric impairment (MCI): neuropsychological, neurobiological and
Association; 2000. neuroimaging outcomes of a randomized clinical trial. Front Aging
29. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical Neurosci. 2018;10:76.
method for grading the cognitive state of patients for the clinician. J 53. Bamidis PD, Fissler P, Papageorgiou SG, Zilidou V, Konstantinidis EI, Billis
Psychiatr Res. 1975;12:189–98. AS, et al. Gains in cognition through combined cognitive and physical
30. Meulenbroek O, Vernooij-Dassen MJFJ, Kessels RPC, Graff MJL, Sjögren MJC, training: the role of training dosage and severity of neurocognitive
Schalk BWM, et al. Informed consent in dementia research. Legislation, disorder. Front Aging Neurosci. 2015;7:152.
theoretical concepts and how to assess capacity to consent. Eur Geriatr 54. Baudic S, Dalla Barba G, Thibaudet MC, Smagghe A, Remy P, Traykov L.
Med. 2010;1:58–63. Executive function deficits in early Alzheimer's disease and their relations
31. Pocock SJ, Simon R. Sequential treatment assignment with balancing for with episodic memory. Arch Clin Neuropsychol. 2006;21:15–21.
prognostic factors in the controlled clinical trial. Biometrics. 1975;31:103–15. 55. Miyake A, Emerson MJ, Friedman NP. Assessment of executive functions in
32. Verhage F. Intelligence and age in a Dutch sample. Hum Dev. 1965;8:238–45. clinical settings: problems and recommendations. Semin Speech Lang.
33. Borg G. Borg’s perceived exertion and pain scales. Champaign: Human 2000;21(2):169–83.
Kinetics; 1998. 56. Nokia MS, Lensu S, Ahtiainen JP, Johansson PP, Koch LG, Britton SL, et al.
34. Reitan RM, Wolfson D. The Trail Making Test as an initial screening Physical exercise increases adult hippocampal neurogenesis in male rats
procedure for neuropsychological impairment in older children. Arch Clin provided it is aerobic and sustained. J Physiol. 2016;594:1855–73.
Neuropsychol. 2004;19:281–8. 57. Lange-Asschenfeldt C, Kojda G. Alzheimer’s disease, cerebrovascular
35. Jensen AR, Rohwer WD. The Stroop color-word test: a review. Acta Psychol. dysfunction and the benefits of exercise: from vessels to neurons. Exp
1966;25:36–93. Gerontol. 2008;43:499–504.
36. Yogev G, Giladi N, Peretz C, Springer S, Simon ES, Hausdorff JM. Dual 58. Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and
tasking, gait rhythmicity, and Parkinson's disease: which aspects of gait are human models of exercise-induced brain plasticity. Trends Cogn Sci.
attention demanding? Eur J Neurosci. 2005;22:1248–56. 2013;17:525–44.
37. Ruff R, Light R, Parker S, Levin H. Benton Controlled Oral Word Association 59. Lista I, Sorrentino G. Biological mechanisms of physical activity in
Test: reliability and updated norms. Arch Clin Neuropsychol. 1996;11:329–38. preventing cognitive decline. Cell Mol Neurobiol. 2010;30:493–503.
38. Schmand B, Groenink S, Van den Dungen M. Letter fluency: 60. Voss MW, Nagamatsu LS, Liu-Ambrose T, Kramer AF. Exercise, brain, and
psychometric properties and Dutch normative data. Tijdschr Gerontol cognition across the life span. J Appl Physiol. 2011;111:1505–13.
Geriatr. 2008;39:64–76. 61. Colcombe S, Kramer AF. Fitness effects on the cognitive function of older
39. Wilson BA, Evans JJ, Alderman N, Burgess PW, Emslie H. Behavioural adults a meta-analytic study. Psychol Sci. 2003;14:125–30.
assessment of the dysexecutive syndrome. In: Methodology of frontal and 62. Gontkovsky ST, Beatty WW. Practical methods for the clinical assessment of
executive function. Abingdon: Psychology Press; 1997. p. 239–50. information processing speed. Int J Neurosci. 2006;116:1317–25.
40. Bucks RS, Willison JR, Byrne LMT, Kessels RPC. Location Learning 63. Arent SM, Landers DM, Etnier JL. The effects of exercise on mood in older
Test—Revised edition (Dutch version). Amsterdam: Hogrefe; 2011. adults: A meta-analytic review. J Aging Phys Act. 2000;8:407–30.
41. Wechsler D. Wechsler Adult Intelligence Scale 3rd edition (WAIS-III): test 64. Rosenberg D, Depp CA, Vahia IV, Reichstadt J, Palmer BW, Kerr J, et al.
manual. New York: Psychological Corporation; 1997. Exergames for subsyndromal depression in older adults: a pilot study of a
42. Wechsler D. Wechsler Memory Scale (WMS-III): administration and scoring novel intervention. Am J Geriatr Psychiatry. 2010;18:221–6.
manual. San Antonio: Psychological Corporation; 1997. 65. Blanco-Silvente L, Castells X, Saez M, Barcelo MA, Garre-Olmo J, Vilalta-
43. Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment. New Franch J, et al. Discontinuation, efficacy, and safety of cholinesterase
York: Oxford University Press; 2004. inhibitors for Alzheimer's disease: a meta-analysis and meta-regression of 43
44. Brands AM, Kessels RPC, Hoogma RP, Henselmans JM, van der Beek Boter randomized clinical trials enrolling 16 106 patients. Int J
JW, Kappelle LJ, et al. Cognitive performance, psychological well-being, and Neuropsychopharmacol. 2017;20:519–28.
brain magnetic resonance imaging in older patients with type 1 diabetes. 66. Cohen J. A power primer. Psychol Bull. 1992;112:155–9.
Diabetes. 2006;55:1800–6. 67. Iwasa H, Gondo Y, Yoshida Y, Kwon J, Inagaki H, Kawaai C, et al.
45. Yi L, Wu T, Luo W, Zhou W, Wu J. A non-invasive, rapid method to Cognitive performance as a predictor of functional decline among the
genotype late-onset Alzheimer's disease-related apolipoprotein E gene non-disabled elderly dwelling in a Japanese community: a 4-year
polymorphisms. Neural Regen Res. 2014;9:69. population-based prospective cohort study. Arch Gerontol Geriatr. 2008;
46. Pedersen AB, Mikkelsen EM, Cronin-Fenton D, Kristensen NR, Pham TM, 47:139–49.
Pedersen L, et al. Missing data and multiple imputation in clinical 68. Rapp MA, Reischies FM. Attention and executive control predict Alzheimer
epidemiological research. Clin Epidemiol. 2017;9:157. disease in late life: results from the Berlin Aging Study (BASE). Am J Geriatr
47. Venturelli M, Sollima A, Cè E, Limonta E, Bisconti AV, Brasioli A, et al. Psychiatry. 2005;13:134–41.
Effectiveness of exercise-and cognitive-based treatments on salivary cortisol 69. Iwasa H, Kai I, Yoshida Y, Suzuki T, Kim H, Yoshida H. Information processing
levels and sundowning syndrome symptoms in patients with Alzheimer’s speed and 8-year mortality among community-dwelling elderly Japanese. J
disease. J Alzheimers Dis. 2016;53:1631–40. Epidemiol. 2014;24:52–9.
Karssemeijer et al. Alzheimer's Research & Therapy (2019) 11:3 Page 13 of 13

70. Salthouse TA. Speed mediation of adult age differences in cognition. Dev
Psychol. 1993;29:722–38.
71. Lamb SE, Sheehan B, Atherton N, Nichols V, Collins H, Mistry D, et al.
Dementia And Physical Activity (DAPA) trial of moderate to high intensity
exercise training for people with dementia: randomised controlled trial.
BMJ. 2018;361:k1675.