Age-associated cognitive decline and its associated illnesses are growing public health concerns with no known cure, and represent a substantial threat to the health, functional independence and well-being of older Australians. These declines, in conjunction with other age-related health conditions can subsequently impair functional performance, which can collectively reduce quality of life (QoL). The underlying mechanism(s) which contribute to cognitive decline are multifaceted but may include low-grade systemic inflammation, which is associated with poorer cognitive performance, age-associated cognitive decline, and neurodegenerative disease. Similarly, an increased concentration of neurotrophic factors, centrally or in circulation, may provide resistance to functional and structural neurodegeneration of the brain. At present there is mixed data regarding whether higher levels of neurological markers and lower concentrations of inflammatory markers are associated with better cognitive function in healthy older adults, while data regarding the associations of these markers with HR-QoL or well-being is lacking.

There is some evidence to suggest that exercise has neuroprotective effects, while emerging research has shown that the simultaneous performance of exercise and cognitive and/or motor training (dual-task exercise) can provide cognitive benefits for both healthy and cognitively impaired older adults. Furthermore, functional exercise and power training can both produce functional advantages for older adults. Many falls in older adults result from insufficient lower limb muscle power to step quickly when balance is lost, while age-related cognitive deficits, particularly in the ability to concentrate and multi-task, also increase falls risk. Given these factors, a dual-task functional power training program may be effective for improving cognitive function and functionality, yet the effects of such a program are currently untested. Similarly, the potential benefits of this type of training on HR-QoL or well-being are unknown. The mechanism(s) underpinning the improvements in cognition following dual-task exercise training that have been previously observed are currently unclear, but may relate to the induction of neurological growth factors and/or the attenuation of lowgrade systemic inflammation. Despite this, the response of these markers to long-term exercise training in older adults has been inconsistently reported. Furthermore, limited evidence suggests that the response of neurological markers to exercise may be regulated by genetic factors, such as the possession of the Met allele of the BDNF gene, and the ε4 variant of the APOE gene, which may impair elderly cognition.

Therefore, an initial aim of this thesis was to identify the associations between various inflammatory and neurological markers and their composite scores with cognitive function, well-being and HR-QoL in older adults residing independently in retirement villages. Given the clinical relevance of muscle power and dual tasking to ‘real life’ situations, the main aims of this 26-week cluster randomised controlled trial were to evaluate the efficacy of dual-task functional power training (DT-FPT) on cognition, health-related quality of life (HR-QoL) and well-being in independently living older adults at risk of falls (Chapters 5-6). In addition, this thesis aimed to determine whether DT-FPT induced improvements in neurological and inflammatory concentrations (Chapter 7). Secondary aims were to determine if the response of any of these variables to DT-FPT differed by sex or genotype.

Twenty-two independent living retirement villages with 300 residents aged >65 years at risk of falling, were randomised to DT-FPT involving high-velocity functional exercises (45-60 minutes, twice per week) performed simultaneously with cognitive and/or motor tasks, or a usual care control (CON) group. Overall 233 (78%) participants completed the study;​ with exercise compliance averaging 50%. At baseline and 26 weeks, cognitive function was assessed via a computerised test battery, while questionnaires were used to assess HR-QoL, well-being, habitual physical activity, health and medical history. Blood samples were collected, and body composition, muscle strength, power and function were also measured.

An assessment of blood data at baseline found that higher levels of circulating BDNF were associated with greater performance in psychomotor function, attention, working-memory and global cognitive function while an inverse relationship between IGF-1 and visual memory and attention was detected. Higher levels of CRP and the pro-inflammatory composite score were associated with lower perceptions of the HRQoL domain of vitality. Polymorphisms of the APOE gene showed differential relationships in the associations between Aβ (1-42) and executive function, and inflammation and working memory. However, the majority of circulating inflammatory and neurological markers were not associated with cognitive function, HR-QoL or well-being.

After 26 weeks, DT-FPT resulted in greater improvements in lower limb muscle power (P<0.001), mobility (P<0.05) and stepping reaction time (P<0.05) than CON, with no differences in dual-task functional performance. For cognition, there was a significant net 0.18-0.20 SD benefit in reaction time/attention (P<0.05) and a composite of psychomotor ability/attention (P<0.05) in DT-FPT versus CON, but no effects on executive function, memory or global cognition. In terms of HR-QoL, DT-FPT only improved the role physical domain, however per protocol analyses detected a significant net benefit in social functioning, the physical component summary score and global HR-QoL. DT-FPT had no effect on circulating levels of pro- or antiinflammatory markers, or neurological markers. The response of cognition, HR-QoL, well-being or blood markers to the intervention was no different between older men and women, with the exception that older men in the training program reported greater net decreases in the domain of general health, and well-being, compared to the control group. Similarly, the response of these variables to DT-FPT was not influenced by genotype.

In conclusion, these findings indicate that DT-FPT provides some cognitive benefits to healthy older adults which may delay an onset of cognitive decline, while also improving functional capacity. Collectively these improvements may maintain an older adult’s ability to perform everyday activities which can prolong functional independence. However, 26 weeks of DT-FPT only provided limited benefits to HRQoL, and did not improve circulating levels of biomarkers. Further research is required to determine the underlying mechanisms of cognitive improvement following dualtask exercise.