Alzheimer?s disease (AD) is the most common cause of dementia. Underlying pathological and physiological changes related to the onset and progression of AD are believed to emerge several years prior to clinical manifestations. Gait abnormalities and motor slowing typically precede the diagnosis of AD by a decade or more, presenting the exciting possibility that changes in gait may act as early noninvasive biomarkers for AD. Previous work by our group has identified key markers of impending and/or accelerated gait speed decline based on physiological measures of the energy cost of slow walking, peak energy capacity, and quantities and patterns of objectively measured free-living physical activity (PA), making them potential preclinical markers of early AD pathology. We propose to use 8 years of existing longitudinal data, and ongoing/new data collection in nearly 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examine the roles of altered energy reserves, and reduced and fragmented daily PA as precursors to clinical markers of Alzheimer?s disease and neuronal injury, which include A? deposition using [11C]-Pittsburgh compound B positron emission tomography, brain atrophy using structural magnetic resonance imaging (MRI), and cognitive performance. We will also explore potential vascular mechanisms linking energy reserves and PA to these outcomes, including cerebral blood flow, ankle brachial index, and pulse wave velocity, as well as the role of mediating or modifying factors such as inflammation and the apolipoprotein E genotype. The BLSA is a continuously enrolled cohort study of aging that already contains repeated measures of cognition and adjudication of cognitive status, in which a subset completes repeated MRI and PiB PET scans. Importantly, our preliminary cross-sectional data from the BLSA indicate strong associations among energy reserves, cognitive performance, b-amyloid burden, and diurnal patterns of daily PA. We propose to investigate the longitudinal associations among these variables to identify physiological thresholds of poor energy reserve and reduced and fragmented patterns of diurnal PA as early precursors to the onset and progression of AD pathology. A better understanding of the association between energy reserves/PA, subclinical AD pathology, and cognitive performance may elucidate a physiological threshold of diminished energy reserve that is associated with increased risk of poor cognitive outcomes over time, and increase our understanding of the complex association between declines in physical and cognitive functioning with age. Moreover, uncovering patterns of daily free-living PA most commonly associated with this threshold will help define a phenotype of reduced and/or fragmented PA that signifies impending emergence and progression of AD. Given the proliferation of wearable devices to monitor PA in the consumer and research markets, identifying changes in PA consistent with the development of AD pathology could provide evidence for future wide-scale screening for early detection of persons at high risk of AD.
Disorders of movement and cognition often coexist in older adults, with recent evidence indicating slowed gait may precede the onset of Mild Cognitive Impairment by 10-15 years. Previous work by our group has identified key markers of impending and/or accelerated gait speed decline based on the energy cost of slow walking, peak energy capacity, and measures of free-living physical activity, but their ability to predict changes in brain and cognitive health are unknown. In the proposed research, we will examine the associations among markers of energy reserves, objectively measured physical activity (PA), and measures of brain and cognitive health (e.g., b-amyloid, atrophy, cognitive decline) to evaluate whether poor energy reserves and reduced and fragmented patterns of daily PA may be markers of the onset and progression of Alzheimer?s Disease (AD) pathology that might be targeted by interventions to prevent or slow AD progression.
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