Does physical activity reduce risk for Alzheimer's disease through interaction with the stress neuroendocrine system?

Figures & data

Figure 1.  Summary diagram: arrows indicate pathways between psychosocial stress and AD (arrows indicate direction of causality). PA = physical activity and is located on arrows where it has been shown to attenuate that pathway (see text).

Table I.  Effects of PA on stress responding human studies.

Author (year)	Study design	Participants	Type of PA	Type of stressor	Reported outcomes
Sinyor et al. (1983)	Case–control study	30 men, 20–30 years old (15 highly trained, 15 untrained control group)	Aerobic fitness level measured by fitness testing	Arithmetic task, quiz, color–word task	Trained individuals had a faster heart rate recovery and a lower state anxiety after psychosocial stress
Holmes and McGilley (1987)	Quasi-experimental clinical trial (no randomization)	67 healthy women aged 17–20 years (Training group: 18 low fit, 19 high fit; non-training group: 15 low fit, 15 high fit)	Aerobic exercise: 50 min per session, twice weekly, for 13 weeks	21-item questionnaire designed to assess subjective cognitive arousal Wechsler Adult Intelligence Scale Questionnaire measuring subjective cognitive and subject somatic arousal	Low-fit subjects showed greater heart rate and subjective responses to the stressor than did high-fit subjects at baseline Aerobic training reduced the heart rate response of low-fit subjects to a psychologic stressor Fitness training did not influence subjects' subjective responses to the psychologic stressor
de Geus et al. (1993)	Quasi-experimental clinical trial (no randomization)	62 participants aged 24–40 years	Aerobic training for 4 or 8 months with self-chosen duration of 1.5–2.5 h a week, except for participants of the 8 months group who exercised at a minimal frequency of 2.5 h per week	Tone avoidance task (four-choice reaction time task) Memory search task Cold pressor test	Fitness level at baseline was not associated with any psychological variables measured (heart rate and blood pressure reactivity, urinary catecholamine excretion) Aerobic training did not produce any effect on psychological make-up
Korkushko et al. (1995)	Case–control study	56 males in three groups: (1) healthy young untrained males 20–34 years (n = 12); (2) healthy elderly untrained males 60–74 years (n = 32); (3) healthy elderly trained male 60–74 years (n = 32)	Aerobic fitness level measured by total energy expenditure and running distance	Bicycle ergometer exercise test	Standard physical load resulted in greater increases in ACTH and cortisol in elderly untrained participants compared with young untrained and elderly trained participants There was an increase in the sympathetic control of the heart and a decrease in parasympathetic control associated with age. This increase was less pronounced in trained individuals
Unger et al. (1997)	Longitudinal study	2860 men and 4667 women, 70 years and older	PA scale based on self-report levels of PA	Widowhood	PA had a positive impact on functional decline and buffered the effects of widowhood on functional decline
Deuster et al. (1998)	Case–control study	5 healthy men and 5 healthy women, 27.3 ± 1.3	Participants reported an average running distance of 20–40 km per week	High-intensity exercise test after taking 4 mg of DEX. Two tests were performed, one at 90% and one at 100% of maximal aerobic capacity	Despite pituitary–adrenal suppression by DEX, plasma ACTH and cortisol increased with exercise testing and there were greater increases when the intensity was higher (100% of maximal aerobic capacity) Plasma cortisol responses, but not ACTH, were higher in women than in men
Broocks et al. (2001)	Clinical trial	12 untrained healthy volunteers, 33.5 ± 5.4 years	10 weeks of moderate aerobic exercise training	Three different challenge tests (m-CPP, ipsapirone, or placebo)	Cortisol response to m-CPP administration was attenuated after exercise training
Kiive et al. (2004)	Case–control study	46 males, mean age 43 years (24 depressed patients, 22 healthy volunteers)	No measures of fitness levels	Bicycle cardiopulmonary exercise testing	Acute bicycle exercise activated HPA axis, increasing cortisol levels in both groups Prolactin levels were only increased in depressed patients
Traustadóttir et al. (2004)	Case–control study	31 females: 9 young (19–36 years), 11 older unfit (59–81 years), 11 older fit (59–81 years)	Classified as unfit or fit based on their maximal oxygen consumption (VO2 max.), their age, and the American Heart Association Classification Criteria	Short bout of treadmill exercise at submaximal intensity	Results indicate a prolonged ACTH recovery, but not cortisol, after high-intensity exercise associated with aging This prolonged recovery of ACTH was attenuated by fitness level
Traustadóttir et al. (2005)	Case–control study	36 females: 10 young unfit (19–36 years), 14 older unfit (59–81 years), 12 older fit (59–81 years)	Classified as unfit or fit based on their maximal oxygen consumption (VO2 max.), their age, and the American Heart Association Classification Criteria	Matt Stress Reactivity Protocol which combines mental challenges, a physical challenge, and a psychosocial stressor	Older unfit women had greater cortisol responses to the challenge than the young-unfit and the older fit women Results suggest that aging is associated with greater reactivity of the HPA axis but PA attenuates this reactivity
Nieman et al. (2005)	Case–control study with no control group	15 healthy and non-obese females. Mean age: 37 years	People that reported to be accustomed to regular walking	Walking for 30 min at an intensity of 60% of VO2 max. Walking using the BODY BAT Aerobic Exerciser	No significant increases in plasma cortisol were seen over time Walking produced modest positive changes in immune parameters
Heiden et al. (2007)	Randomized controlled trial	75 participants with stress-related illnesses (28 cognitive behavioral intervention; 23 PA intervention; 24 usual care control group Mean age: 44 years	Two sessions per week for 10 weeks	Autonomic regulation tests (mental arithmetic, handgrip, and deep breathing at a rate of 6 breaths/min) Algometric measurements (pressure pain thresholds) Questionnaires about physical and mental health and behavioral patterns	Neither PA nor cognitive behavior training produced significant improvements in autonomic activities and pressure pain thresholds compared with usual care
Rimmele et al. (2007)	Case–control study	22 trained elite sportsmen (21.50 ± 2.35 years) and 22 healthy untrained men (21.84 ± 2.24 years)	Trained men were mostly endurance athletes with a Swiss Olympic Card and/or members of the Swiss national teams. Untrained men reported to exercise for less than 2 h per week	Psychosocial laboratory stressor (Trier Social Stress Test)	Elite sportsmen showed significant lower cortisol secretion and lower heart rate reactivity to psychosocial stress than untrained men Trained men were also generally calmer and exhibited better mood and lower anxiety
Rimmele et al. (2009)	Case–control study	18 elite sportsmen (24.17 ± 0.89 years); 50 amateur sportsmen (24.82 ± 0.43 years); 24 untrained men (23.65 ± 0.61 years)	Participants were classified into three groups based on a physical fitness test and a self-report questionnaire	Psychosocial laboratory stressor (Trier Social Stress Test)	Elite sportsmen showed significant lower cortisol secretion, heart rate, and state anxiety responses than untrained men Amateur sportsmen showed a significant heart rate response reduction but no differences in cortisol responses than untrained men

Table II.  Effects of PA on stress responding rodent studies.

Author (year)	Animals	Type of PA	Type of stressor	Reported outcomes
Watanabe et al. (1990)	Male albino Wistar rats	Forced swimming 60 min a day 5 days a week during4 weeks	Swimming	Plasma levels of ACTH and corticosterone after acute exercise are reduced with exercise training
White-Welkley et al. (1995)	Ovariectomized female Sprague-Dawley rats	Forced treadmill running for 6 weeks	Treadmill runningNovel immobilization	Exercised rats showed an attenuated ACTH and prolactin response to running, but an increased ACTH response to immobilization compared with sedentary rats
White-Welkley et al. (1996)	Ovariectomized female Sprague-Dawley rats	Forced treadmill running for 6 weeks	Treadmill runningNovel footshockNovel immobilization	Exercised rats showed increased HPA axis responses to novel footshock compared with sedentary rats
Dishman et al. (2000)	Female Sprague-Dawley rats	Forced treadmill running for 6 weeks	Familiar treadmill runningNovel immobilization	Increased norepinephrine levels in hypothalamic and limbic brain regions with treadmill running and immobilization in exercised rats
Moraska et al. (2000)	Male Sprague-Dawley rats	Forced treadmill running for 8 weeks	Forced treadmill running with footshock	Forced running had similar effect as chronic stress with adrenal hypertrophy, thymic involution, decreased serum corticosteroid-binding globulin, increased lymphocyte nitrite concentrations, suppressed lymphocyte proliferation, and suppressed antigen-specific IgM
Fleshner et al. (2002)	Male Harlan Sprague-Dawley specific pathogen-free rats	Voluntary wheel running for 6–8 weeks	Tails shock and bacterial challenge	PA enhanced the benefits of acute stress on innate immunity
Droste et al. (2003)	Male C57BL/6N mice	Voluntary wheel running for 4 weeks	Forced swimming and restraint stressNovel environment	Exercising mice had higher corticosterone levels in response to forced swimming or restraint stress compared with sedentary mice, but ACTH levels remained similarExercising mice presented lower ACTH responses to novel environment compared with sedentary mice
Timofeeva et al. (2003)	Male Wistar rats	Acute bout of 60 min of intense forced treadmill running	Treadmill running	Acute intense treadmill running leads to a strong expression of c-fos mRNA and activates the hypophysiotropic CRH system
Park et al. (2005)	Sprague-Dawley rats	Forced daily swimming 45 min/day, 5 days a week, during 2, 4, and 6 weeks	Swimming and sham exercise	HPA response to exercise training is not attenuated if exercise intensity is gradually increasedExercise training prevents increases in basal pituitary–adrenal activity
Droste et al. (2006)	Male C57BL/6N mice	Voluntary wheel running	Novel environmentRestraint stress	Exercising mice had higher plasma corticosterone levels in response to restraint stress compared with sedentary ratsExercising rats presented lower plasma corticosterone response to a novel environment compared with sedentary rats
Fediuc et al. (2006)	Male Sprague-Dawley rats	Voluntary wheel running for 5 weeks	Restraint stress	Exercising rats showed normal circadian corticosteroid secretion, normal negative-feedback inhibition, and an attenuated increase in plasma ACTH levels after a novel stress compared with sedentary rats
Droste et al. (2007)	Male Sprague-Dawley rats	Voluntary wheel running for 4 weeks	Forced swimmingNovel environment	Exercising rats had higher corticosterone levels in response to forced swimming or restraint stress compared with sedentary ratsExercising rats presented lower corticosterone response to a novel environment compared with sedentary ratsACTH levels remained similar for both groups in both types of stressors
Greenwood et al. (2007)	Adult male Fischer F344 rats	Voluntary wheel running for 2 and 6 weeks	Shuttle box escape after uncontrollable footshock	Voluntary wheel running for 6 weeks, initiated after stressor exposure, reduced the expression of conditioned freezing and reversed the escape deficit from the shuttle box. Two weeks of wheel running did not produce any effects
Campbell et al. (2009)	Male Sprague-Dawley rats	Voluntary short-term (2 weeks) and long-term (8 weeks) wheel running	Restraint stress and ACTH challenge	Two weeks of voluntary wheel running initially produces hyperactivity of HPA axis through increase in adrenal sensitivity to ACTH, but long-term training attenuates this effect
Droste et al. (2009)	Male Sprague-Dawley rats	Voluntary wheel running for 2 days, 1 week, and 4 weeks	Forced swimmingNovel environment	Four weeks of voluntary wheel running produced no differences in hippocampal-free corticosterone responses to stress between exercised and sedentary rats
Hill et al. (2010)	Male Sprague-Dawley rats	Voluntary wheel running for 4 weeks	Wheel running	Regular exercise produces extensive changes in the GABAergic system that could explain some of the changes observed in stress sensitivity and emotionality with exercise
Kannangara et al. (2010)	Young and aged female mice	Voluntary wheel running for 11 days	Wheel runningIsolated housing	Voluntary exercise reduces stress and increases hippocampal cell proliferation in aged female mice

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