Physical activity, apolipoprotein-ɛ4 and cognition among cognitively healthy older adults: a longitudinal study

Introduction: Alzheimer’s disease (AD) is fast becoming a public health priority. In the absence of effective drug treatment, the focus has shifted towards lifestyle change for prevention. Physical activity (PA) engagement is consistently associated with preserved cognition and lower risk of cognitive decline among older adults. Whether PA mitigates enhanced risk for dementia via APOEɛ4 allele carriage, demographic and/or biomarker risk factors is less understood. This thesis aimed to evaluate the longitudinal relationship between PA and cognition among cognitively healthy older adults, alongside the role of other demographic, genetic and peripheral biomarkers. Methods: Data of 901 cognitively healthy older adults (60-85 years; mean age = 68.7 ± 3.9) collected as part of a prospective observational cohort study, CHARIOT: PRO, were utilised. The mean follow-up period was 18.5 months (SD 1.7), ranging from baseline to 30-months. Mixed-models regression methods were used to analyse the associations between PA and cognition over time, including effect modification by APOEɛ4 carrier status, age, and sex. Moderation and mediation by peripheral amyloid-beta and brain-derived-neurotrophic-factor (BDNF) were explored. All analyses were controlled for a priori selected health and demographic factors. Results: Being physically active was positively associated with longitudinal cognitive performance, with the largest effect sizes among those reporting high PA in both mid- and late-life. The positive association between late-life PA and delayed memory trajectories were augmented among APOEɛ4 carriers, when compared to non-carriers. Conversely, APOEɛ4 stratified analysis found associations to be consistently augmented among APOEɛ4 non-carriers for remaining domains. Age and sex did not significantly modify the association between PA and cognition. BDNF was not associated with PA or cognition, nor modified by APOEɛ4 carrier status. There was an inverse association between amyloid-beta plasma levels and global cognition and attention index scores, which were modified by late-life PA, especially among APOEɛ4 non-carriers. Conclusion: This thesis highlights the benefits of PA in mitigating cognitive decline in older age, especially among certain risk groups. Elucidating the complex interrelations between modifiable and non-modifiable risk factors for AD will aid in promoting lifestyle intervention as a viable preventative strategy for public health recommendations.Open Acces