The Relationship Between Fitness and Structural Brain Integrity in Midlife: Implications for Biomarker Development and Aging Interventions

Abstract

An aging global population and accompanying increases in the prevalence of age-related disorders are leading to greater financial, social, and health burdens. Alzheimer’s disease and related dementias are one such category of age-related disorders that are associated with progressive loss of physical and cognitive ability. One proposed preventative measure against risk for such dementias is improving cardiovascular fitness, which may help reverse or buffer age-related brain atrophy associated with worse aging-related outcomes and cognitive decline. However, research into this potential of cardiovascular fitness has suffered from extreme heterogeneity in study design methodology leading to a lack of cohesion in the field and undermining any potential causal evidence that may exist. In addition, while direct measures of cardiovascular fitness (e.g., VO2Max) and healthy lifestyle behaviors typically associated with better cardiovascular fitness (e.g., exercise, diet, smoking status) are not necessarily highly correlated, they are often conflated in existing research. This has contributed to a lack of clarity in generalizing and comparing results. This dissertation presents results from four original research projects addressing open empirical questions about possible links between cardiovascular fitness, healthy lifestyle behaviors, and structural brain integrity in midlife, which has become a target of intervention research seeking to stave off cognitive decline and risk for dementia before irreversible damage has accrued. Each section of the dissertation builds on increasingly complex aspects of these links with the goal of providing supporting evidence that may aid future biomarker research and clinical trials design. All studies involved were conducted using behavioral data, physiological data, and structural MRI data from the Dunedin Study, which has followed a population-representative birth cohort to midlife.Across four empirical sections, results collectively suggest that there is a modest association between cardiovascular fitness and both grey and white matter structural integrity as well as between healthy lifestyle behaviors and grey matter structural integrity. Further, results indicate that these associations may extend beyond cross-sectional data and have relevance for measures capturing the extent of age-related atrophy in the brain. In addition, the results reinforce prior findings that cardiovascular fitness and healthy lifestyle behaviors are independent constructs and suggest that the differentially mapping of these constructs onto specific features of brain integrity in midlife may be useful in directing the search for risk biomarkers and designing clinical trials.