Journal of Clinical and Experimental Neuropsychology

ISSN: 1380-3395 (Print) 1744-411X (Online) Journal homepage: https://www.tandfonline.com/loi/ncen20

Effects of physical activity on delayed memory

measures in randomized controlled trials with
nonclinical older, mild cognitive impairment, and
dementia participants

Philip Gerard Gasquoine

To cite this article: Philip Gerard Gasquoine (2018) Effects of physical activity on delayed memory
measures in randomized controlled trials with nonclinical older, mild cognitive impairment, and
dementia participants, Journal of Clinical and Experimental Neuropsychology, 40:9, 874-886, DOI:
10.1080/13803395.2018.1442815

To link to this article: https://doi.org/10.1080/13803395.2018.1442815

Published online: 06 Mar 2018.

Submit your article to this journal

Article views: 259

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ncen20
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
2018, VOL. 40, NO. 9, 874–886
https://doi.org/10.1080/13803395.2018.1442815

Effects of physical activity on delayed memory measures in randomized

controlled trials with nonclinical older, mild cognitive impairment, and
dementia participants
Philip Gerard Gasquoine
Department of Psychological Science, University of Texas Rio Grande Valley, Edinburg, TX, USA

ABSTRACT ARTICLE HISTORY

Introduction: Longitudinal studies have found that physical activity protects against Alzheimer disease, Received 20 December 2017
but the mechanism is unknown. The prevailing model derives from animal research and has physical Accepted 5 February 2018
activity directly affecting brain physiology by increasing brain volume, brain-derived neurotrophic KEYWORDS
factor (BDNF), and hippocampal neurogenesis with consequent gains in neuropsychological test scores. Aerobic exercise;
Supporting evidence has been mixed, with physical-activity-related gains across multiple neuropsycho- brain-derived neurotrophic
logical domains considered indicative of the protective effect. Hippocampal-mediated delayed memory factor; hippocampal volume;
functioning is the first neurocognitive skill to be impaired in the early stages of Alzheimer disease, and neurogenesis;
physical-activity-related gains on delayed memory measures would provide the strongest support for neuropsychological testing
the model. Results: Review of 26 randomized controlled trials with nonclinical older, mild cognitive
impairment, and dementia participants found only one with significant physical-activity-related gains in
delayed memory compared to controls. This evidence does not support the physiological brain change
model. Similarly, there is questionable support from those randomized controlled trials that have
measured physical-activity-related brain volume and blood BDNF levels (neurogenesis having no
valid labeling technique in living humans). Conclusion: Physical-activity-related protective effects
against Alzheimer disease are likely mediated through pathways outside the central nervous system.

Physical activity has been proposed as a nonpharmaceu-
tical method of dementia delay or prevention (e.g., Barnes
& Yaffe, 2011; Erickson, Weinstein, & Lopez, 2012).
Primary support for this pathway comes from prospec-
tive, longitudinal, epidemiological studies of nonclinical
older cohorts that are followed over several years to
determine the characteristics of those that develop
dementia. Meta-analytic review of 16 such studies con-
ducted between 1990 and 2007 found that greater self-
reported physical activity (optimal amount and type
undetermined) reduced the risk of developing
Alzheimer disease, the most common form of dementia,
by 45%, but had no significant effect on the risk of
developing Parkinson disease (Hamer & Chida, 2009).
Self-report measurement is subject to recall and reporting
biases, but the protective effect has also been found when
physical activity was measured objectively with wrist acti-
graphs (e.g., Buckman et al., 2012).
Physical activity also reduces the risk of mild cogni-
tive impairment (MCI), which involves neurocognitive
decline in older persons in the absence of dementia
(Winblad et al., 2004). Meta-analysis of 15 prospective,
longitudinal, epidemiological studies conducted
between 2001 and 2008 found that MCI respondents
aged >65 years who self-reported a high level of physical
activity were 38% less likely to exhibit decline on neu-
rocognitive tests (most commonly the Mini-Mental
State Examination) than those who self-reported being
sedentary (Sofi et al., 2011). For low to moderate physi-
cal activity the risk reduction was 35%. MCI is concep-
tualized as an intermediate stage between nonclinical
aging and dementia, although the likelihood of an
older person with MCI showing further neurocognitive
deterioration into dementia is far from certain (Mitchell
& Shiri-Feshki, 2009).
Regarding causation, it is unrealistic for longitudi-
nal, epidemiological studies to be able to isolate the
protective effect of physical activity from other aspects
of a healthier lifestyle (Plassman, Williams, Burke,
Holsinger, & Benjamin, 2010). Initially it was consid-
ered that physical activity acted in combination with
associated lifestyle factors like better diet and reduced
alcohol and nicotine intake to increase cardiovascular
health, secondarily lowering Alzheimer disease risk

CONTACT Philip Gerard Gasquoine drgdrg13@yahoo.com Department of Psychological Science, University of Texas Rio Grande Valley, 1201 W. University
Drive, Edinburg, TX 78541, USA.
© 2018 Informa UK Limited, trading as Taylor & Francis Group
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
(e.g., Woo, 2000). Then it was argued that the protec-
tive effect resulted from direct changes in the molecular
structure of the brain (Cotman & Berchtold, 2002).
This concept evolved from decades of research dating
from Krech, Rozenzweig, and Bennett (1960) that
showed laboratory animals raised in enriched environ-
ments developed heavier cerebral cortices relative to
body weight and had altered brain chemistry in com-
parison to their less stimulated peers. Similar physio-
logical changes were demonstrated to occur with
increased physical activity in older animals (e.g., van
Praag, Shubert, Zhao, & Gage, 2005).
In the extension of this animal research to humans,
physical-activity-related brain changes have been
considered to lower the risk of Alzheimer disease and
neurocognitive decline during the aging process by some
combination of: (a) increases in total or regional brain
volumes as measured by magnetic resonance imaging
(MRI: e.g., Colcombe et al., 2006; Erickson, Leckie,
& Weinstein, 2014; Ruscheweyh et al., 2011; ten Brinke
et al., 2015); (b) increases in levels of brain-derived
neurotrophic factor (BDNF), as measured by blood
serum or plasma levels (e.g., Barha, Davis, Falck,
Nagamatsu, & Liu-Ambrose, 2017; Chieffi et al., 2017;
Cotman & Berchtold, 2002; Groot et al., 2016; Head,
Singh, & Bugg, 2012; ten Brinke et al., 2015); and (c)
neurogenesis in the hippocampus (e.g., Barha et al., 2017;
Cotman & Berchtold, 2002; Groot et al., 2016; Head et al.,
2012; Lautenschlager et al., 2008; Maass et al., 2015; Pereira
et al., 2007; Reiter et al., 2015; ten Brinke et al., 2015) that
has no valid measure in living humans. These molecular
changes are considered to enhance neurocognitive ability
as evidenced by gains on neuropsychological test scores
with consequent delay or prevention of the neurocognitive
decline characteristic of nonclinical aging, MCI, and
Alzheimer disease.
This physical-activity-related molecular brain
change concept has generated a great deal of research
interest with mixed results. This review attempts to
shed some light on the contradictory findings by
focusing solely upon one central aspect of neurocogni-
tion that is associated with Alzheimer disease, namely
memory impairment, in terms of both its behavioral
manifestation and physiological underpinnings.
Longitudinal studies have consistently shown that
memory is the first neuropsychological domain to be
impaired in the early preclinical stages of Alzheimer
disease (e.g., Mickes et al., 2007). The memory impair-
ment is typically termed “episodic memory (i.e., the
ability to learn and retain new information)” (Albert
et al., 2011, p. 271), although it is also known as ante-
rograde amnesia. On neuropsychological tests it is
assessed by long-term or delayed measures with
875
immediate memory capacity being relatively spared
(Cermak & Butters, 1972). The actual mechanism
behind the delayed impairment, be it faulty encoding
or rapid forgetting, is still unclear (e.g., Ally, Hussey,
Ko, & Molitor, 2013), so the key clinical measures that
pertain to Alzheimer disease onset are either delayed
recall or recognition scores from tests of episodic
memory.
Following the well-known case of H.M. (Scoville
& Milner, 1957), impaired delayed memory is primarily
associated with hippocampal dysfunction, although it can
also occur with damage to other regions within the medial
temporal lobe. Alzheimer disease associated tau and amy-
loid abnormalities begin in the lateral entorhinal cortex, a
region of the medial temporal lobe that is involved in
“retaining hippocampal-dependent memories over brief
delays” (Khan et al., 2014, p. 309). Hippocampal atrophy,
which precedes clinically evident memory decline, is an
accepted biomarker for Alzheimer disease (Jack et al.,
2013), but it also occurs in nonclinical aging at a lesser
rate (1.6% yearly compared to 2.8% in MCI, and 3.5 to 4%
in Alzheimer disease: Jack et al., 2000).
Effect of physical activity on
neuropsychological test scores in randomized
controlled trials
Nonlongitudinal studies of physical-activity-related
brain and/or neurocognitive change in older persons
can be divided into cross-sectional and randomized
controlled designs. Cross-sectional designs can avoid
self-reporting bias of physical activity levels by using
fitness (most commonly measured as maximal oxygen
consumption, VO2max), or objective recording devices
such as an accelerometer (Makizako et al., 2015), yet
they are still considered the weaker of the two designs as
results can be confounded by age, gender, or unmea-
sured factors (e.g., lifetime stress; body mass index:
Erickson et al., 2014). Randomized controlled trials
whereby participants are randomly assigned to an exer-
cise or more sedentary (or no) intervention with post
minus pre outcome measures avoid these confounds.
Such randomized controlled trials have been found to
achieve good levels of participation, adherence, and
retention with older participants. Nevertheless, they
are not representative of the aging population in that
individuals deemed incapable of completing the physical
activity program and those who are already physically
active are typically excluded from participation.
Randomized controlled trials with older participants
have differed in the type and quantity of exercise pro-
vided to the physically more active group. Both main
types of exercise, aerobic (e.g., walking; cycling) and
876 P. G. GASQUOINE

resistance (e.g., lifting weights), have been studied often trials), “episodic” memory (11), and word fluency (12)
within a combined exercise program. Resistance exer- skills (Barha et al., 2017).
cises have also comprised the control intervention for
the aerobic group (e.g., Smiley-Oyen, Lowry, Francois,
Kohut, & Ekkekakis, 2008), but more commonly the MCI and dementia participants
control group receives stretching, balancing, and/or
Meta-analysis of 14 randomized controlled trials pub-
toning exercises, or no physically active intervention.
lished between 1966 and 2012 on “MCI” participants
Trial durations/intensity also vary widely, ranging from
(studies included those with formally diagnosed MCI
6 weeks × 30 min × 3 days per week (Scherder et al.,
and those with participant mean Mini-Mental Status
2005) to 2 years × 2 center-based visits plus 3–4 home-
Examination scores of 24 to 28) concluded: “the vast
based activities per week (Sink et al., 2015). Neither of
majority of outcomes (92%) were nonsignificant, provid-
these trials reported a significant effect of physical
ing no strong or consistent evidence that exercise of any
activity on neurocognitive abilities. The World Health
particular type significantly or robustly improves cogni-
Organization (2010) recommends a weekly minimum
tion” (Gates, Singh, Sachdev, & Valenzuela, 2013, p.
of 150 min of moderate or 75 min of vigorous intensity
1095). In contrast, meta-analytic review of 11 randomized
aerobic activity per week for adults >65 years of age.
controlled trials published pre February 2015 with MCI
Multiple recent reviews of randomized controlled
participants concluded that aerobic exercise significantly
trials with nonclinical older, MCI, and dementia parti-
improved global neurocognitive skills (no overall effect
cipants comparing physical activity to more sedentary
size was reported as study measures were deemed incom-
(or no) interventions using all manner of neuropsycho-
patible: Zheng, Xia, Zhou, Tao, & Chen, 2016).
logical test scores as outcome measures have been
A Cochrane review of 12 randomized controlled
conducted with decidedly mixed results.
studies conducted between 1997 and 2012 concluded
that physical activity did not significantly (p = .08)
Nonclinical older participants improve neurocognition in older (>65 years) dementia
patients of all types (effect size = .43: Forbes, Forbes,
A Cochrane review of 12 randomized controlled trials
Blake, Thiessen, & Forbes, 2015). In contrast, meta-
conducted pre 2013 concluded that aerobic activity has
analytic review of 18 randomized controlled trials con-
no effect on the neurocognitive abilities of nonclinical
ducted between 1960 and 2015 reported that aerobic
older (>55 years) participants (Young, Angevaren,
activity significantly improved global neurocognitive
Rusted, & Tabet, 2015). Similarly, a meta-analysis of 25
abilities that were typically (11 studies) measured with
randomized controlled trials conducted between 2002
the Mini-Mental Status Examination in dementia
and 2012 that isolated the effects of physical activity type
patients (effect size = .42: Groot et al., 2016). This effect
by specific neuropsychological skill found significant
size was similar in the six studies that were limited to
improvements in only 3 of 29 comparisons (resistance
Alzheimer disease participants. Nonaerobic physical
training vs. stretching/toning on reasoning measures; tai
activity interventions had no significant effect on neu-
chi vs. no exercise on measures of attention and proces-
rocognitive ability. Interventions that exceeded
sing speed: Kelly et al., 2014).
150 min of physical activity per week had a signifi-
In contrast, meta-analytic review of 39 randomized
cantly smaller effect than those of shorter duration.
controlled trials published pre October 2016 with non-
clinical older participants analyzed by gender (higher vs.
lower numbers of women/men) and exercise type on
Methodological differences across randomized
specific neuropsychological domains found: (a) all types
controlled trials
of exercise training improved visuospatial functions in
both genders (14 trials); (b) women were more likely to There are numerous difference variables across trials that
show physical-activity-related benefits in executive can potentially contribute to these conflicting review
functions than men (32 trials); (c) mixed (aerobic plus results. Those considered in reviews to date include exer-
resistance) physical activity programs improved “episo- cise type and gender (Barha et al., 2017; Kelly et al., 2014;
dic” memory (both immediate and delayed measures Zheng et al., 2016). There has also been wide variation in
were included in this definition) in both genders (4 the number of participants randomized, with as few as 29
trials); (d) aerobic was more likely than resistance train- institutionalized dementia (19 in the physical activity and
ing to benefit global neurocognitive (7 trials) and execu- 10 in the control group: Hokkanen et al., 2008) and as
tive (21) functions; and (e) mixed programs were more many as 1,635 nonclinical older participants (818 in the
likely than aerobic to benefit global neurocognitive (8 physical activity and 817 in the control group: Sink et al.,
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
2015). Both these studies reported nonsignificant effects
of physical activity on neurocognition.
Another variable that has not been properly consid-
ered is how neuropsychological test measures within a
given domain are analyzed within and across trials.
Global, executive, processing speed, and memory are
the neuropsychological domains most commonly
assessed, but within those domains there is no agree-
ment as to what neuropsychological tests to use or,
more importantly, what specific measures from a
given neuropsychological test are the most clinically
relevant. It has been an all too frequent practice to
analyze multiple neuropsychological test measures,
ignore those that are nonsignificant, and declare sig-
nificant effects as proof of physical-activity-related pro-
tective effects without consideration as to how the
overall pattern of significant/nonsignificant test results
is clinically relevant (i.e., contributes to a reduced risk
of Alzheimer disease).
As illustration, Brown, Lui-Ambrose, Tate, and Lord
(2009) randomly assigned 154 institutionalized, nonclini-
cal older participants to six-month trials of resistance/
balance, flexibility/relaxation, and no exercise groupings.
Of the 11 neuropsychological measures that were analyzed
post intervention, two showed significant gains for the
resistance/balance versus no exercise groupings. These
were the Wechsler Adult Intelligence Scale subtests of
Similarities and Arithmetic, classified within the fluid intel-
ligence domain. It was concluded that the: “exercise pro-
gramme can modify age-related declines in certain
domains of cognitive function” (Brown et al., 2009, p.
613). Yet the study did not show any significant effect for
neuropsychological measures within domains most subject
to age-related decline and the onset of Alzheimer disease,
namely delayed memory and executive function.
Effect of physical activity on delayed memory
in randomized controlled trials with nonclinical
older, MCI, and dementia participants
Table 1 summarizes how delayed memory measures
have been affected by random assignment to physical
activity trials in nonclinical older, MCI, and dementia
participants in comparison to more sedentary (or no)
interventions. Trials were selected for inclusion in
Table 1 from: (a) a literature search conducted in
October 2016 that followed Preferred Reporting Items
for Systematic Reviews and Meta-Analysis (PRISMA)
guidelines with keywords related to “physical activity,”
“cognition,” and “aging” (Barha et al., 2017). That
search identified 41 trials with nonclinical older parti-
cipants in which neuropsychological measures were
used to assess post minus pre neurocognitive
877
functioning in any domain with physical activity in
comparison to more sedentary (or no) control group-
ings; (b) four additional similarly designed trials with
nonclinical older participants were uncovered from a
Google Scholar search (conducted to form Table 2) on
trials primarily reporting brain volume measurement
outcomes (Jonasson et al., 2016; Maass et al., 2015;
Niemann, Godde, & Voelcker-Rehage, 2014;
Ruscheweyh et al., 2011); and (c) 36 similarly designed
trials with MCI and dementia participants were identi-
fied from five recent review studies (Forbes et al., 2015;
Gates et al., 2013; Groot et al., 2016; Hess, Dieberg,
McFarlane, & Smart, 2014; Zheng et al., 2016).
This generated a total of 81 trials, 45 with nonclinical
older and 36 with MCI/dementia participants. Within
these, 26 (14 nonclinical older; 12 MCI/dementia) had
administered a delayed (≥5-min) memory measure, and
these are listed in Table 1. Measures of immediate or
working memory, combined immediate and delayed
memory measures, and measures that used a delay of
<5 min were excluded. All studies in Table 1 used delayed
measures taken from episodic memory tests with well-
established reliability and validity in the assessment of
memory disorders, except for the locally developed
Colour Slide Test (Molloy, McLaughlin, de la Querriere
Richardson, & Crilly, 1988).
In Table 1 four trials recorded a significant phy-
sical-activity-related improvement in delayed recall
compared to controls, but in three of these the
results were equivocal as to the effect being exclu-
sively physical activity related. In Klusmann et al.
(2010) gains by the physical activity grouping were
not significantly different from those of a computer
training grouping, although both differed signifi-
cantly from the sedentary control grouping.
Similarly, in Lam, Chan, Leung, Fung, and Leung
(2015) a mixed cognitive/physical intervention, but
not the physical activity intervention alone, showed
significant post minus pre gains over the control
grouping. In Mortimer et al. (2012) significant
gains were recorded by the tai chi group, but not
the more physically active walking group, in compar-
ison to the control grouping. The results in Table 1
do not support a physical-activity-related benefit in
delayed memory over the duration of the trials
(<2 years) for nonclinical older, MCI, or dementia
participants.
Analysis by neuropsychological test measure explains
some conflicting conclusions regarding a significant effect
of physical activity on episodic memory reported in prior
reviews of randomized controlled trials. For example,
Barha et al. (2017) concluded that mixed physical activity
interventions improved episodic memory, but this was
878 P. G. GASQUOINE

Table 1. Randomized controlled trials on the effect of physical activity on delayed memory measures with nonclinical older, mild
cognitive impairment, and dementia participants.
Study N randomized/designation Physical activity Delayed memory measures
(age range or mean)
Alves et al. (2013) 56 nonclinical women (60– 24 weeks resistance Delayed (5-min) Recall Test of the Brief Cognitive Screening Battery.
80 years)
Antunes, de Mello, et al. 45 nonclinical (60–75 years) 6 months aerobic ROCF delayed (20-min) recall.
(2015)
Antunes, Santos- 51 nonclinical women (60– 6 months aerobic WMS–III Logical Memory delayed (30-min) recall*; ROCF delayed (20
Galduróz, et al. (2015) 70 years) min) recall*.
Baker et al. (2010) 33 MCI (55–85 years) 6 months aerobic Story Recall delayed (30-min) recall; List Learning delayed (20-min)
recall; Delayed-Match-to-Sample (30 min).
Barnes et al. (2013) 126 nonclinical (≥65 years) 12 weeks aerobic RAVLT delayed (20-min) recall.
Cheng et al. (2014) 110 institutionalized 12 weeks tai chi 15-item word-list delayed (30-min) recall.
dementia (M = 82 years)
Eggermont et al. (2009) 97 institutionalized 6 weeks walking Eight Words Test delayed (15-min) recall and recognition.
dementia (>70 years)
Ferreira et al. (2015) 102 nonclinical (60–79 6 months aerobic WMS Logical Memory delayed (30-min) recall.
years)
Hokkanen et al. (2008) 29 institutionalized (M = 81 9 weeks dance and CERAD Word List Memory savings [% delayed (15-min) recall
years) movement compared to Learning Trial 3].
Ijuin et al. (2013) 65 nonclinical (M = 74 20 weeks walking 5-Cog cued delayed (10-min) recall; WMS–R Logical Memory delayed
years) (30-min) recall.
Klusmann et al. (2010) 259 nonclinical women (70– 6 months aerobic/ RBMT Story Recall delayed (30 min).a
93 years) strength/flexibility
Komulainen et al. (2010) 1,335 nonclinical (57–78 2 years aerobic and CERAD Word List Memory delayed (15-min) recall and recognition;
years) resistance and diet CERAD Constructional Praxis delayed (15-min) recall.
Lam et al. (2012) 389 at risk for cognitive 12 months tai chi ADAS–Cog delayed (10-min) recall.
decline (>65 years)
Lam et al. (2015) 555 MCI (>60 years) 1 year aerobic/tai chi ADAS–Cog delayed (10-min) recallb.
Lautenschlager et al. 170 self-reported memory 24 weeks aerobic/ CERAD Word List Memory delayed (15 min) recall.
(2008) problems (>50 years) strength
Maass et al. (2015) 40 nonclinical (60–77 years) 3 months aerobic VLMT delayed (30-min) recall and recognition.
Maki et al. (2012) 150 nonclinical (>65 years) 3 months walking 5-Cog cued delayed (10-min) recall.
Molloy et al. (1988) 50 institutionalized women 3 months resistance/ Colour Slide Test delayed (30–45-min) recognition.
(73–90 years) balance
Mortimer et al. (2012) 120 nonclinical (60–79 40 weeks tai chi and AVLT delayed (30-min) recall and recognitionc
years) walking
Nagamatsu et al. (2013) 86 MCI women (70–80 6 month aerobic/ RAVLT delayed (20-min) recall.
years) resistance
Ruscheweyh et al. (2011) 62 nonclinical (50–78 years) 6 month walking/ AVLT delayed (30-min) recall minus false positives.
gymnastics
Scherder et al. (2005) 43 MCI (74–94 years) 6 weeks walking VLMT delayed (20-min) recall and recognition.
Sink et al. (2015) 1635 nonclinical (70–89 2 years walking/ HVLT–R delayed (15-min) recall.
years) resistance/flexibility
Suzuki et al. (2012) 50 amnestic MCI (65–93 12 months aerobic/ WMS–R Logical Memory delayed (30-min) recall.
years) resistance
van de Rest et al. (2014) 127 nonclinical (>65 years) 24 weeks resistance/ WLT delayed (20-min) recall, recognition, and decay (delayed recall–
protein supplement Trial 5).
van Uffelen et al. (2008) 152 MCI (70–80 years) 12 months walking RAVLT delayed (20-min) recall.
Note. ADAS–Cog = Alzheimer’s Disease Assessment Scale–Cognitive subscale; AVLT = Auditory Verbal Learning Test; CERAD = Consortium to Establish a Registry for
Alzheimer Disease; FCSRT = Free and Cued Selective Reminding Test; HVLT–R = Hopkins Verbal Learning Test–Revised; MCI = mild cognitive impairment; RAVLT =
Rey Auditory Verbal Learning Test; RBMT = Rivermead Behavioural Memory Test; ROCF = Rey–Osterrieth Complex Figure; VLMT = Verbal Learning and Memory Test;
WMS–R = Wechsler Memory Scale–Revised; WMS–III = Wechsler Memory Scale–Third Edition; WLT = Word Learning Test; 5-Cog = Five Cognitive Tests.
a
Both physical activity and computer training groups showed significant pre to post improvement while the no intervention group did not. bA mixed
cognitive/physical intervention showed significant pre to post gains in comparison to a social control group but there was no significant difference with
the physical activity group. cTai chi group only (i.e., walking group had no significant effect).
*p < .05.

based on four trials that included Klusmann et al. (2010) Physical activity and brain volume
and two studies that did not administer delayed memory
Physical activity has been considered to lower the risk
measures. Similarly, Zheng et al. (2016) concluded that
of Alzheimer disease and neurocognitive decline by
delayed memory measures administered in 7/11 studies
increasing total or regional brain volume as measured
with MCI participants showed significant aerobic-activity-
by MRI (e.g., Colcombe et al., 2006; Erickson et al.,
related improvements (effect size = .25). However, the only
2014; Ruscheweyh et al., 2011; ten Brinke et al., 2015).
significant effect was in Hu et al. (2014) where the three-
An implicit assumption is that increased brain volume
word recall item from the Mini-Mental State Examination
equates to increased neurocognitive ability, but this has
was considered a measure of delayed recall.
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
only partially been supported by over a century of prior
research.
The most well researched link between brain volume
and neurocognitive ability has involved total brain
volumes and measures of general intelligence (g) with
investigations dating from the 18th century. Prior to
the advent of MRI technology, investigators correlated
brain volume measures of weight, intracranial capacity
(postmortem skull volume), or head circumference
with measures of g, like scholastic achievement or
full-scale IQ. Typically, the correlations were small
and usually confounded with other physical attributes,
such as height (e.g., Passingham, 1979). Qualitative
review of studies primarily conducted between 1900
and 1930 suggested that the best estimate of the corre-
lation between head circumference and IQ was .3 (van
Valen, 1974). Clarke (1994) offered the predominant
opposing view that: “there is little evidence for a rela-
tionship between brain size and intelligence, and
instead, brain size seems to be closely tied to body
height and body surface area” (p. 45).
Research conducted in the modern neuroimaging
era has produced results consistent with earlier find-
ings, as head circumference and MRI assessed intracra-
nial volume are positively correlated (.56 for older
males and .68 for older females: Wolf et al., 2003).
Meta-analytic review of 24 (McDaniel, 2005) and 88
(Pietschnig, Penke, Wicherts, Zeiler, & Voracek, 2015)
MRI studies across all age groups reported correlations
between brain volume and IQ of .29 and .24, respec-
tively. Both reviews suggested these figures were likely
inflated by publication bias (i.e., nonsignificant results
being less likely to be published).
Such correlations fail to explain why males, who have
much larger (about 11%) total brain volumes than
females (Ruigrok et al., 2014), score equally on measures
of g. Similarly, within the clinical realm, some individuals
with congenital spina bifida and hydrocephalus develop
average g despite brain volumes that are about 5% of
normal (Lewin, 1980). These and similar anomalies led
Pietschnig et al. (2015) to conclude that: “differences in
brain size among humans are only one of many inter-
changeable and compensatory correlates of intelligence
differences . . . (albeit) a modest one” (p. 428).
Brain size and risk of Alzheimer disease
No clear relationship between head circumference (treated
as a proxy for total volume of intact brains) and risk of
Alzheimer disease has been uncovered. For example, in an
epidemiological study that followed 1,869 nonclinical older
participants over a mean of 4 years, Graves et al. (2001)
reported that only those individuals with head
879
circumference in the lowest third of the sample who also
possessed the apolipoprotein E type 4 (APOE ε4) allele
incurred an increased risk of developing Alzheimer dis-
ease. Similarly, baseline gray matter volume in the medial
temporal lobe did not predict three-year memory decline
on delayed recall measures from the Rey Auditory Verbal
Learning Test among a sample of nonclinical older parti-
cipants at genetic risk for developing Alzheimer disease
(Lancaster et al., 2016). What did predict such decline was
axial diffusivity in medial temporal lobe white matter
tracts. Axial diffusivity is a diffusion tensor imaging mea-
sure that is the primary correlate of axonal injury (Budde,
Xie, Cross, & Song, 2009), a likely predecessor of neuronal
loss-mediated brain atrophy. Reduced hippocampal
volume is not unique to aging/dementia, but has also
been found in several psychiatric disorders, such as depres-
sive disorder (Campbell, Marriott, Nahmias, & MacQueen,
2004; Mathias et al., 2016) and schizophrenia (Shepherd,
Laurens, Matheson, Carr, & Green, 2012). It has also been
reported in adolescents with low social standing (Ellwood-
Lowe et al., 2017).
Physical activity and hippocampal volume in
nonclinical older and MCI participants
Recent qualitative review of 23 predominantly (19)
cross-sectional studies conducted between 2003 and
2012 that measured MRI-assessed brain volume in
nonclinical older participants found that increased fit-
ness or physical activity was associated with greater
hippocampal volume in four studies. Other brain
volume increases were reported in: total gray matter
(4 studies); total gray and white matter (4); the frontal
lobe (3); caudate nucleus and nucleus accumbens (1);
and age-, lifetime-stress-, or postmenopausal-hor-
mone-related reduction (3). Four studies did not report
any physical-activity-related brain volume effects. It
was concluded: “the impact that greater gray matter
volume has on cognitive function remains largely spec-
ulative” (Erickson et al., 2014, p. S27).
Table 2 shows physical-activity-related brain volume
effects from randomized controlled trials among older
participants that were identified from a Google Scholar
search that combined the phrases “older,” “randomized
controlled trial,” “brain volume,” and “physical activ-
ity,” or variants. All studies used nonclinical older or
MCI participants with none being conducted on
dementia participants. Of the nine trials, six reported
physical-activity-related volumetric increases in at least
one brain region with three of these reporting regional
increases in hippocampal (or medial temporal) volume.
Cellular changes responsible for physical-activity-
related gray matter volume increases are speculative.
880 P. G. GASQUOINE

Table 2. Randomized controlled trials linking physical activity and brain volume with nonclinical older and mild cognitive
impairment participants.
Study
Best et al. (2015)
Colcombe et al. (2006)
Erickson et al. (2011)
Jonasson et al. (2016)
Maass et al. (2015)
Mortimer et al. (2012)
Niemann et al. (2014)
Ruscheweyh et al. (2011)
ten Brinke et al. (2015)
Note. MCI = mild cognitive impairment.
N randomized/designation
(age range) Physical activity Physical-activity-related brain volume effects
155 nonclinical women 1 year resistance No effect on cortical gray matter or hippocampal
(65–75 years) volume; less (0.8% vs. 2%) decrease in white matter
volume.
59 nonclinical 6 months walking Increased gray matter in anterior cingulate,
(60–79 years) supplementary motor area, middle frontal gyrus, left
superior temporal lobe; and white matter in the
corpuscollosum. No hippocampal effects.
120 nonclinical 1 year walking Increased hippocampal (by 2%) but not thalamic or
(55–80 years) caudate nuclei volume.
60 nonclinical 6 months aerobic No difference in cortical thickness or hippocampal
(64–78 years) volume.
40 nonclinical 3 months aerobic No effect on hippocampal volume.
(60–77 years)
120 nonclinical 40 weeks tai chi and Total brain volume was significantly increased in the tai
(60–79 years) walking chi and social interaction, but not walking, groupings
compared to the no intervention grouping.
91 nonclinical 1 year cardiovascular Hippocampal volume increased significantly in both
(62–79 years) and coordination cardiovascular (by 3.6%) and coordination (by 2.8%)
exercise groups.
62 nonclinical 6 months walking/ Increased gray matter volume in cingulate cortex
(50–78 years) gymnastics supplementary motor area, and middle frontal gyrus
but not in medial temporal lobe.
86 MCI women 6 months aerobic/ Hippocampal volume was increased (by 4%) in the
(70–80 years) resistance aerobic but not resistance training groups.

Thomas et al. (2016), who found hippocampal volume
increases after just 6 weeks of aerobic exercise in young
and middle-aged adults, argued for increased myelina-
tion. In that study the volumetric changes were tem-
porary, returning to baseline by 6 weeks post exercise.
Physical activity and brain-derived
neurotrophic factor (BDNF)
Animal studies have uncovered multiple enriched
environment/physical-activity-related brain chemical
changes including the increased presence of neurotro-
phins, the most intensively studied of which in relation
to physical activity in humans is brain-derived neuro-
trophic factor (BDNF: Mattson, 2012). In the intact
brain, BDNF is highly expressed in the hippocampus
and exists as both pro- and mature forms with the
former being a precursor for the latter. The two
forms have contrasting positive and negative effects
on neurons (Numakawa et al., 2010). Positive effects
are mediated through the mature form at TrKB
(Tyrosine receptor Kinase B) receptors and include:
(a) the survival and growth of neurons in both the
central and peripheral nervous systems; (b) dendritic
growth and branching; and (c) the maintenance of
long-term potentiation, the most commonly studied
process of synaptic structural alteration that is consid-
ered to underlie delayed memory. Negative effects are
mediated through the pro- form at p75 receptors and
include: (a) induction of apoptosis; and (b) long-term
depression (forgetting).
In humans BDNF can cross the blood–brain barrier,
meaning that concentrations in blood serum or plasma
are thought to approximate those found in the brain.
In a meta-analytical review of 24 studies published
between 2003 and 2010 that related physical activity
and BDNF blood levels, 69% of those with nonclinical
participants and 86% of those with clinical participants
(MCI; multiple sclerosis; major depressive disorder;
spinal cord injury; obesity; panic disorder) showed a
significant transient increase in BDNF levels with aero-
bic (but not resistance) training (Knaepen, Goekint,
Heyman, & Meeusen, 2010).
BDNF levels in MCI and Alzheimer disease
Studies on BDNF blood levels in living patients with
Alzheimer disease have produced conflicting results.
Levels have been significantly reduced (e.g., Laske
et al., 2007), no different (O’Bryant et al., 2009), or
significantly increased (Angelucci et al., 2010; Faria
et al., 2014) compared to those of nonclinical older
controls. Meta-analytic review of 15 studies concluded
that BDNF blood levels in Alzheimer disease patients
were lower than those in nonclinical older controls
(effect size = –.28: Ng et al., 2016). BNDF blood levels
in individuals with MCI did not differ significantly
from those of nonclinical older or Alzheimer disease
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
participants. Low blood levels of BDNF are not unique
to Alzheimer disease but are also found in drug-naïve
and medicated patients with schizophrenia (Green,
Matheson, Shepherd, Weickert, & Carr, 2011) and in
depressive disorders (Molendijk et al., 2014).
The reasons for the disparate results are speculative
but may be related to measurement issues, such as an
inability to distinguish between pro- and mature forms of
BDNF (Lim, Zhong, & Zhou, 2015), or uncontrolled
transient influences on BDNF levels from diet, sleep,
and other environmental factors. In support of this
hypothesis postmortem studies that use mRNA (messen-
ger RNA) measures have been more consistent, typically
reporting decreased BDNF levels in patients with
Alzheimer disease. For example, a longitudinal study
found that autopsy-derived BDNF expression in the dor-
solateral prefrontal cortex was negatively associated with
neurocognitive decline, with the association being highest
for those individuals diagnosed with dementia of any type
(Buckman et al., 2016). Research has also considered that
only certain BDNF polymorphisms increase the risk of
Alzheimer disease, but this has not proved fruitful. The
most frequently studied polymorphism has been
Val66Met, a common (20–30% of the population)
amino acid substitution of valine to methionine at
codon 66 that decreases BDNF secretion. Recent neuroi-
maging/genetic analysis in a large dataset found that
BDNF genetic variation was not associated with an indi-
vidual being diagnosed with Alzheimer disease (Honea
et al., 2013). Similarly, meta-analytic review concluded
that the Val66Met polymorphism was not associated with
hippocampal volumes (Harrisberger et al., 2015).
Effects of physical exercise on BDNF blood levels in
randomized controlled trials with nonclinical older
participants
Three of the 33 randomized controlled trials in Tables
1 and 2 measured blood BDNF levels as outcome
measures, all with nonclinical older participants.
BDNF levels did not differ significantly between phy-
sically active and control groupings in two (Erickson
et al., 2011; Ruscheweyh et al., 2011), and in the third
(Baker et al., 2010) they were significantly reduced in
the physical activity group.
Physical activity and neurogenesis
Research with laboratory animals has shown that
enriched environment/physical-activity-related physiolo-
gical changes within the brain include regional increases
in the length and number of dendrites, more synapses per
neuron, increased vascularization, and more plentiful glia
881
cells (Colcombe et al., 2006). Altman (1962) was the first
to include adult neurogenesis among these physiological
changes. In the extension of this animal research to
humans, claims of neurogenesis have been limited to
the dendate gyrus of the hippocampus and the olfactory
bulb (Kempermann, Song, & Gage, 2015), but they
remain controversial as there is no validated method of
labeling adult-born neurons in living humans, although
indirect measures (e.g., increased physical-activity-related
cerebral blood flood in the dendate gyrus of the hippo-
campus: Pereira et al., 2007) have been proposed.
In postmortem examinations, the seminal study of
Eriksson et al. (1998) claimed evidence of neurogenesis
in the human adult hippocampus when a radioactive
marker, bromodeoxyuridine (BrdU), used diagnostically
to identify new cancer cells, highlighted noncancerous
cells. Subsequently, it was reported that BrdU is a marker
of DNA synthesis rather than cell proliferation, and it
labels normally occurring cell processes like DNA repair
and cell death in the same fashion as neurogenesis
(Taupin, 2007). Several other postmortem labeling tech-
niques have subsequently been proposed (Briley et al.,
2016; Knoth et al., 2010; Spalding et al., 2013), but none
has been validated. Aside from the inability to identify
adult-born neurons, the role of any new neurons in non-
clinical aging and Alzheimer disease is unclear (Aimone
et al., 2014).
Summary and future directions
Longitudinal, epidemiological studies have established
that physical activity protects against Alzheimer disease
but the causative mechanism is unclear. A prevailing
model has physical activity increasing total or regional
brain volumes, levels of BDNF, and hippocampal neu-
rogenesis with consequent gains in neuropsychological
test scores, thereby delaying or preventing neurocogni-
tive decline.
Behavioral evidence supporting this model from
randomized controlled trials has been mixed with all
manner of physical-activity-related neuropsychological
test score gains being claimed as evidence of the pro-
tective effect. Memory is the first neuropsychological
domain to be impaired in the early preclinical stages of
Alzheimer disease, and this impairment, which is
widely considered to result from hippocampal atrophy,
manifests as a reduction in the ability to retain new
material over a delay. Thus, gains on neuropsychologi-
cal tests of delayed memory would provide the stron-
gest support for the protective nature of physical
activity stemming from physiological brain changes.
Previous reviews have uncovered 81 randomized trials,
45 with nonclinical older and 36 with MCI/dementia
882 P. G. GASQUOINE
participants, where physical activity was compared to a
more sedentary (or no) control group with neuropsycho-
logical test scores as outcome measures. Within these, 26
(14 nonclinical older; 12 MCI/dementia) had adminis-
tered a measure of delayed recall or recognition memory.
Only one of these reported unequivocal, significant, phy-
sical-activity-related score increases in comparison to
controls. This evidence does not support a physiological
brain change model for the protective effects of physical
activity on Alzheimer disease. An important caveat is that
the duration of the physical activity was limited to the
duration of the trial (<2 years), as studies typically
(Lautenschlager et al., 2008, excepted) selected partici-
pants who were currently sedentary. Therefore, results
do not necessarily extend to individuals who lead con-
tinuously physically active lifestyles into old age.
Similarly, physical-activity-related neurocognitive
changes in nonmemory neuropsychological domains
(e.g., visuospatial functions, Barha et al., 2017) were
reported across multiple trials, although how this relates
to protection against Alzheimer disease is unclear as
impaired hippocampal atrophy-mediated delayed mem-
ory is the neurocognitive function that defines Alzheimer
disease onset.
Evidence relating physical activity to direct outcome
measures of brain physiology also provided questionable
support for physical-activity-related brain change protec-
tive effects. Cross-sectional and randomized controlled
studies have found physical-activity-related increases in
volume in multiple brain regions including the hippocam-
pus with nonclinical older and MCI participants, but brain
volume in general has historically been found to explain
less than 10% of the variance in neuropsychological test
scores, and the physiology underlying these volumetric
changes is unknown. Studies of the effect of physical
activity on blood BDNF levels with older participants
have produced mixed results, possibly due to measurement
error, while its role in neurogenesis in the dendate gyrus of
the hippocampus cannot be confirmed as there is no
technique for birth-dating neurons in living humans.
Alternative causative mechanisms have protective
effects of physical activity on Alzheimer disease deriving
from non-central-nervous-system-related health changes.
Studies with community-dwelling, nonclinical older parti-
cipants have found that those who engage in higher levels
of regular physical activity tend to: be male; have more
years of education; have a lower prevalence of type 2
diabetes; have a lower prevalence of cardiovascular disease
including stroke; and are less likely to report ever having
smoked or more likely to be a former smoker than their less
physically active peers (Shih, Paul, Haan, Yu, & Ritz, 2018).
Thus, physical activity is associated with a reduction in
multiple peripheral Alzheimer disease risk factors,
pertaining to gender, education, smoking, depression,
type 2 diabetes, hypertension, and obesity, which may
each confer a protective effect independently of each other.
In a different conception, the protective effect of phy-
sical exercise may be mediated through a single generic
disease fighting pathway, with a strengthened immune
system the most likely candidate. As humans age,
immune system dysregulation results in a chronic, gen-
eralized, low-grade inflammation that is a significant risk
factor in most age-related diseases (Franceschi &
Campisi, 2014). Regular physical activity reduces visceral
fat mass and adipose tissue, which contribute to this
inflammation (Gleeson et al., 2011). The relative failure
of antiamyloid treatment strategies has increased interest
in the potential role of this inflammation in the patho-
genesis of Alzheimer disease (e.g., Heneka et al., 2015).
Postmortem studies show that reactive microglia
(immune system glia cells) colocalize with amyloid pla-
que pathology (Calsolaro & Edison, 2016). Immune sys-
tem dysregulation may be responsible for relatively mild
neuropsychological test score impairments in delayed
memory and executive functions associated with chronic,
noncentral nervous system, medical conditions like
hypertension, type 2 diabetes, and obesity (Gasquoine,
2011), but the mechanism of causation and its potential
contribution to the onset of Alzheimer disease remains
theoretical. Irrespectively, the protective effect of physical
exercise on Alzheimer disease likely requires a much
longer duration than that covered by the randomized
controlled trials reviewed here to manifest.
Disclosure statement
No potential conflict of interest was reported by the author.
Funding
No funding has been received for this study and/or prepara-
tion of this manuscript.
References
Aimone, J. B., Li, Y., Lee, S. W., Clemenson, G. D., Deng, W.,
& Gage, F. H. (2014). Regulation and function of adult
neurogenesis: From genes to cognition. Physiological
Reviews, 94, 991–1026.
Albert, M. S., Dekosky, S. T., Dickson, D., Dubois, B.,
Feldman, H. H., Fox, N. C., & Phelps, C. H. (2011). The
diagnosis of mild cognitive impairment due to Alzheimer’s
disease: Recommendations from the National Institute on
Aging-Alzheimer’s Association workgroups on diagnostic
guidelines for Alzheimer’s disease. Alzheimer’s &
Dementia, 7, 270–279.
Ally, B. A., Hussey, E. P., Ko, P. C., & Molitor, R. J. (2013).
Pattern separation and pattern completion in Alzheimer’s
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
disease: Evidence of rapid forgetting in amnestic mild
cognitive impairment. Hippocampus, 23, 1246–1258.
Altman, J. (1962). Are new neurons formed in the brains of
adult mammals? Science, 135, 1127–1128.
Alves, C. R., Merege Filho, C. A., Benatti, F. B., Brucki, S.,
Pereira, R. M., de Sa Pinto, A. L., & Gualano, B. (2013).
Creatine supplementation associated or not with strength
training upon emotional and cognitive measures in older
women: A randomized double-blind study. PLoS One, 8,
e76301.
Angelucci, F., Spalletta, G., di Iulio, F., Ciaramella, A., Salani,
F., Varsi, A. E., & Bossù, P. (2010). Alzheimer’s Disease
(AD) and Mild Cognitive Impairment (MCI) patients are
characterized by increased BDNF serum levels. Current
Alzheimer Research, 7, 15–20.
Antunes, H. K. M., de Mello, M. T., de Aquino Lemos, V.,
Santos-Galduróz, R. F., Galdieri, L. C., Bueno, O. F. A., &
D’Almeida, V. (2015). Aerobic physical exercise improved
the cognitive function of elderly males but did not modify
their blood homocysteine levels. Dementia and Geriatric
Cognitive Disorders Extra, 5, 13–24.
Antunes, H. K. M., Santos-Galduróz, R. F., de Aquino
Lemos, V., Bueno, O. F. A., Rzezak, P., de Santana, M.
G., & de Mello, M. T. (2015). The influence of physical
exercise and leisure activity on neuropsychological func-
tioning in older adults. Age, 37, 71.
Baker, L. D., Frank, L. L., Foster-Schubert, K., Green, P. S.,
Wilkinson, C. W., McTiernan, A., & Craft, S. (2010).
Effects of aerobic exercise on mild cognitive impairment:
A controlled trial. Archives of Neurology, 67, 71–79.
Barha, C. K., Davis, J. C., Falck, R. S., Nagamatsu, L. S., &
Liu-Ambrose, T. (2017). Sex differences in exercise effi-
cacy to improve cognition: A systematic review and meta-
analysis of randomized controlled trials in older humans.
Frontiers in Neuroendocrinology, 46, 71–85.
Barnes, D. E., Santos-Modesitt, W., Poelke, G., Kramer, A. F.,
Castro, C., Middleton, L. E., & Yaffe, K. (2013). The
mental activity and eXercise (MAX) trial. Journal of the
American Medical Association, Internal Medicine, 173,
797–804.
Barnes, D. E., & Yaffe, K. (2011). The projected effect of risk
factor reduction in Alzheimer’s disease prevalence. Lancet
Neurology, 10, 819–828.
Best, J. R., Chiu, B. K., Hsu, C. L., Nagamatsu, L. S., & Liu-
Ambrose, T. (2015). Long-term effects of resistance exer-
cise training on cognition and brain volume in older
women: Results from a randomized controlled trial.
Journal of the International Neuropsychological Society,
21, 745–756.
Briley, D., Ghirardi, V., Woltjer, R., Renck, A., Zolochevska,
O., Taglialatela, G., & Micci, M. A. (2016). Preserved
neurogenesis in non-demented individuals with AD neu-
ropathology. Science Reports, 6, 27812.
Brown, A. K., Lui-Ambrose, T., Tate, R., & Lord, S. R. (2009).
The effect of group-based exercise on cognitive performance
and mood in seniors residing in intermediate care and self-
care retirement facilities: A randomized controlled trial.
British Journal of Sports Medicine, 43, 608–614.
Buckman, A. S., Boyle, P. A., Yu, L., Shah, R. C., Wilson, R.
S., & Bennett, D. A. (2012). Total daily physical activity
and the risk of AD and cognitive decline in older adults.
Neurology, 78, 1323–1329.
883
Buckman, A. S., Yu, L., Boyle, P. A., Schneider, J. A., de
Jager, P. L., & Bennett, D. A. (2016). Higher brain BDNF
gene expression is associated with slower cognitive decline
in older adults. Neurology, 86, 735–741.
Budde, M. D., Xie, M., Cross, A. H., & Song, S.-K. (2009).
Axial diffusivity is the primary correlate of axonal injury
in the EAE spinal cord: A quantitative pixelwise analysis.
Journal of Neuroscience, 29, 2805–2813.
Calsolaro, V., & Edison, P. (2016). Neuroinflammation in
Alzheimer’s disease: Current evidence and future direc-
tions. Alzheimer’s & Dementia, 12, 719–732.
Campbell, S., Marriott, M., Nahmias, C., & MacQueen, G. M.
(2004). Lower hippocampal volume in patients suffering
from depression: A meta-analysis. American Journal of
Psychiatry, 161, 589–607.
Cermak, L. S., & Butters, N. (1972). The role of interference
and encoding in the short-term memory deficits of
Korsakoff patients. Neuropsychologia, 10, 89–96.
Cheng, S.-T., Chow, P. K., Song, Y. Q., Yu, E. C. S., Chan, A.
C. M., Lee, T. M., & Lam, J. H. M. (2014). Mental and
physical activities delay cognitive decline in older persons
with dementia. American Journal of Geriatric Psychiatry,
22, 63–74.
Chieffi, S., Messina, G., Villano, I., Messina, A., Valenzano,
A., Moscatelli, F., & Monda, M. (2017). Neuroprotective
effects of physical activity: Evidence from human and
animal studies. Frontiers in Neurology, 8, 188.
Clarke, J. M. (1994). Neuroanatomy: Brain structure and
function. In D. W. Zaidel (Ed.), Neuropsychology (pp.
29–52). New York, NY: Academic Press.
Colcombe, S. J., Erickson, K. I., Scalf, P. E., Kim, J. S.,
Prakash, R., McAuley, E., & Kramer, A. F. (2006).
Aerobic exercise training increases brain volume in aging
humans. Journal of Gerontology, Series A: Biological
Sciences and Medical Sciences, 61A, 1166–1170.
Cotman, C. W., & Berchtold, N. C. (2002). Exercise: A
behavioral intervention to enhance brain health and plas-
ticity. Trends in Neuroscience, 25, 295–301.
Eggermont, L. H. P., Swaab, D. F., Hol, E. M., & Scherder, E.
J. A. (2009). Walking the line: A randomised trial on the
effects of a short term walking programme on cognition in
dementia. Journal of Neurology, Neurosurgery, and
Psychiatry, 80, 802–804.
Ellwood-Lowe, M., Humphreys, K., Sacchet, M., Camacho,
M. C., Ordaz, S., & Gotlib, I. (2017). Perceived social
standing predicts hippocampal volume over and above
the effects of income. Biological Psychiatry, 81, S188.
Erickson, K. I., Leckie, R. L., & Weinstein, A. M. (2014).
Physical activity, fitness, and gray matter volume.
Neurobiology of Aging, 35, S20–S28.
Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo,
A., Chaddock, L., & Kramer, A. F. (2011). Exercise train-
ing increases size of hippocampus and improves memory.
Proceedings of the National Academy of Sciences, USA, 108,
3017–3022.
Erickson, K. I., Weinstein, A. M., & Lopez, O. L. (2012).
Physical activity, brain plasticity, and Alzheimers’s disease.
Archives of Medical Research, 43, 615–621.
Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.
M., Nordberg, C., Peterson, D. A., & Gage, F. H. (1998).
Neurogenesis in the adult human hippocampus. Nature
Medicine, 4, 1313–1317.
884 P. G. GASQUOINE
Faria, M. C., Gonçalves, G. S., Rocha, N. P., Moraes, E. N.,
Bicalho, M. A., Cintra, M. T. G., . . . Souza, L. P. (2014).
Increased plasma levels of BDNF and inflammatory mar-
kers in Alzheimer disease. Journal of Psychiatric Research,
53, 166–172.
Ferreira, L., Tanaka, K., Santos-Galduróz, R. F., & Galduróz,
J. C. (2015). Respiratory training as strategy to prevent
cognitive decline in aging: A randomized controlled trial.
Clinical Interventions in Aging, 10, 593–603.
Forbes, D., Forbes, S. C., Blake, C. M., Thiessen, E. J., &
Forbes, S. (2015). Exercise programs for people with
dementia. Cochrane Database System Review, 4, CD006489.
Franceschi, C., & Campisi, J. (2014). Chronic inflammation
(inflammaging) and its potential contribution to age-asso-
ciated diseases. Journal Of Gerontology, Series A: Biological
Sciences And Medical Sciences, 69, S4–S9.
Gasquoine, P. G. (2011). Cognitive impairment in common,
noncentral nervous system medical conditions of adults
and the elderly. Journal of Clinical and Experimental
Neuropsychology, 33, 486–496.
Gates, N., Singh, M. A. F., Sachdev, P. S., & Valenzuela, M.
(2013). The effect of exercise training on cognitive func-
tion in older adults with mild cognitive impairment: A
meta- analysis of randomized controlled trials. American
Journal of Geriatric Psychiatry, 21, 1086–1097.
Gleeson, M., Bishop, N. C., Stensel, D. J., Lindley, M. R.,
Mastana, S. S., & Nimmo, M. A. (2011). The anti-inflam-
matory effects of exercise: Mechanisms and implications
for the prevention and treatment of disease. Nature
Reviews Immunology, 11, 607–615.
Graves, A. B., Mortimer, J. A., Bowen, J. D., McCormick, W.
C., McCurry, S. M., Schellenberg, J. D., & Larson, E. B.
(2001). Head circumference and incident Alzheimer’s dis-
ease: Modification by apolipoprotein E. Neurology, 57,
1453–1460.
Green, M. J., Matheson, S. L., Shepherd, A., Weickert, C. S.,
& Carr, V. J. (2011). Brain-derived neurotrophic factor
levels in schizophrenia: A systematic review with meta-
analysis. Molecular Psychiatry, 16, 960–972.
Groot, C., Hooghiemstra, A. M., Raijmakers, P. G. H. M.,
von Berchel, B. N. M., Scheltens, P., Scherder, E. J. A., &
Ossenkoppele, R. (2016). The effect of physical activity on
cognitive function in patients with dementia: A meta-
analysis of randomized control trials. Ageing Research
Reviews, 25, 13–23.
Hamer, M., & Chida, Y. (2009). Physical activity and risk of
neurodegenerative disease: A systematic review of pro-
spective evidence. Psychological Medicine, 39, 3–11.
Harrisberger, F., Smieskova, R., Schmidt, A., Lenz, C., Walter,
A., Wittfeld, K., & Borgwordt, S. (2015). BDNF Val66Met
polymorphism and hippocampal volume in neuropsychia-
tric disorders: A systematic review and meta-analysis.
Neuroscience and Biobehavioral Reviews, 55, 107–118.
Head, D., Singh, T., & Bugg, J. M. (2012). The moderating role
of exercise on stress-related effects on the hippocampus and
memory in later adulthood. Neuropsychology, 26, 133–143.
Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E.,
Brosseron, F., Feinstein, D. L., & Kummer, M. P. (2015).
Neuroinflammation in Alzheimer’s disease. Lancet
Neurology, 14, 388–405.
Hess, N. C. L., Dieberg, G., McFarlane, J. R., & Smart, N. A.
(2014). The effect of exercise intervention on cognitive
performance in persons at risk of, or with, dementia: A
systematic review and meta-analysis. Healthy Aging
Research, 3, 1–10.
Hokkanen, L., Rantala, L., Remes, A. M., Härkönen, B.,
Viramo, P., & Winblad, I. (2008). Dance and movement
therapeutic methods in management of dementia: A ran-
domized, controlled study. Journal of the American
Geriatric Society, 56, 771–772.
Honea, R. A., Cruchaga, C., Perea, R. D., Sayhin, A. J., Burns,
J. M., Weinberger, D. R., & Goate, A. M. (2013).
Characterizing the role of brain derived neurotrophic fac-
tor genetic variation in Alzheimer’s disease neurodegen-
eration. PLoS One, 8, e76001.
Hu, J. P., Guo, Y.-H., Wang, F., Zhao, X.-P., Zhang, Q.-H., &
Song, Q.-H. (2014). Exercise improves cognitive function
in aging patients. International Journal of Clinical and
Experimental Medicine, 7, 3144–3149.
Ijuin, M., Sugiyama, M., Sakuma, N., Inagaki, H., Miyamae, F.,
Ito, K., & Awata, S. (2013). Walking exercise and cognitive
functions in community-dwelling older adults: Preliminary
results of a randomized controlled trial. International
Journal of Geriatric Psychology, 28, 109–110.
Jack, C. R., Knopman, D. S., Jagust, W. J., Petersen, R. C.,
Weiner, M. W., Aisen, P. S., . . . Trojanowski, J. Q. (2013).
Tracking pathophysiological processes in Alzheimer’s dis-
ease: An updated hypothetical model of dynamic biomar-
kers. Lancet Neurology, 12, 207–216.
Jack, C. R., Jr., Petersen, R. C., Xu, Y., O’brian, P. C., Smith,
G. E., Ivnik, R. J., & Kokmen, E. (2000). Rates of hippo-
campal atrophy correlate with change in clinical status in
aging and AD. Neurology, 55, 484–489.
Jonasson, L. S., Nyberg, L., Kramer, A. F., Lundquist, A., Riklund,
K., & Boraxbekk, C.-J. (2016). Aerobic exercise intervention,
cognitive performance, and brain structure: Results from the
Physical Influences on Brain in Aging (PHIBRA) Study.
Frontiers in Aging Neuroscience, 8, Article 336.
Kelly, M. E., Loughrey, D., Lawlor, B. A., Robertson, I. H.,
Walsh, C., & Brennan, S. (2014). The impact of exercise on
the cognitive functioning of healthy older adults: A sys-
tematic review and meta-analysis. Ageing Research
Reviews, 16, 12–31.
Kempermann, G., Song, H., & Gage, F. H. (2015).
Neurogenesis in the adult hippocampus. Cold Spring
Harbor Perspectives in Biology, 7, a018812.
Khan, U. A., Liu, L., Provenzano, F. A., Berman, D. E.,
Profaci, C. P., Sloan, R., & Small, S. A. (2014). Molecular
drivers and cortical spread of lateral entorhinal cortex
dysfunction in preclinical Alzheimer’s disease. Nature
Neuroscience, 17, 304–311.
Klusmann, V., Evers, A., Schwarzer, R., Schlattmann, P.,
Reischies, F. M., Heuser, I., & Dimeo, F. C. (2010).
Complex mental and physical activity in older women
and cognitive performance: A 6-month randomized con-
trolled trial. Journal of Gerontology, Series A: Biological
Sciences and Medical Sciences, 65A, 680–688.
Knaepen, K., Goekint, M., Heyman, E. M., & Meeusen, R.
(2010). Neuroplasticity – Exercise- induced response of
peripheral brain-derived neurotrophic factor: A systematic
review of experimental studies in human subjects. Sports
Medicine, 40, 765–801.
Knoth, R., Singec, I., Ditter, M., Pantazis, G., Capetian, P.,
Meyer, R. P., & Kempermann, G. (2010). Murine features
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
of neurogenesis in the human hippocampus across the
lifespan from 0 to 100 years. PloS One, 5, e8809.
Komulainen, P., Kivipelto, M., Lakka, T. A., Savonen, K.,
Hassinen, M., Kiviniemi, V., & Rauramaa, R. (2010).
Exercise, fitness and cognition – A randomized controlled
trial in older individuals: The DR’s EXTRA study.
European Geriatric Medicine, 1, 266–272.
Krech, D., Rozenzweig, M. R., & Bennett, E. L. (1960). Effects
of environmental complexity and training on brain chem-
istry. Journal of Comparative and Physiological Psychology,
53, 509–519.
Lam, L. C. W., Chan, W. C., Leung, T., Fung, A. W. T., &
Leung, E. M. (2015). Would older adults with mild cognitive
impairment adhere to and benefit from a structured lifestyle
activity intervention to enhance cognition? A cluster rando-
mized controlled trial. PLoS One, 10, e0118173.
Lam, L. C. W., Chau, R. C. M., Wong, B. M. L., Fung, A. W.
T., Tam, C. W. C., Leung, G. T. Y., & Chan, W. M. (2012).
A 1-year randomized controlled trial comparing mind
body exercise (Tai Chi) with stretching and toning exer-
cise on cognitive function in older Chinese adults at risk of
cognitive decline. Journal of the American Medical
Directors Association, 13, 568e15–e20.
Lancaster, M. A., Seidenberg, M., Smith, J. C., Nielson, K. A.,
Woodard, J. L., Durgerian, S., & Rao, S. M. (2016).
Diffusion tensor imaging predictors of episodic memory
decline in healthy elders at genetic risk for Alzheimer’s
disease. Journal of the International Neuropsychological
Society, 22, 1005–1015.
Laske, C., Stransky, E., Leyhe, T., Eschweiler, G. W.,
Maetzler, W., Wittorf, A., & Schott, K. (2007). BDNF
serum and CSF concentrations in Alzheimer’s disease,
normal pressure hydrocephalus and healthy controls.
Journal of Psychiatric Research, 41, 387–394.
Lautenschlager, N. T., Cox, K. L., Flicker, L., Foster, J. K., van
Bockxmeer, F. M., Xiao, J., & Almeida, O. P. (2008). Effect
of physical activity on cognitive function in older adults at
risk for Alzheimer disease: A randomized trial. Journal of
the American Medical Association, 300, 1027–1037.
Lewin, R. (1980). Is your brain really necessary? Science, 210,
1232–1234.
Lim, Y., Zhong, J. H., & Zhou, X. F. (2015). Development of
mature BDNF-specific sandwich ELISA. Journal of
Neurochemistry, 134, 75–85.
Maass, A., Düzel, S., Goerke, M., Becke, A., Sobieray, U.,
Neumann, K., & Düzel, E. (2015). Vascular hippocampal
plasticity after aerobic exercise in older adults. Molecular
Psychiatry, 20, 585–593.
Maki, Y., Ura, C., Yamaguchi, T., Murai, T., Isahai, M.,
Kaiho, A., & Yamaguchi, H. (2012). Effects of intervention
using a community-based walking program for prevention
of mental decline: A randomized controlled trial. Journal
of the American Geriatric Society, 60, 505–510.
Makizako, H., Liu-Ambrose, T., Shimada, H., Doi, T., Park,
H., Tsutsumimoto, K., & Suzuki, T. (2015). Moderate-
intensity physical activity, hippocampal volume, and
memory in older adults with mild cognitive impairment.
Journal of Gerontology, Series A: Biological Sciences and
Medical Sciences, 70A, 480–486.
Mathias, S. R., Knowles, E. E. M., Kent, J. W., Jr., McKay, D.
R., Curran, J. E., de Almeida, M. A. A., & Glahn, D. C.
(2016). Recurrent major depression and right
885
hippocampal volume: A bivariate linkage and association
study. Human Brain Mapping, 37, 191–202.
Mattson, M. P. (2012). Evolutionary aspects of human exer-
cise-Born to run purposefully. Ageing Research Reviews,
11, 347–352.
McDaniel, M. A. (2005). Big-brained people are smarter: A
meta-analysis of the relationship between in vivo brain
volume and intelligence. Intelligence, 33, 337–346.
Mickes, L., Wixted, J. T., Fenema-Notestine, C., Galasko, D.,
Bondi, M. W., Thal, L. J., & Salmon, D. P. (2007).
Progressive impairment on neuropsychological tasks in a
longitudinal study of preclinical Alzheimer’s disease.
Neuropsychology, 21, 696–705.
Mitchell, A. J., & Shiri-Feshki, M. (2009). Rate of progression
of mild cognitive impairment to dementia — Meta-analy-
sis of 41 robust inception cohort studies. Acta Psychiatrica
Scandinavica, 119, 252–265.
Molendijk, M. L., Spinhoven, P., Polak, M., Bus, B. A. A.,
Penninx, B. W. J. H., & Elzinga, B. M. (2014). Serum
BDNF concentrations as peripheral manifestations of
depression: Evidence from a systematic review and meta-
analyses on 179 associations (N = 9,484). Molecular
Psychiatry, 19, 791–800.
Molloy, D. W., McLaughlin, J. S., de la Querriere Richardson,
L., & Crilly, R. G. (1988). The effects of a three-month
exercise programme on neuropsychological function in
elderly institutionalized women: A randomized controlled
trial. Age and Ageing, 17, 303–310.
Mortimer, J. A., Ding, D., Borenstein, A. R., Decarli, C., Guo,
Q., Wu, Y., & Chu, S. (2012). Changes in brain volume and
cognition in a randomized trial of exercise and social inter-
action in a community-based sample of non-demented
Chinese elders. Journal of Alzheimer’s Disease, 28, 757–766.
Nagamatsu, L. S., Chan, A., Davis, J. C., Beattie, B. L., Graf,
P., Voss, M. W., & Liu-Ambrose, T. (2013). Physical
activity improves verbal and spatial memory in older
adults with probable mild cognitive impairment: A 6-
month randomized controlled trial. Journal of Aging
Research, 2013, 1–10.
Ng, K. S. T., Ho, C. S., Wilson, T., Kua, E. H., & Ho, R.
C.-M. (2016). Serum brain-derived neurotrophic factos
(BDNF) levels in patients with Alzheimer’s disease
(AD), individuals with mild cognitive impairment
(MCI), and healthy controls: A systematic review,
meta- analysis, and meta-regression. Alzheimer’s &
Dementia, 12, 1181.
Niemann, C., Godde, B., & Voelcker-Rehage, C. (2014). Not
only cardiovascular, but also coordinate exercise increases
hippocampal volume in older adults. Frontiers in Aging
Euroscience, 6, Article 170.
Numakawa, T., Suzuki, S., Kumamaru, E., Adachi, N.,
Richards, M., & Kunugi, H. (2010). BDNF function and
intracellular signaling in neurons. Histology and
Histopathology, 25, 237–258.
O’Bryant, S. E., Hobson, V., Hall, J. R., Waring, S. C., Chan,
W., Massman, P., & Diaz-Arrastia, R. (2009). Brain-
derived neurotrophic factor levels in Alzheimer’s disease.
Journal of Alzheimer’s Disease, 17, 337–341.
Passingham, R. E. (1979). Brain size and intelligence in man.
Brain, Behavior and Evolution, 16, 253–270.
Pereira, A. C., Huddleston, D. E., Brickman, A. M., Sosunov,
A. A., Hen, R., McKhann, G. M., & Small, S. A. (2007). An
886 P. G. GASQUOINE
in vivo correlate of exercise-induced neurogenesis in the
adult dendate gyrus. Proceedings of the National Academy
of Sciences, USA, 104, 5638–5643.
Pietschnig, J., Penke, L., Wicherts, J. M., Zeiler, M., &
Voracek, M. (2015). Meta-analysis of associations between
human brain volume and intelligence differences: How
strong are they and what do they mean? Neuroscience
and Biobehavioral Reviews, 57, 411–432.
Plassman, B. L., Williams, J. W., Burke, J. R., Holsinger, T., &
Benjamin, S. (2010). Systematic review: Factors associated
with risk for and possible prevention of cognitive decline
in later life. Annals of Internal Medicine, 153, 182–193.
Reiter, K., Nielson, K. A., Smith, T. J., Weiss, L. R., Alfini, A.
J., & Smith, J. C. (2015). Improved cardiorespiratory fit-
ness is associated with increased cortical thickness in mild
cognitive impairment. Journal of the International
Neuropsychological Society, 21, 757–767.
Ruigrok, A. N. V., Salim-Khorshidi, G., Lai, M.-C., Baron-
Cohen, S., Lombardo, M. V., Tait, R. J., & Suckling, J.
(2014). A meta-analysis of sex differences in human brain
structure. Neuroscience and Biobehavioral Reviews, 39, 34–50.
Ruscheweyh, R., Willemer, C., Krüger, K., Duning, T.,
Warnecke, T., Sommer, J., & Flöel, A. (2011). Physical
activity and memory functions: An interventional study.
Neurobiology of Aging, 32, 1304–1319.
Scherder, E. J. A., van Paasschen, J., Deijen, J.-B., van der
Knokke, S., Orlebeke, J. F. K., Burgers, I., & Sergeant, J. A.
(2005). Physical activity and executive functions in the
elderly with mild cognitive impairment. Aging & Mental
Health, 9, 272–280.
Scoville, W. B., & Milner, B. (1957). Loss of recent memory
after bilateral hippocampal lesions. Journal of Neurology,
Neurosurgery, and Psychiatry, 20, 11–21.
Shepherd, A. M., Laurens, K. R., Matheson, S. L., Carr, V. J., &
Green, M. J. (2012). Systematic meta-review and quality
assessment of the structural brain alterations in schizophre-
nia. Neuroscience and Biobehavioral Reviews, 36, 1342–1356.
Shih, I., Paul, K., Haan, M., Yu, Y., & Ritz, B. (2018). Physical
activity modifies the influence of apoloproprotein E ε4
allele and type 2 diabetes on dementia and cognitive
impairment among older Mexican Americans.
Alzheimer’s & Dementia, 14, 1–9.
Sink, K. M., Espeland, M. A., Castro, C. M., Church, T.,
Cohen, R., Dodson, J. A., & Williamson, J. D. (2015).
Effect of a 24-month physical activity intervention vs
health education on cognitive outcomes in sedentary
older adults: The LIFE randomized trial. Journal of the
American Medical Association, 314, 781–790.
Smiley-Oyen, A. L., Lowry, K. A., Francois, S. J., Kohut, M.
L., & Ekkekakis, P. (2008). Exercise, fitness, and neuro-
cognitive function in older adults: The “selective improve-
ment” and “cardiovascular fitness” hypothesis. Annals of
Behavioral Medicine, 36, 280–291.
Sofi, F., Valecchi, D., Bacci, D., Abbate, R., Gensini, G. F.,
Casini, A., & Macchi, C. (2011). Physical activity and risk
of cognitive decline: A meta-analysis of prospective stu-
dies. Journal of Internal Medicine, 269, 107–117.
Spalding, K. L., Bergmann, O., Alkass, K., Bernard, S.,
Salehpour, M., Huttner, H. B., & Frisén, J. (2013).
Dynamics of hippocampal neurogenesis in adult humans.
Cell, 153, 1219–1227.
Suzuki, T., Shimada, H., Makizado, H., Doi, T., Yoshida, D.,
Tsutsamimoto, K., & Park, H. (2012). Effects of multi-
component exercise on cognitive function in older adults
with amnestic mild cognitive impairment: A randomized
controlled trial. BMC Neurology, 12, 128.
Taupin, P. (2007). BrdU immunohistochemistry for studying
adult neurogenesis: Paradigms, pitfalls, limitations, and
validation. Brain Research Reviews, 53, 198–214.
ten Brinke, L. F., Bolandzadeh, N., Nagamatsu, L. S., Hsu, C.
L., Davis, J. C., Miran-Khan, K., & Liu-Ambrose, T.
(2015). Aerobic exercise increases hippocampal volume
in older women with probable mild cognitive impairment:
A 6-month randomized controlled trial. British Journal of
Sports Medicine, 49, 248–254.
Thomas, A. G., Dennis, A., Rawlings, N. B., Stagg, C. J.,
Matthews, L., Morris, M., & Johansen- Berg, H. (2016).
Multi-modal characterization of rapid anterior hippocam-
pal volume increase associated with aerobic exercise.
Neuroimage, 131, 162–170.
van de Rest, O., van der Zwaluw, N. L., Tieland, M., Adam, J.
J., Hiddink, G. J., van Loon, L. J., & de Groot, L. C. (2014).
Effect of resistance-type exercise training with or without
protein supplementation on cognitive functioning in frail
and pre-frail elderly: Secondary analysis of a randomized,
double-blind, placebo-controlled trial. Mechanisms of
Ageing and Development, 136–137, 85–93.
van Praag, H., Shubert, T., Zhao, C., & Gage, F. H. (2005).
Exercise enhances learning and hippocampal neurogenesis
in aged mice. Journal of Neuroscience, 25, 8680–8685.
van Uffelen, J. G. Z., Chinapaw, M. J. M., van Mechelen, W.,
& Hopman-Rock, M. (2008). Walking or vitamin B for
cognition in older adults with mild cognitive impairment?
A randomized controlled trial. British Journal of Sports
Medicine, 42, 344–351.
van Valen, L. (1974). Brain size and intelligence in man.
American Journal of Physical Anthropology, 40, 417–424.
Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni,
L., Wahlund, L.-O., & Petersen, R. C. (2004). Mild cogni-
tive impairment – Beyond controversies, towards a con-
sensus: Report of the international working group on mild
cognitive impairment. Journal of Internal Medicine, 256,
240–246.
Wolf, H., Kruggel, F., Hensel, A., Wahlund, L. O., Arendt, T.,
& Gertz, H. J. (2003). The relationship between head size
and intracranial volume in elderly subjects. Brain
Research, 973, 74–80.
Woo, J. (2000). Relationships among diet, physical activity
and other lifestyle factors and debilitating diseases in the
elderly. European Journal of Clinical Nutrition, 54
(Supplement 3), 143–S147.
World Health Organization. (2010). Global recommendations
on physical activity for health. Geneva: Author.
Young, J., Angevaren, M., Rusted, J., & Tabet, N. (2015).
Aerobic exercise to improve cognitive function in older
people without known cognitive impairment. Cochrane
Database System Reviews, 4, CD005381.
Zheng, G., Xia, R., Zhou, W., Tao, J., & Chen, L. (2016).
Aerobic exercise ameliorates cognitive function in older
adults with mild cognitive impairment: A systematic
review and meta- analysis of randomized controlled trials.
British Journal of Sports Medicine, 50, 1443–1450.