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Alzheimer's disease (AD) is the most common neurological disorder associated with ageing and has a global prevalence of 6% in people older than 65 years.1 It is also the most common cause of dementia, accounting for 50%–60% of all cases.2 The increase in life expectancy of the world population is expected to translate into many more cases of dementia—it is estimated that 1 in 85 persons worldwide will be affected by AD in 2050.1 Clearly, AD is a major public health problem.
To examine whether physical activity (PA) may influence the risk of AD requires a brief review of pathogenesis. Risk factors for the disease include advanced age, family history of dementia, low educational accomplishment and presence of the ε4 isoform of the apolipoprotein E (apoE).3 ApoE ε4 has been associated with all the AD-related biochemical disturbances such as β-amyloid deposition, tangle formation, oxidative stress, lipid homeostasis deregulation, synaptic plasticity loss and cholinergic dysfunction.3 Individuals who are homozygotes for the APOE ε4 genotype have up to 15 times higher risk of developing AD compared with non-carriers.4 Further, the median age at AD onset is reduced from 84 years in non-ε4 carriers to 68 years in ε4 homozygotes.5 The presence of APOE ε4 acts in synergy with several lifestyle factors (fat and alcohol intake, smoking and also physical inactivity) to increase the risk for AD.6
Biochemical underpinnings of pa's beneficial effect on ad mechanisms
How does PA influence the biochemical disturbances described above?7/sup> In AD mouse models, 5 months of aerobic exercise delayed β-amyloid accumulation and enhanced the rate of learning.9 PA augmented brain plasticity10 by facilitating regenerative, adaptative and protective processes through the mediation of neurotrophic factors.7 In addition, aerobic exercise stimulated gene expression of nerve growth factors that are important for neurogenesis and production and function of neurotransmitters, especially in the hippocampal region, where AD pathology is severe.8 In the brain of an AD transgenic mouse model, regular voluntary exercise (incage running wheel for 3 weeks) triggered an immune response that was associated with a decrease in neurotoxic cytokines and increased β-amyloid clearance.11
Epidemiological underpinnings of pa's beneficial effect on ad
Simple lifestyle changes may slow the onset and progression of AD. During follow-up periods of 5–7 years, highly active persons had between 20% and 50% lower risk of dementia than those who were less active.12 Patients with AD were less active (both intellectually and physically) in midlife, and inactivity was associated with a 250% increased risk of developing AD.13 To date, few randomised controlled trials (RCTs) have been designed to test whether exercise intervention reduced the risk of AD.14 Australian researchers found modest improvements in cognitive function after a 6-month PA programme in adults aged 50 years or older who had mild cognitive impairment that did not meet the threshold for dementia.15 Importantly, the beneficial effects of PA persisted for 12 months, after the intervention was discontinued. The effect of PA on cognitive function was higher for the APOE ε4 non-carriers in the intervention group than for the APOE ε4 carriers from the intervention and control groups. The relatively low number of APOE ε4 carriers (30%, n=24 and n=27 in the PA and in the control group, respectively) precludes conclusions regarding possible gene–lifestyle interactions. Several epidemiological studies also raised the possibility of an existing APOE–exercise interaction so that the association of exercise with cognitive decline or dementia risk depends on the individual's APOE genotype, but the evidence is not consistent.16 17 van Uffelen et al18 examined the effects of 12-month aerobic training (twice-weekly, groupbased, moderate-intensity walking programme) or vitamin B supplementation on cognitive function in adults aged 70–80 years with mild cognitive impairment. They showed that neither the walking programme nor the vitamin B supplementation was effective in improving cognition within 1 year. A subanalysis of those with better adherence revealed that the walking programme improved memory in men and memory and attention in women.
Pa and ability to continue to perform activities of daily living (adls)
Major ADLs include complex, instrumental activities (eg, housekeeping, meal preparation, money management or shopping) and simple self-care activities (eg, eating, bathing, using the toilet, dressing). Loss of ability to cope with ADLs, also referred to as “functional decline,” is prevalent in patients with AD and is a major contributor to poor health-care outcome.8 Progressive mental deterioration with disorientation, memory disturbance and confusion, together with other factors yet to be determined, interfere with the patients' ability to perform ADLs.19 Besides increasing the burden for the care giver and the community, functional decline is the main factor affecting AD patients' quality of life20 and is a major risk factor for hospitalisation,21 institutionalisation22 and death.23 Physical deterioration and reduced muscle mass are also linked with AD, resulting in higher risks of falls and fractures, further functional decline and loss of independence.24
Two recent RCTs assessed the effects of regular PA on the ability of AD patients to cope with ADLs (as evaluated with the classic Katz or Barthel index). A simple exercise training programme (two sessions per week of 1 h walking, toning, balance and flexibility exercises) performed during a 1-year period attenuated the rate of decrease over time in the ability of AD patients to perform ADLs.25 More recently, we showed that a much shorter (12 weeks) and more intense programme (three sessions per week individually supervised, each combining resistance training with elastic bands, joint mobility and coordination exercises) significantly improved patients' ability to perform self-care activities.26 Differences in the findings may have arisen because of differences in type, intensity, frequency and duration of the intervention, as well as the disease severity of the patients enrolled. While keeping in mind the relatively small size of the population samples, especially in the study by Santana-Sosa et al26 (n=16), the results of both RCTs suggest a dose–response relationship in the health benefits of regular PA; such a phenomenon increases the likelihood, but does not prove, that the relationship is causal. These early RCT results extend the findings reported from more than 100 prospective studies performed in the past in a wide range of diseased and healthy populations.10 27
Regular PA has other health benefits in people with AD. Rolland et al28 showed using a non-controlled design that a 7-week programme of endurance exercise training consisting of walking and bicycling reduced nutritional and behavioural complications and risk of falls in AD patients. Teri et al29 demonstrated that a home-based exercise training (performed during a 3-month period) combined with teaching care givers behavioural management techniques improved physical health and depression in patients with AD. Together with improved ability to cope with ADLs, we also showed training-induced improvements in several indices of functional capacity such as upper and lower body muscle strength and flexibility, agility and dynamic balance, cardiorespiratory fitness, and gait and balance abilities (with subsequent decrease in risk of falls).26
Future human intervention studies should consider learning from the animal data that an enriched environment promotes PA, socialisation and problem solving. These studies would also eventually help define the type, frequency, intensity and duration of PA that is most beneficial in preventing cognitive deterioration and delaying the onset of AD.27
The current PA recommendations for older adults (≥65 years) call the population to enrol in aerobic and strength activities most days of the week.30 It might be possible to prevent the risk of cognitive deterioration by promoting ≥30 min on 5 days a week of moderate-intensity aerobic PA or vigorous-intensity aerobic PA for a minimum of 20 min on 3 days each week. We join with Professor Steven Blair in arguing that physical inactivity is the major public health problem of the 21st century.31 PA is likely to mitigate the risk of cognitive impairment and possibly AD—and this is just one of the multiple health benefits of PA.32
This work was supported by the Spanish Ministry of Education (EX-2007-1124), the Loo and Hans Ostermans Foundation 2009 (2009Oste0043) and Fondo de Investigaciones Sanitarias (FIS, grant #PI061183).
AL and JRR drafted the manuscript and contributed equally.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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