|Exercise to Prevent Cognitive Decline and Alzheimer’s disease: For Whom,
When, What, and (most importantly) How Much?
|Eef Hogervorst*, Angela Clifford, Jennifer Stock, Xu Xin and Stephan Bandelow
|School of Sport, Exercise and Health Sciences, Loughborough University, UK
||Professor E Hogervorst
Applied Cognitive Research
School of Sport, Exercise and Health Sciences
Ashby Road LE11 3TU, UK
Tel: + 44 1509 223020
Fax + 44 1509
|Received May 22, 2012; Accepted May 24, 2012; Published May 26, 2012
|Citation: Hogervorst E, Clifford A, Stock J, Xin X, Bandelow S (2012) Exercise
to Prevent Cognitive Decline and Alzheimer’s disease: For Whom, When, What,
and (most importantly) How Much?. J Alzheimers Dis Parkinsonism 2:e117.
|Copyright: © 2012 Hogervorst E, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
|In several reviews, exercise was reported to be effective in reducing
the risk for cognitive decline and dementia [1,2]. However, not all
reviews concluded this. One recent review  stated that there was still
insufficient evidence, as most studies were too small and had insufficient
methodological information (intensity, duration) to enable appropriate
evaluation. Here we discuss potential confounds or mediators that may
explain these discrepancies.
|We found that most observational studies showed at least some
positive associations of exercise, but not always on the same cognitive
tests . Variance in studies was induced by inconsistent use of cognitive
assessments (e.g. fluid intelligence compound scores vs Symbol Digit
Modalities Test (SDMT) scores by itself); different assessments of
fitness (objective vs. self reported hours of exercise engaged in); and
different cut-offs for high/low exercise across studies. These limitations
were echoed by others and recent reviews also illuminated potential
confounds associated with both exercise and cognitive improvement,
such as lifting of depression, as well as social and cognitive stimulation
, and an increase in self efficacy (Stock, in press), which have
usually not been taken along in analyses or adequately controlled for.
Observational studies are limited in their ability to establish causality
and many people could have stopped exercise because of other
confounding morbidity, which may also affect cognitive function
(e.g. vascular disease, see below). Randomised controlled trials (RCT)
are better at establishing causality, but can also be affected by choice
of measurements and population, suffer from baseline differences,
regression to the mean and design of the control conditions (e.g. without
social or cognitive stimulating aspects), as well as the above mentioned
limitations of potential non-assessed confounds or mediators, such as
|In our earlier review of 26 RCT studies in community dwelling
elderly without known dementia or cognitive impairment, which had
been carried out up to 2009 , only 6 studies showed overall cognitive
improvement, 13 some improvement and 7 none at all. The most
consistent cognitive tests to be affected by exercise interventions in
this group were simple tests, such as those of concentration and those
using simple reaction times. Several earlier reviews suggested that
more complex cognitive tests were most affected by exercise. However,
our review finding was substantiated by those of the Cochrane metaanalyses
, which is a gold standard medical review system. About
half of RCT studies we had included in our review , which had used
a simple test of concentration and working memory (Digit Span) found
that it displayed significant positive results of exercise, but the other
half of studies using this test (n=5) had not found any improvement. Of
the complex information processing tests previously thought to be most
sensitive to exercise, 21 tests (including the Stroop 4x, Symbol Digit
Modalities test (SDMT) 4x, CRT 3x, memory search 2x, and abstract
reasoning) showed no effects of exercise, versus only 10 tests of complex
information processing that did (including the Stroop 1x, verbal Fluency
3x, and Digit Span backwards 2x, and CRT 2x, and 2 other complex
tests). This suggests a 50% chance of finding an exercise effect on a
simple concentration test, versus only a 32% chance of finding this when
using complex cognitive tests. A recent meta-analysis  reported no greater effect for any specific cognitive domain (investigating Complex
or Choice Reaction Times (CRT), executive or memory function tests)
when extended cognitive test practice (n=25 studies) was compared
to aerobic exercise (n=17 studies), although better study quality was
associated with larger effect sizes. After both interventions, effect sizes
seemed larger on executive function tests than on memory or CRT tests
echoing earlier reviews. However, as the authors reflected, outcomes
studied may have not fitted within the domain or combined several
domains. Learning effects are clearly greater on executive function tests
and without adequate control, it is difficult to establish whether exercise
promotes implicit learning (how to do the test) over and above that of
exposure to the test per se. However, other reviews showed that studies
which had controlled for session number and psychosocial exposure
by including an assumed non active intervention (e.g. using stretching
and/or balancing exercises) did show additional cognitive effects of
aerobic and/or strength training over and above participating in control
(i.e. practice) sessions [1,2].
|Our review  suggested that aerobic exercise of sufficient
intensity which had been assessed objectively showed the best results
in improving cognition in community dwelling elderly. However, again
only half of the studies that reported an increase in VO2 measures found
a positive effect on cognition. On the other hand, all studies which
reported an improvement in muscle strength found that this type of
exercise improved cognition. Resistance and strength exercise was thus
thought to contribute positively to brain function, either by itself or in
combination with aerobic exercise. However, flexibility, balancing and
stretching exercise by itself (such as yoga) did not show overall positive
effects on improving cognition. In recent reviews it is often seen to be
used as a control treatment for this reason.
|While intensity of exercise was important, a higher frequency of
exercise did not necessarily induce more cognitive improvement .
Effects were seen already after only 4  to 8 weeks , but adherence
in many studies to exercise regimes was low, possibly contributing to
null findings in some studies . A recent study performed in our
laboratory with sedentary older participants (40-65 years old) showed
that resistance exercise (30 min 3x week for 12 weeks using resistance
bands at home) had high adherence (90%) and improved memory
(episodic and semantic memory using a word list recall and a verbal
fluency test, respectively) when compared to yoga exercises of a similar duration in an order balanced cross over design. Other tests (of complex
speeded information processing, such as the TMT and SDMT) were not
improved by exercise. Effects in our study were particularly apparent
in middle-aged women . Others mention an optimum of 30 min 5
times a week of moderate aerobic intensity and resistance training twice
a week to conform to Department of Health guidelines [2,8] (see also
DH online guidelines 2011), with for those over 65 years of age, sessions
lasting at least 10 min.
|However, a trade-off between adherence and intensity needs to be
made to promote long term sustainability of behavior. Carry-over effects
with those in control conditions or cross over conditions carrying on
with exercise and/or engaging with other activities (walking, gardening)
need to be controlled for in future studies through objective assessment
of strength and endurance. In our study, grip and leg strength did not
mediate the improvement in cognition .
|We also reviewed prospective studies investigating risk of dementia
which was found to be reduced in those who exercise in 9 of 13 studies
. However, there was a wide variety in whether effects were mainly
shown for particular dementia subtypes (vascular or Alzheimer’s
disease) or all types of dementia without a clear consensus. The studies
not finding effects had mainly used exercise self reports which have
limited validity and again various definitions for exercise and high/low
activity were included. Consistent with the greater effects of exercise
on cognition in women in our recent intervention study , three
observational prospective studies found the risk for dementia with
exercise to be more reduced in women, although one study did not find
a gender difference .
|The four randomized controlled trials we reviewed  that had
investigated exercise in participants with cognitive impairment or
dementia also showed that those two which had included mainly
women had the best results. One study reported that walking (30 min
3x per week for 6 weeks) improved complex information processing
(executive function) in older women with cognitive impairment .
Another study that had included mainly women with dementia used
mixed strength and aerobic exercises (once a week, which increased
from 15 min to 45 min/week at 60% VO2max after 12 months) and
showed effects on global cognitive function already after 6 months,
which were further enhanced at 12 months . In the latter study
stretching, use of weights and aerobic components (staircase exercise
etc.) were combined. The other two studies found no effects, but both
intensity and adherence were thought to be possibly too low to induce
improved cognitive performance . However, in a recent review which
had included more recent RCTs from 2008 to 2011, (aerobic) walking,
but also movement or chair training exercises were shown to improve
memory in 5 - and executive function in 4 - of 8 studies. In this recent
review, all 8 studies showed some effects on cognition, which may
reflect better procedures used in the studies, or, alternatively, inadequate
search strategy or publication bias. Three studies of this review (not
included in our review) had included participants with (subjective)
memory impairment or dementia and in one of these studies women
again had better executive function after aerobic exercise than men .
|Findings of strongest effects of exercise on cognition in older
women are intriguing. In pooled analyses of several mainly European
countries the risk for Alzheimer’s disease (AD, the most common form
of dementia) was found to be doubled for women [11,12]. This may
be the case because women tend to live longer than men and age is
a major risk factor for dementia. While AD is only seen in very few
elderly around 65 years of age, the risk doubles with every 5 years of age
onwards . One in three babies born in the UK today is estimated to live to 100 years and many of these eventually will be afflicted with
dementia. With an aging population worldwide, AD is a growing
problem with high human and economic costs . In the U.K., there
were an estimated 800,000 suffers costing society almost $30 billion in
2010, and two thirds of these were women . Data from 2011 ONS
statistics show that currently in the U.K. dementia is the third leading
cause of mortality in women (and the 8th in men) after ischemic heart
disease and cerebrovascular disease. Dying of dementia related causes
in women increased by 14% between 2004 and 2009 alone (Figure 1).
|Many of the risk factors for AD overlap with those for cerebro- and
cardiovascular disease, such as smoking, high blood pressure, total
cholesterol, and obesity in midlife [16,17]. The link between midlife
vascular disease and later AD may explain the gender difference in
AD prevalence . Women present with vascular disease on average
7-10 years later than men . In past cohorts, possibly because of
differences in lifestyle (smoking, work related stress), more men than
women would have died because of circulatory disease before they could
reach an old enough age to develop AD and VaD (Figure 1). However,
survival rates for men after vascular incidents (stroke, myocardial
infarct) have shown a steady improvement over the past decades. On
the other hand, in 2007 more women died of vascular disease than
men, reversing the trend that existed only 10 years earlier . This
relationship between vascular disease and AD may also explain why in
many American cohorts, with a high incidence of obesity in both men
and women, gender differences in AD are no longer found .
|Central obesity and associated silent killers (high blood pressure
and high cholesterol) is associated with a culture of unhealthy diets,
work related stress, smoking and sedentary lifestyles . The risk for
both AD and vascular disease could be reduced in those who exercise
possibly because it reduces these risk factors, such as stress, abdominal
obesity, high blood pressure and high total cholesterol and triglycerides
and it may encourage smoking cessation [8,17]. Meta analyses show
that when women present with acute coronary disease (ACD), they are
more likely to suffer from hypertension, high cholesterol, and diabetes,
while men are more likely to smoke .
|The question is whether these are true gender related differences
in risk factors or whether - when assessed by self report rather than
objective assessment - they reflect women being more aware of suffering
from these morbidities and already receiving medical treatment for
these. If women really have a higher load of these vascular risk factors,
they may respond better to exercise better than men because exercise would benefit those with a high vascular risk most substantially.
However, women also have an increased tendency to seek screening
and treatment earlier for these conditions, which may also be why they
present a decade later with ACD . An alternative explanation for the
gender difference in response to exercise is that women adhere more
to the exercise treatment regimen than men, in line with their overall
more health promoting behavior.
|Another explanation for the increased risk in women for dementia
and cardiovascular disease after menopause could be the dramatic
reduction of levels of sex steroids associated with menopause . Sex
steroids affect most of the mechanisms associated with protection of the
brain and vascular system and could thus reduce dementia risk .
While estrogen in older women is perhaps less effective and could even
increase risk for dementia and vascular disease , androgens may
be an alternative therapy. Short term aerobic and resistance exercise
can increase androgen levels in women and men, but this may depend
on exercise type, training regimen, age and other factors [21,22]. For
instance, long term intense training regimes can also be associated with
lower androgen levels  and there may thus be optimum levels of
training to confer the best benefits. These could mimic the optimum
levels of testosterone found in both older women and men to be
associated with optimal cognitive function .
|In conclusion, these gender related exercise results suggest that
while exercise may help to prevent dementia, exercise of sufficient
intensity (at least once to 3-5x per week for 30 min, walking and/or using
weights and resistance bands) can also help improve global cognitive
function even in those who already have dementia. This suggests that
reduction of vascular risk factors in midlife is not the only pathway in
prevention of cognitive decline. Perhaps mediation of androgen effects
on the brain and vascular systems and/or the direct effect of exercise
in improving oxygenation and neuro-genesis of the hippocampus and
other parts of the brain associated with exercise of sufficient intensity
[1,8] can explain improved cognitive function in those with dementia.
Whether resistance exercise by itself is sufficient to improve cognition
and whether psychosocial improvements and/or testosterone elevation
mediate this association should be further investigated.
|Acknowledgements and Financial Disclosure
|The authors have nothing to disclose nor do they have any vested interest
in any of the products mentioned in this editorial. The work discussed in this
editorial was made possible through grants from NDA, Loughborough University,
Universitas Indonesia and the Alzheimer’s Research Trust UK. The authors would
like to thank all students, participants and collaborators for their help with the
- Clifford A, Bandelow S, Hogervorst E (2010) The Effects of Physical Exercise on Cognitive function in the Elderly. Handbook of Cognitive Aging: Causes, Processes and Mechanisms, Garepy, Ménard (Eds) Nova Sciences: NY, 109-150.
- Denkinger MD, Nikolaus T, Denkinger C, Lukas A (2012) Physical activity for the prevention of cognitive decline: current evidence from observational and controlled studies. Z Gerontol Geriatr 45: 11-16.
- Snowden M, Steinman L, Mochan K, Grodstein F, Prohaska TR, et al. (2011) Effect of exercise on cognitive performance in community-dwelling older adults: review of intervention trials and recommendations for public health practice and research. J Am Geriatr Soc 59: 704-716.
- Miller DI, Taler V, Davidson PS, Messier C (2012) Measuring the impact of exercise on cognitive aging: methodological issues. Neurobiol Aging 33: 622.
- Angevaren M, Aufdemkampe G, Verhaar HJJ, Aleman A, Vanhees L (2008) Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Libr 1-37.
- Hindin SB, Zelinski EM (2012) Extended practice and aerobic exercise interventions benefit untrained cognitive outcomes in older adults: a meta-analysis. J Am Geriatr Soc 60: 136-141.
- Clifford A, Bandelow S, Hogervorst E (2011) Preventing cognitive decline in the elderly through physical activity in midlife. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 7.
- Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC (2011) Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc 86: 876-884.
- Eggermont L, Swaab D, Luiten P, Scherder E (2006) Exercise, cognition and Alzheimer's disease: more is not necessarily better. Neurosci Biobehav Rev 30: 562-575.
- Kwak YS, Um SY, Son TG, Kim DJ (2008) Effect of regular exercise on senile dementia patients. Int J Sports Med 29: 471-474.
- Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, et al. (1999) Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology 52: 78-84.
- Gao S, Hendrie HC, Hall KS, Hui S (1998) The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry 55: 809-815.
- Wimo A, Jönsson L, Gustavsson A, McDaid D, Ersek K, et al. (2011) The economic impact of dementia in Europe in 2008-cost estimates from the Eurocode project. Int J Geriatr Psychiatry 26: 825-832.
- Society AS. Dementia Infograffic.
- Office for National Statistics.
- Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, et al. (2006) Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol 5: 735-741.
- Clifford A, Udechuku AY, Edwards L, Bandelow S, Hogervorst E (2009) Maintaining cognitive health in elderly women. Aging Health 5: 655-670.
- Claassen M, Sybrandy KC, Appelman YE, Asselbergs FW (2012) Gender gap in acute coronary heart disease: Myth or reality? World J Cardiol 4: 36-47.
- Bachman DL, Wolf PA, Linn RT, Knoefel JE, Cobb JL, et al. (1993) Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study. Neurology 43: 515-519.
- Hogervorst E (2009) Hormones, Cognition and Dementia. Cambridge University Press: Cambridge.
- Enea C, Boisseau N, Fargeas-Gluck MA, Diaz V, Dugué B (2011) Circulating androgens in women: exercise-induced changes. Sports Med 41: 1-15.
- Crewther BT, Christian C, Marco C, Robert WP, Tim L (2011) Two Emerging Concepts for Elite Athletes: The Short-Term Effects of Testosterone and Cortisol on the Neuromuscular System and the Dose-Response Training Role of these Endogenous Hormones. Sports Med 41: 103-123.
- Hogervorst E, Matthews FE, Brayne C (2010) Are optimal levels of testosterone associated with better cognitive function in healthy older women and men? Biochim Biophys Acta 1800: 1145-1152.