Alzheimers Dement (N Y)
Alzheimers Dement (N Y) 2022 Jun 29; 8(1):e12308
AG054345, HD007065, AG054345, AG038070
Introduction: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease and related dementias (ADRDs), affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and APOE ε4 affect similar processes in the body and brain. While both APOE ε4 and exercise have been studied extensively, their interactive effects are not well understood.
Methods: To address this, male and female APOE ε3/ε3, APOE ε3/ε4, and APOE ε4/ε4 mice ran voluntarily from wean (1 month) to midlife (12 months). Longitudinal and cross-sectional phenotyping were performed on the periphery and the brain, assessing markers of risk for dementia such as weight, body composition, circulating cholesterol composition, murine daily activities, energy expenditure, and cortical and hippocampal transcriptional profiling.
Results: Data revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum low-density lipoprotein concentration dependent on APOE genotype. Additionally, murine daily activities and energy expenditure were significantly influenced by an interaction between APOE genotype and running in both sexes. Transcriptional profiling of the cortex and hippocampus predicted that APOE genotype and running interact to affect numerous biological processes including vascular integrity, synaptic/neuronal health, cell motility, and mitochondrial metabolism, in a sex-specific manner.
Discussion: These data in humanized mouse models provide compelling evidence that APOE genotype should be considered for population-based strategies that incorporate exercise to prevent ADRDs and other APOE-relevant diseases.
Foley, Kate E; Diemler, Cory A; Hewes, Amanda A; Garceau, Dylan; Sasner, Michael; and Howell, Gareth R, "APOE ε4 and exercise interact in a sex-specific manner to modulate dementia risk factors" (2022). Faculty Research 2022. 150.
Research reported in this publication was partially supported by The Jackson Laboratory’s Genetic Engineering Technologies Scientific Service. The authors wish to thank Todd Hoffert from Clinical Assessment Services for blood chemistry, HeidiMunger and the Genome Technologies group for RNA sequencing. We would also like to thank Dr. Gregory Carter and Dr. Christoph Pruess for their continued advice on computational analysis and support for these projects.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License.