Alzheimer's Disease and Exercise: A Literature Review

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs memory and cognitive judgment. It is the leading cause of dementia in late adult life and is associated with a significant social burden and increased morbidity and mortality in the elderly. Because of mixed effectiveness of medications, exercise has been considered as a treatment for pre-clinical AD, late stage AD, and as a prevention strategy. Exercise appears to improve brain blood flow, increase hippocampal volume, and improve neurogenesis. Prospective studies indicate that physical inactivity is one of the most common preventable risk factors for developing AD and that higher physical activity levels are associated with a reduced risk of development of disease. Exercise as a treatment for AD shows improvement in cognitive function, decreased neuropsychiatric symptoms, and a slower decline in activities of daily living (ADL). Exercise has been shown to have fewer side effects and better adherence compared to medications.

Introduction

Alzheimer's disease (AD) represents a significant challenge for the aging health of our country. Because of medical advances, the life expectancy of our residents is increasing. By the year 2030, it is estimated that more than 20% of the United States residents will be older than 65 yr (²⁵). Advancing age is related to an increased risk of dementia. AD is the most common cause of dementia, accounting for an estimated 60% to 80% of cases (¹). Aging also is the greatest risk factor for development of AD and the Alzheimer's Association estimates that 81% of people who have AD are 75 yr or older (¹).

The impact of AD on the population is significant. Official records indicate a 71% increase in deaths due to AD from 2000 to 2013 (¹). This is compared with a 14% decrease in heart disease in the same time span. AD rose from the 25th most burdensome disease in the United States to the 12th in a 10-yr time span and an increase from the 32nd to the 9th worse in regards to years of life lost. This was the largest increase for any disease over that interval of time (¹).

There are many challenges involved in the diagnosis and treatment of AD. Studies show mixed effectiveness of medications and there are few good solutions for treating AD in those diagnosed with preclinical AD or mild cognitive impairment (MCI). MCI is defined as a syndrome of cognitive decline greater than expected for an individual's age and education level without interfering significantly with activities of daily life. It is notable that more than half of those with MCI will progress to AD within 5 yr (¹¹).

Given the potential for medication side effects, there has been great interest in nonpharmacological treatment of AD (²³). Treatments, such as cognitive training and cognitive stimulation, have demonstrated mixed and inconsistent benefits (²⁴). Regular exercise has shown promise in both prevention and treatment of AD, MCI, and dementia. The purpose of this article is to review significant new research in this field and consider recommendations for our patients with AD.

AD General Review

AD is a progressive neurodegenerative disease that impairs memory and cognitive judgment. It is the leading cause of dementia in late adult life. It has characteristic neuropathological findings including intracellular neurofibrillary tangles and plaques consisting of amyloid protein deposition (²¹). However, not all individuals with this prototypical neuropathology will manifest symptoms of clinical AD or dementia.

Symptoms vary among individuals but the most common presentation is an insidiously worsening ability to remember new information. As neurons in other parts of the brain malfunction and die, other symptoms develop including more severe memory loss that may affect activities of daily living (ADL), difficulties with problem solving, orientation and visual spatial relationships. Eventually, neuropsychiatric issues, such as mood and personality changes, may occur. The degree of this decline is different from person to person.

The biggest risk factor for AD is age. Although there may be a small risk (less than 1%) of genetic mutation in the amyloid precursor proteins, up to 40% to 65% of patients diagnosed with AD also are likely to have alterations in the APOE-e4 gene (¹). Other risk factors are a family history, prior MCI, cardiovascular disease risk factors, education level, social and cognitive engagement, and traumatic brain injury (¹).

Diagnosis is largely clinical and typically involves the patient's primary care doctor. Obtaining a good medical, family, and neuropsychiatric history is important. Routine labs to rule out other causes of dementia (complete blood count, comprehensive metabolic panel, thyroid stimulating hormone, vitamin B12, and folic acid) as well as neuroimaging with magnetic resonance imaging (MRI) also should be considered part of the routine workup. The diagnosis can be strengthened with neuropsychological testing and serologies for biomarkers as necessary. Biomarkers currently being explored can be obtained from the serum or the cerebral spinal fluid (CSF). Core CSF biomarkers have a high diagnostic accuracy with sensitivity and specificity of 85% to 90% (²¹).

Current pharmacological treatment involves acetylcholinesterase inhibitors and N-methyl d-aspartate receptor antagonists (memantine). They contribute minimally on early stages of disease. They do slow the progression of AD in later stages and provide some symptomatic relief but do not achieve a definite cure (¹⁴). For these reasons, exercise has been explored as a viable means of prevention and treatment for early-stage and late-stage disease due to its relative safety with few side effects.

Neurophysiology

Exercise may be one strategy to prevent or delay cognitive decline in the aging brain. As such, a great deal of effort and research has gone into understanding the physiology of the aging brain and how exercise may combat or temper it. Three areas of the brain that exercise may have an effect on are the vascular physiology, hippocampal volumes, and neurogenesis (³).

Brain blood flow is adversely affected with advancing age and is associated with cognition. Moderate-intensity exercise has been shown to result in acute augmentation of blood flow to the brain (³). Studies have shown higher cerebral blood flow in exercise-trained men versus sedentary (²). A randomized trial of exercise training over a span of 12 wk did show higher resting cerebral blood flow in the anterior cingulate region in the exercise group (⁶).

Hippocampal circuits also are thought to be very important for episodic memory, and they are affected early in AD. Large hippocampal volumes are thought to be associated with improved cognitive functioning. Mild to moderate exercise over a 1-yr period appears to prevent hippocampal volume atrophy (⁷). Hippocampal volume changes also were correlated with cardiovascular fitness changes (⁷). Erickson et al. (⁸) also showed that physical training improves cognitive performance and is associated with increased hippocampal volumes in humans.

Adult hippocampal neurogenesis also is crucial for learning and memory. Determining neurogenesis is fairly difficult to study in humans, but it has been shown that exercise improves hippocampal neurogenesis in rats (¹⁸). Research is under way to evaluate ways to test and evaluate neurogenesis of the human brain.

Exercise to Prevent AD and Dementia

Exercise has been implicated as a potential lifestyle intervention that could help reduce the incidence of dementia and AD. Epidemiological and large prospective trials have shown promising results to address this hypothesis.

Barnes and Yaffe (⁴) estimated that 54% of AD risk factors might be preventable. Using relative risks from existing meta-analysis, Norton and Matthews (¹⁶) estimated the population-attributable risks of AD worldwide for seven potentially modifiable risk factors. They found the highest attributable risk was for physical inactivity.

Hamer and Chida (¹²) ran prospective data on 163,000 nondemented participants and pooled the relative risk of dementia in the highest physical activity category compared with the lowest. They found that physical activity reduces the risk of dementia and AD by 28% and 45%, respectively.

Smith et al. (²²) completed a large systematic review of randomized controlled trials between 1966 and 2009 looking at the association of exercise and cognitive performance. Studies had to be of sufficient size for effect and have supervised aerobic programs and control groups. They demonstrated significant improvements in attention and processing speed, executive function and memory improvement in the exercise groups. The effects on working memory were less consistent. One thing they also noticed was that the duration or intensity of exercise did not seem to matter for the beneficial effects to occur.

As discussed prior, patients with dementia also have decay in the hippocampus. Because exercise has been effective at reducing cortical decay in the elderly, Erickson et al. (⁸) looked at the relationship between exercise and hippocampal volume. Using MRI, they found that in 165 nondemented older adults, there was a triple association of higher fitness levels, larger hippocampi volume, and better spatial memory performance for active individuals.

Population-based prospective studies also have demonstrated benefits of exercise for reducing cognitive decline and dementia. A German population study over a time course of 14 yr demonstrated that subjects with self-reported regular physical activity had a reduced risk of developing MCI and AD and had better performance on neuropsychological testing (²⁰). Another prospective trial tested the hypothesis that an objective measure of total daily activity could predict the incidence of AD and MCI (⁵). In this study, participants wore wrist actigraphs to look at their total physical activity rather than rely on self-reported questionnaires. At a 4-yr follow-up, it was determined the level of total daily physical activity was associated with the rate of global cognitive decline and AD incidence. Higher levels of physical activity were associated with significantly reduced risk of AD. Finally, a prospective study over 8 yr showed that women who walked more, as their physical activity, had significantly less cognitive decline over the span of the study (²⁶).

A recent Cochrane review looked at the effects of aerobic activity in cognitively healthy older adults (²⁷). Their goal was to evaluate if cardiovascular fitness accounted for the effects of physical activity on cognition. To this end, they included only trials where an increase in cardiovascular fitness had been demonstrated, such as from V˙O_2max testing. Their results did not find any evidence of benefit from exercise in any cognitive domain. They also found a moderate-to-high risk of bias in the studies they included. It is important to realize that their review included no studies where exercise intervention would not be expected to increase cardiovascular fitness, such as light aerobic activity, weight lifting, or stretching exercises. They also only included studies where V˙O_2max testing or other cardiovascular fitness testing was done. This review might be useful for particular subgroups of individuals, but should be interpreted with caution. Other systematic reviews and meta-analysis show clear improvements and benefits with exercise on cognition (^12,22,23).

Exercise as Treatment for AD

While many studies exist that demonstrate a prospective benefit from exercise on reducing cognitive decline, what is the evidence for exercise on those with AD? Several studies in the past had limitations related to randomization and supervision of the treatment groups. There also have been fewer large studies that specifically look at a population of Alzheimer’s patients.

One randomized, controlled trial looked to eliminate some of these issues by assessing whether an exercise program would reduce ADL decline in nursing home residents with AD (¹⁷). With an intervention of 1 h twice weekly of aerobic, strength, balance, and flexibility training for a period of a year, they found a slower decline in ADL than in nonexercise groups. Unfortunately, they found no effect on behavioral disturbances, depression, or nutritional scores.

In 2015, Strohle et al. (²³) attempted to compare medication effects for AD and MCI against the effects of exercise. Studies that were allowed for inclusion had a treatment arm of either exercise or a pharmacological intervention. Exercise had a moderate to strong pooled effect size for AD and small effects for MCI. Drug treatments with cholinesterase inhibitors and memantine resulted in a small effect on cognition for AD and no effect for MCI. It should be noted that the discontinuation rate for medications was very high, but much lower for the exercise arms.

A recent randomized controlled trial looked at the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD (¹³). Performing 60-min sessions three times a week for 16 wk showed no benefits on cognitive performance but did show significantly improved scores on neuropsychiatric symptoms. This study did have issues with subjects adhering to the training program. This is a common issue with these studies and is why most of them use intent to treat models.

The longer the intervention of a study, the more likely you might expect to see compliance break down through the course of it. This brings into question the duration of intervention that is necessary to see a change. A randomized study over only 3 months looked at a supervised exercise program three times weekly (⁶). They found improvement in immediate and delayed memory through the training interval. The exercise group also demonstrated higher resting cerebral blood flow in the anterior cingulate region. However, it is hard to compare these results to patients with AD, because these were all cognitively normal adults. This study also suffered from small sample size (37 participants) and any lack of follow-up. Another small study of eight individuals with MCI looked at a 9-month intervention with two 3-month training intervals (¹⁹). They showed improvement in cognitive performance, but the influence waned after stopping the training.

A recent Cochrane review examined the effect of exercise for older people with dementia (¹⁰). Their meta-analysis revealed no clear evidence of benefit from exercise on cognitive functioning. However, they did find a benefit from exercise on the ability to perform ADL. One should note that the reviewers found the results and studies to be heterogeneous and actually rated the quality of evidence as very low. They recommended that more well-designed trials that assessed different types and severity of dementia would be helpful in improving the quality of further reviews (¹⁰).

Lastly, another recent systematic review with an accompanying meta-analysis found six randomized controlled trials that did demonstrate a positive effect in patients with AD who underwent an exercise program (⁹). They demonstrated a decreased rate of cognitive decline and positive effect on global cognitive function.

Conclusion

What does this mean for our patients? Prospective studies show that physical activity, even at mild to moderate intensity, can decrease the likelihood of dementia and AD (^{4,5,8,12,16,20,22,26}). It is not clear if the relationship is dose dependent, but it would appear that higher levels of physical activity lead to a decreased risk (²⁶). This could be important for our patients with risk factors of AD or those developing early MCI. For those of our patients with diagnosed AD, exercise appears to have potential benefits. Systematic reviews and meta-analysis do show possible improvement in cognitive function, decreased neuropsychiatric symptoms, and a slower decline in ADL (^10,12,22). Exercise also has fewer side effects and better compliance than medications in one large systematic review (²³). There also are the intrinsic benefits of exercise on cardiovascular health and individual wellness.

Given the research available, it is hard to make specific exercise recommendations for our patient's with AD or for prevention of AD. The studies are very heterogeneous regarding the types of exercise that were instituted and the duration of the intervention. It is this author's opinion that the recommendations for exercise in the aging adult from the American College of Sports Medicine and the American Heart Association would be the most comprehensive (¹⁵). These recommendations also are more likely to cover the majority of necessary activity required to see potential benefits.

AD will be a great challenge for medicine and the country over the next several decades. Despite large amounts of rigorous and large-scale research, there is still much to be learned. Neuropathological and physiological reasons for disease manifestation are currently being evaluated. Current pharmacological treatments for AD are targeted at late stages when severe morbidity, mortality, and caregiver burden may accumulate. Exercise would appear to be a useful modality of treatment and prevention for early stages of AD as well as prevention of dementia in general. Large-scale prospective trials, as well as systematic reviews and meta-analysis, have demonstrated benefits of activity. Many of these reviews and studies, unfortunately though, suffer from methodological issues and noted heterogeneity in populations. More high-quality randomized trials are necessary to truly determine if exercise has potential to prevent and treat AD and MCI.