Life expectancy is projected to rise over the coming decades for most industrialized countries [1]. The proportion of world’s older population should increase from 12–22% between 2015 and 2020 [2]. Despite the increase in longevity, the number of years spent in good physical health (e.g., no mobility, functional, and/or cognitive impairments) has remained unchanged over the past few years in Canada [3]. There is a growing number of older individuals with age-related normative cognitive decline as well as Alzheimer’s disease and related dementias (ADRD). Recent estimates suggest that worldwide ~ 50 million people currently have dementia and by 2030 this is predicted to increase to ~ 82 million [4]. In Canada ~ 500,000 older adults are now living with dementia [5]. Almost 40% of Canadians over the age of 65 have some degree of cognitive impairment [5]. Their direct cost care was estimated to be $10.4 billion CDN dollars in 2019 and are projected to climb to $16.6 billion CDN by 2031 [5]. The personal costs of dementia and these alarming public health estimates are motivating efforts to identify lifestyle interventions that can slow the progression of ADRD. In addition to focusing on treatment, studies have been targeting prevention of neurodegenerative diseases with the aim of mitigating, delaying or preventing the onset of ADRD [6–10].
Exercise is a promising method to reduce the of dementia in both healthy older adults and those at elevated risk of ADRD due to cardiovascular risk factors [11]. The physiological benefits of exercise in older adults are clear in the research literature and include improved arterial compliance (i.e., ability of a vessel to expand as needed), endothelial function, energy metabolism, sleep quality, and muscle mass/strength [12]. Exercise also promotes cardiovascular fitness by improving global vascular health, including increases in middle cerebral artery vasodilation responses and cerebral blood flow (CBF) [13]. These brain adaptations could play an important role in delaying the onset of ADRD as greater CBF may prevent and/or reduce the accumulation of amyloid β in the brain, which is one of the main pathological hallmarks of AD [14]. Additionally, improved cerebral hemodynamics may help prevent or slow other conditions that act as risk factors for cognitive decline and ADRD, such as cardiovascular disease (CVD) and diabetes [15]. Although steady state CBF normally declines with post-maturation aging, chronic diseases like CVD, hypertension, and diabetes can accelerate age-related CBF alterations and lead to disruption of neuronal homeostasis [16, 17].
Existing scientific literature suggests that high levels of physical activity can positively impact cognitive function in middle-aged (50–64 years) and older (> 65 years) individuals [18–24]. Sofi and colleagues (2011) examined 15 prospective cohort studies that collectively followed more than 30,000 healthy older adults over 1–12 years. Individuals who were more physically active before the follow-up period had a 38% reduced risk of cognitive decline compared to those with a sedentary lifestyle at baseline [22]. Cross-sectional studies have found an association between higher levels of physical activity in older adults with both better performance on specific cognitive tasks [23, 25] and reduced risk of cognitive decline [24].
Evidence from neuroimaging studies also supports the positive effects of exercise on brain health. Exercise has been shown to reduce age-related atrophy in grey and white matter [26], decrease both brain [27] and hippocampal atrophy [28], and increase white matter integrity [29, 30]. Animal models suggest neural changes in response to exercise may be partially mediated by enhanced levels of brain-derived neurotrophic factor (BDNF) and insulin like-growth factor (IGF-1) in the hippocampus [31]. BDNF improves overall neural health by increasing brain vascularization, neurogenesis, and synaptic efficiency in the hippocampus [31]. As BDNF plays a role in memory formation, enhanced levels of BDNF in the brain may help prevent memory loss and cognitive decline with aging [31].
The literature on the associations between exercise, cognition, and brain health in older individuals is primarily comprised of epidemiological and observational studies [22–24, 29, 30]. These study designs only allow passive observation of events and are prone to selection, information, and confounding bias compared to RCTs, and cannot be used to determine causality. The few RCTs investigating the relationship between exercise, cognition, and brain health, have found, however, contradictory results [12, 32–34]. Possible explanations for the conflicting literature include sub-optimal study design and methods, such as small sample sizes, short exercise interventions, and inadequate tracking of participant adherence to prescribed exercise routines [8, 32, 35]. The methodological limitations of previous studies support the need for new well-designed RCTs to investigate the association between exercise and cognitive function in older adults [21].
Most prior RCTs of the effects of exercise did not include older participants at greater risk for ADRD due to CVD and/or genetic risk factors. Both CVD and ADRD share a number of risk factors (i.e., age, obesity, physical inactivity, smoking, elevated blood pressure, and high cholesterol) [36]. Older individuals with CVD risk factors may benefit more from exercise interventions in terms of their brain health and/or cognitive performance. People who have a family history of ADRD might also gain more from exercise programs due to their genetic susceptibility from, for example, carrying the apolipoprotein E (APOE) e4 allele. Individuals with at least one APOE e4 allele copy are at greater risk of developing AD [37].
Given the estimates of the burden of ADRD and the promising evidence of the benefits of exercise on cognitive health, we propose a RCT of aerobic exercise for individuals at increased risk of ADRD. This RCT will test the efficacy of a 6-month aerobic exercise intervention for primary and secondary prevention of ADRD in older adults (50–80 years old). We will measure cognitive and cerebrovascular outcomes, including vascular reactivity, vascular biomarkers, and changes in brain structure and function using magnetic resonance imaging (MRI). A unique feature of this study is the inclusion of assessments linking vascular risk factors, neuroimaging markers, sleep, genetic risk, and cognitive health outcomes. The first aim of this study is to determine the independent effect of aerobic exercise on cognitive performance. We hypothesize that participants randomized to the 6-month aerobic exercise intervention will perform better on cognitive tests following training compared to participants allocated to a stretching-toning exercise intervention (control group). The second specific aim is to determine which cerebrovascular/physiological, genetic, neuroimaging, sleep, cognitive, and/or other psychological factors potentially mediate the relationship among exercise, cognition, and brain health. It is hypothesized that exercise will improve cognition due to changes at molecular/cellular (biomarkers), vascular (CBF), anatomical and functional (neuroimaging), and behavioural (sleep quality and other psychological factors) levels. Additionally, we hypothesize that genetic risk factors (e.g., presence of the APOE e4 allele) will moderate exercise-related cognitive outcomes. Finally, the last aim is to examine whether exercise-related changes persist 1 year after completion of the exercise intervention and if a telephone behavioural support intervention leads to improved maintenance of the exercise-related benefits. We hypothesize that the effects of improved aerobic fitness and brain health (e.g., increase in resting CBF) due to aerobic exercise will be, at least partially, maintained over the 1-year after completion of an exercise intervention. We also expect that the telephone behavioural support intervention will lead to persistent lifestyle changes and greater retention of any benefits that arise. To test these hypotheses, the participants will be randomly allocated into one of four treatment arms: (1) aerobic exercise and health behaviour support, (2) aerobic exercise and no health behaviour support, (3) stretching-toning and health behaviour support, and (4) stretching-toning and no health behaviour support.