Longitudinal Associations Between Self-reported Exercise Levels And Alzheimers Related Biomarkers In Autosomal Dominant Alzheimer’S Disease

PURPOSE: Exercise may delay or prevent the onset of Alzheimer’s disease (AD). To our knowledge, no study has investigated the longitudinal impact of exercise on AD-related biomarkers in individuals with Autosomal dominant Alzheimer’s disease (ADAD) mutations who are destined to develop AD. This study examined longitudinal associations between self-reported exercise levels and AD-related biomarkers in a cohort of ADAD mutation carriers and investigated whether observed associations depended upon disease stage. METHODS: This prospective cohort study included participants from the Dominantly Inherited Alzheimer’s Network (DIAN). Participants were n = 308 ADAD mutation carriers aged 39.7 ± 10.8 years (56.5% female) with data available for self-reported exercise participation and either brain imaging (hippocampal volume, total volume, gray matter volume, white matter hyperintensities, brain Aβ), or biomarkers quantified from cerebrospinal fluid (Aβ40, Aβ42, p-tau, t-tau, p-tau/Aβ42, and Aβ42/40). Participants reported their average time partaking in various leisure-time exercise activities (e.g., walking, running, cycling etc.) over the past 12-months to yield a measure of exercise minutes per week. Associations between exercise and AD biomarkers (i.e., from brain imaging and CSF) were examined using linear mixed models. RESULTS: Greater weekly baseline exercise was associated with slower accumulation of brain Aβ at preclinical disease stages (β = -0.16, 95% CI -0.23 - -0.08), and slower decline of right and left hippocampal volume (β = 0.06, 95% CI 0.03-0.08; β = 0.06, 95% CI 0.02-0.09, respectively), total cortical volume (β = 0.03, 95% CI 0.01-0.05), total subcortical gray matter volume (β = 0.03, 95% CI 0.01-0.05), and total gray matter volume (β = 0.03, 95% CI 0.01-0.05), effects which became significant approximately 5 years before predicted cognitive symptom onset. CONCLUSIONS: These findings demonstrate that exercise is associated with more favourable profiles of AD-related biomarkers in those with ADAD mutations. The causal direction of this research is difficult to ascertain, thus future study designs investigating the therapeutic potential of exercise in both ADAD and late-onset AD should be considered before clinical recommendation of exercise is implemented. Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA), the Alzheimer's Association (SG-20-690363-DIAN, AARFD-21-851415), the German Center for Neurodegenerative Diseases (DZNE).