Association of Physical Inactivity with MRI Markers of Brain Aging: Assessing Mediation by Cardiometabolic and Epigenetic Factors

Article type: Research Article

Authors: Spartano, Nicole L.^{a; b; *} | Wang, Ruiqi^c | Yang, Qiong^c | Chernofsky, Ariel^c | Murabito, Joanne M.^{b; d} | Levy, Daniel^{b; e} | Vasan, Ramachandran S.^{b; f; g; h} | DeCarli, Charlesⁱ | Maillard, Paulineⁱ | Seshadri, Sudha^{b; j; k; l; 1} | Beiser, Alexa S.^{b; c; j; 1}

Affiliations: [a] Section of Endocrinology, Diabetes, Nutrition, and Weight Management, Boston University Chobanian & Avedisian School of Medicine (BUCASM), Boston, MA, USA | [b] National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study, Framingham, MA, USA | [c] Department of Biostatistics, Boston University School of Public Health (BUSPH), Boston, MA, USA | [d] Section of General Internal Medicine, Department of Medicine, BUCASM, Boston, MA, USA | [e] Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA | [f] Section of Preventive Medicine and Epidemiology, Evans Department of Medicine, BUSM, Boston, MA, USA | [g] Department of Epidemiology, BUSPH, Boston, MA, USA | [h] UT School of Public Health in San Antonio, TX, and UT Health Sciences Center in San Antonio, TX, USA | [i] Department of Neurology University of California Davis, Davis, CA, USA | [j] Department of Neurology, BUSM, Boston, MA, USA | [k] Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, USA | [l] Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA

Correspondence: [*] Correspondence to: Nicole Spartano, PhD, Boston University Chobanian & Avedisian School of Medicine, Section of Endocrinology, Diabetes, Nutrition & Weight Management, 72 East Concord St, Suite Collamore 301, Boston, MA 02118, USA. Tel.: +1 315 415 2040; E-mail: spartano@bu.edu.

Note: [1] Shared Senior Authorship

Abstract: Introduction:Cardiometabolic risk factors and epigenetic patterns, increased in physically inactive individuals, are associated with an accelerated brain aging process. Objective:To determine whether cardiometabolic risk factors and epigenetic patterns mediate the association of physical inactivity with unfavorable brain morphology. Methods:We included dementia and stroke free participants from the Framingham Heart Study Third Generation and Offspring cohorts who had accelerometery and brain MRI data (n = 2,507, 53.9% women, mean age 53.9 years). We examined mediation by the 2017-revised Framingham Stroke Risk Profile (FSRP, using weights for age, cardiovascular disease, atrial fibrillation, diabetes and smoking status, antihypertension medications, and systolic blood pressure) and the homeostatic model of insulin resistance (HOMA-IR) in models of the association of physical inactivity with brain aging, adjusting for age, age-squared, sex, accelerometer wear time, cohort, time from exam-to-MRI, and season. We similarly assessed mediation by an epigenetic age-prediction algorithm, GrimAge, in a smaller sample of participants who had DNA methylation data (n = 1,418). Results:FSRP and HOMA-IR explained 8.3–20.5% of associations of higher moderate-to-vigorous physical activity (MVPA), higher steps, and lower sedentary time with higher brain volume. Additionally, FSRP and GrimAge explained 10.3–22.0% of associations of physical inactivity with lower white matter diffusivity and FSRP explained 19.7% of the association of MVPA with lower free water accumulation. Conclusion:Our results suggest that cardiometabolic risk factors and epigenetic patterns partially mediate the associations of physical inactivity with lower brain volume, higher white matter diffusivity, and aggregation of free water in the extracellular compartments of the brain.

Keywords: Alzheimer’s disease, dementia, exercise, physical activity, sedentary time

DOI: 10.3233/JAD-230289

Journal: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 561-572, 2023