Physical Activity for Older Adults at Risk for Alzheimer Disease

In the last 35 years, there has been increased appreciation for the health value of habitual exercise and increased attention to the importance of improved physical fitness throughout the lifespan. Exercise appears beneficial for older adults particularly for maintaining function with aging and reducing risk and improving outcomes for common age-related chronic diseases.¹ Past controversies over exercise and heart disease (especially risk of sudden cardiac death) have given way to a general consensus that exercise is an important lifestyle intervention.²

Physicians and public health experts have been prescribing exercise like a medication, given that its benefits have been amply demonstrated in cohort studies and randomized clinical trials.^{3 - 7} The effects of exercise on health are perhaps best documented and greatest in primary and secondary prevention of all-cause and cardiovascular disease mortality and diabetes. Effect sizes can be quite dramatic. One review of randomized clinical trials of prevention of diabetes concluded that programs of diet and exercise reduced incidence of diabetes 40% to 60% over 3 to 4 years.⁸ A randomized clinical trial involving modest physical activity for at least 150 minutes per week showed a number needed to treat of 7 to prevent 1 case of diabetes in 3 years, compared with 14 for the metformin-treated group.⁹ A pertinent question is whether physical activity can influence cognitive changes in late life and delay development of Alzheimer disease and late-life dementias.

The article by Lautenschlager and colleagues¹⁰ in this issue of JAMA evaluates the effect of physical activity on cognitive function. In this study, a group at higher risk for cognitive decline and dementia—older patients complaining of memory impairment—was randomly assigned to receive either usual care or a 24-week home-based program of increased physical activity. At the 18-month follow-up, the trial showed a statistically significant difference of 0.69 point between the treatment and control groups in changes on the primary outcome measure, the Alzheimer Disease Assessment Scale–Cognitive Subscale scale (ie, 70-point scale of 11 brief cognitive tests). The mean “improvement” in the exercise group was 0.73 point vs 0.04 point for the control group. Neither patients, family members, nor clinicians could easily detect that level of difference, despite its statistical significance. As in most community-based trials involving walking and modest levels of exercise, adverse events were not an important consequence of the intervention.

Comparing physical activity with other possible interventions for cognitive impairment, the authors point out that trials of cholinesterase inhibitors neither provide evidence that donepezil delays onset of Alzheimer disease nor support its use in patients with mild cognitive impairment: “Positive benefits are minor, short lived and associated with significant side effects.”¹¹ Even though it is difficult to estimate the potency of cholinesterase inhibitors compared with an exercise program, results of the most widely cited prevention trial¹² and Cochrane Reviews on cholinesterase inhibitors in mild cognitive impairment¹¹ and Alzheimer disease¹³ suggest that the effects of cholinesterase inhibitors are at best modest and, in everyday practice, typically difficult to detect.

Adverse effects are easier to detect than is effectiveness, and adverse effects are common with cholinesterase inhibitors¹³ but not common in exercise trials. Although most patients might find it easier to take a pill a day, patients and their families are likely to be gratified by the benefits of habitual exercise and often may be disappointed with the effects of cholinesterase inhibitors. Neither is very potent, and to date randomized trials have provided no evidence that either exercise or cholinesterase inhibitors prevent conversion to Alzheimer disease. The absence of subjective benefit (of drug or exercise) makes adherence critical. In the United States, pharmaceutical direct-to-consumer advertising has sensitized patients and the public to using cholinesterase inhibitors for Alzheimer disease. This illustrates the appeal of “doing something—anything” that might help prevent a dreaded disease, even if its value is minimal. Promoting habitual exercise for aging patients seems more worthy.

An important issue is how well the trial by Lautenschlager et al¹⁰ applies to the population of older adults at greatest risk of cognitive decline who also may have more difficulty adhering to an exercise program. Older individuals experience an increasing burden of complicating chronic diseases, especially osteoarthritis. The trial recruited individuals older than 50 years with subjective memory impairment, much younger than the population most at risk of Alzheimer disease and the dementias. To assess the true value of this intervention in reducing cognitive decline, a study enrolling a higher proportion of older adults should be conducted. In older populations, prevalence of mild cognitive impairment is highest, cognitive decline occurs more commonly, and dysfunction caused by dementia is most important from personal and public health perspectives. The greatest proportional increase in incidence rates of Alzheimer disease and dementia occurs between the age groups of 75 and 79 and 80 and 84 years, with incidence rates of dementia increasing from 13.5 per 1000 person-years to 38.0 per 1000 person-years, respectively. The incidence rate reaches 58.5 per 1000 person-years among those aged 85 to 89 years and 89.3 per 1000 person-years in those older than 90 years.¹⁴

The nosology of mild cognitive impairment is still evolving. Reported rates differ greatly,¹⁵ but mild cognitive impairment and subjective memory complaints are more common than dementia. Reported conversion rates of mild cognitive impairment also vary widely. The most-cited rate is 10% to 15% per year among individuals with the amnestic form¹² and rates in clinical trial populations range from 4.5% to 16.5%.^{15 - 16} Conversion to Alzheimer disease among “normal elderly people” is generally considered to be 1% to 2% per year.¹² However, this rate applies only to individuals aged 75 to 79 years,¹⁴ not to those older than 80, among whom conversion rates are considerably higher.

The mechanism through which physical activity may slow decline is unknown but possibilities include reduction of vascular risk and improved cerebrovascular functioning and brain perfusion.¹⁰ Recent observations of the correlation of microvascular infarcts with late-life dementia¹⁷ emphasize the increasing importance of vascular pathologies in late-life dementias.¹⁸ Increased brain plasticity through synaptogenesis, neurogenesis, and attenuation of brain responses, especially in the hippocampus in response to stress, could also be a mechanism by which habitual physical activity preserves brain function, as noted by Lautenschlager et al.¹⁰

Although physical activity has consistently been shown to be beneficial, the optimal dose, duration of treatment, timing during the lifespan, and durability of the effect to achieve optimal cognitive effects are unknown. In the study by Lautenschlager et al,¹⁰ treatment benefit occurred at 18 months with a “modest” dose of exercise. In contrast, despite some transient benefits,¹² prevention trials indicate no effect of cholinesterase inhibitors with longer follow-up.^{11 - 12 ,16} It may be difficult to intervene effectively in late life, because all people, if they live long enough, likely will reach a stage when they can no longer exercise habitually. Furthermore, from the standpoint of Alzheimer disease pathophysiology, it may be important to intervene earlier. The neuropathologic changes associated with Alzheimer disease are commonly found at autopsy even in brains of adults without cognitive impairment, suggesting that changes found in Alzheimer disease are likely a matter of degree and location, rather than presence vs absence.¹⁷ Clinical dementia seems unlikely to be prevented in the way a vaccine prevents polio.

Therefore, for an illness that typically starts so late in life, prevention means delaying onset. Delaying onset for several years in even a fraction of the population at risk can produce a large absolute decline in disease prevalence¹⁹ because of competing sources of mortality—a patient may die of another disease before dementia can develop. Delaying disease onset may also compress intervals between onset of cognitive morbidity and death. In the Health and Retirement Study,²⁰ an observational cohort study, absolute rates of cognitive impairment among those older than 70 years were 12.2% in 1993 vs 8.7% in 2002, with a significant decrease in the interval between the onset of cognitive decline and death. The later the disease starts, the shorter the survival after onset of illness²¹ and thus the smaller the effect on survival. For example, men with onset of Alzheimer disease at 90 years have only slightly reduced average survival compared with US population survival data.²¹ If exercise is protective and if its effects can be sustained, presumably with minimal adverse effects and costs, then it becomes an attractive option and perhaps a key strategy to help reduce cognitive morbidity in an increasingly aging society.

Exercise has additional benefits throughout the lifespan. A previous randomized trial demonstrated that an even more modest exercise program plus behavioral counseling involving individuals with mild dementia reduced physical decline and behavior disturbances tending to institutionalization.²² However, the trial by Lautenschlager et al,¹⁰ using rigorous methods, makes the important contribution of “proof of concept” by establishing that a relatively small dose of habitual exercise modestly improved cognition relative to placebo, and therefore has the potential to help prevent Alzheimer disease. Although adherence to regular exercise—despite its many known beneficial effects—is among the lowest for any of the commonly recommended preventive health strategies,²³ the widespread fear of Alzheimer disease and other catastrophic brain diseases may help motivate older individuals and society to become more physically active. The findings point to the need to learn more about exercise as an intervention to prevent cognitive decline and Alzheimer disease—and especially how to promote adherence and widespread behavior change.

Future larger multisite trials across a broad age range, especially including persons older than 70 years, could test the effect of interventions to promote habitual exercise on cognitive decline and conversion to dementias. These studies should also evaluate which methods are most worthwhile to promote behavior change and adherence. Meanwhile, interventions to promote physical activity are known to be effective, especially those with some professional guidance and ongoing professional support.²⁴ One promising approach currently available to all physicians is the so-called green prescription approach.^{25 - 26} This intervention consists of screening for low physical activity, followed by primary care physicians discussing increasing physical activity and reaching agreement with patients on setting appropriate goals. The goals, usually home-based physical activity or walking, are then written on a standard prescription sheet and given to the patient. Follow-up support is provided by telephone and quarterly newsletters and feedback given during follow-up visits with a personal physician.²⁵

Health advances of the past century have led to more individuals surviving to extreme old age, when their risk of Alzheimer disease and related dementias increases substantially.²⁷ Exercise—and possibly other lifestyle factors—appear to affect vascular risk and late-life brain health.²⁸ In addition to traditional medical approaches to prevent this dreaded disease, social factors such as providing universal education, general medical care, a suitable environment, adequate nutrition, habitual exercise, and opportunities for continued social interactions throughout the lifespan also may contribute significantly to improve well-being in late life.