American College of Sports Medicine. ACSM’s guidelines for exercise testing and prescription. 10th ed. Indianapolis: Wolters Kluwer; 2017.

Google Scholar 

Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985;100(2):126–31.

CAS  Google Scholar 

Erickson KI, Weinstein AM, Lopez OL. Physical activity, brain plasticity, and Alzheimer’s disease. Arch Med Res. 2012;43(8):615–21. https://doi.org/10.1016/j.arcmed.2012.09.008.

Article  Google Scholar 

Brown BM, Rainey-Smith SR, Dore V, Pfeiffer JJ, Burnham SC, Laws SM, et al. Self-reported physical activity is associated with tau burden measured by positron emission tomography. J Alzheimers Dis. 2018;63(4):1299–305.

Article  CAS  Google Scholar 

Lindsay J, Laurin D, Verreault R, Hébert R, Helliwell B, Hill GB, et al. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol. 2002;156(5):445–53.

Article  Google Scholar 

Okonkwo OC, Schultz SA, Oh JM, Larson J, Edwards D, Cook D, et al. Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology. 2014;83(1753):1760.

Google Scholar 

Kennedy G, Hardman RJ, Macpherson H, Scholey AB, Pipingas A. How does exercise reduce the rate of age-associated cognitive decline? A review of potential mechanisms. J Alzheimers Dis. 2017;55:1–18.

Article  Google Scholar 

Farrer, Lindsay A, Cupples LA, Haines JL, HYman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. JAMA J Am Med Assoc. 1997;278(16):22–9.

Article  Google Scholar 

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of alipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3 www.sciencemag.org.

Article  CAS  Google Scholar 

Flowers SA, Rebeck GW. APOE in the normal brain. Neurobiol Dis. 2020;136(January):104724. https://doi.org/10.1016/j.nbd.2019.104724.

Article  CAS  Google Scholar 

Smith JC, Nielson K a, Woodard JL, Seidenberg M, Rao SM. Physical activity and brain function in older adults at increased risk for Alzheimer’s disease. Brain Sci. 2013;3(1):54–83.

Article  Google Scholar 

de Frutos-Lucas J, Frost N, Erickson KI, Serrano JM, Maestu F, Laws SM, et al. Does APOE genotype moderate the relationship between physical activity, brain health and dementia risk? A systematic review. Ageing Res Rev. 2020;64:101173. https://doi.org/10.1016/j.arr.2020.101173.

Article  CAS  Google Scholar 

Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science (80-). 1992;256:184–5.

Article  CAS  Google Scholar 

Caselli RJ, Hentz JG, Osborne D, Graff-Radford NR, Barbieri CJ, Alexander GE, et al. Apolipoprotein E and intellectual achievement. J Am Geriatr Soc. 2002;50(1):49–54.

Article  Google Scholar 

Huang YR, Liu RT. The toxicity and polymorphism of β-amyloid oligomers. Int J Mol Sci. 2020;21(12):1–19.

Article  Google Scholar 

Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, et al. Apolipoprotein e, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci. 2012;32(43):15181–92.

Article  CAS  Google Scholar 

Moore KM, Girens RE, Larson SK, Jones MR, Restivo JL, Holtzman DM, et al. A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2016;85:218–24. https://doi.org/10.1016/j.nbd.2015.11.004.

Article  CAS  Google Scholar 

Brown BM, Peiffer J, Rainey-Smith SR. Exploring the relationship between physical activity, beta-amyloid and tau: a narrative review. Ageing Res Rev. 2019;50:9–18. https://doi.org/10.1016/j.arr.2019.01.003.

Article  CAS  Google Scholar 

Sofi F, Valecchi D, Bacci D, Abbate R, Gensini GF, Casini A, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med. 2011;269(1):107–17.

Article  CAS  Google Scholar 

Chow VW, Mattson MP, Wong PC, Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med. 2010;12(1):1–12.

Article  CAS  Google Scholar 

Koo JH, Kang EB, Oh YS, Yang DS, Cho JY. Treadmill exercise decreases amyloid-β burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer’s disease. Exp Neurol. 2017;288:142–52. https://doi.org/10.1016/j.expneurol.2016.11.014.

Article  CAS  Google Scholar 

Liu H li, Zhao G, Zhang H, de Shi L. Long-term treadmill exercise inhibits the progression of Alzheimer’s disease-like neuropathology in the hippocampus of APP/PS1 transgenic mice. Behav Brain Res. 2013;256:261–72. https://doi.org/10.1016/j.bbr.2013.08.008.

Article  CAS  Google Scholar 

Zhang J, Guo Y, Wang Y, Song L, Zhang R, Du Y. Long-term treadmill exercise attenuates Aβ burdens and astrocyte activation in APP/PS1 mouse model of Alzheimer’s disease. Neurosci Lett. 2018;666(324):70–7. https://doi.org/10.1016/j.neulet.2017.12.025.

Article  CAS  Google Scholar 

Vasconcelos-Filho FSL, da Rocha Oliveira LC, de Freitas TBC, de Pontes PADS, da Rocha-e-Silva RC, Godinho WDN, et al. Effect of involuntary chronic physical exercise on beta-amyloid protein in experimental models of Alzheimer’s disease: systematic review and meta-analysis. Exp Gerontol. 2021;153(January):111502.

Article  CAS  Google Scholar 

Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15(9):501–18. https://doi.org/10.1038/s41582-019-0228-7.

Article  CAS  Google Scholar 

Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011;3(89):89ra57.

Article  CAS  Google Scholar 

Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, et al. apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J Clin Invest. 2008;118(12):4002–13.

Article  CAS  Google Scholar 

Riphagen JM, Ramakers IHGM, Freeze WM, Pagen LHG, Hanseeuw BJ, Verbeek MM, et al. Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer’s pathology. Neurobiol Aging. 2020;85:96–103.

Article  Google Scholar 

Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, et al. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. 2013;110(19):E1807-16.

Article  CAS  Google Scholar 

Roda AR, Montoliu-Gaya L, Villegas S. The role of apolipoprotein E isoforms in Alzheimer’s disease. J Alzheimers Dis. 2019;68(2):459–71.

Article  Google Scholar 

Jiang Q, Lee CYD, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, et al. ApoE promotes the proteolytic degradation of Aβ. Neuron. 2008;58(5):681–93.

Article  CAS  Google Scholar 

He XF, Liu DX, Zhang Q, Liang FY, Dai GY, Zeng JS, et al. Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice. Front Mol Neurosci. 2017;10:144.

Article  Google Scholar 

Moore KM, Girens RE, Larson SK, Jones MR, Restivo JL, Holtzman DM, et al. A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2016;85:218–24. https://doi.org/10.1016/j.nbd.2015.11.004.

Article  CAS  Google Scholar 

Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-ε4 allele. Am J Pathol. 2003;162(1):313–9. https://doi.org/10.1016/S0002-9440(10)63822-9.

Article  CAS  Google Scholar 

Miners JS, Van Helmond Z, Chalmers K, Wilcock G, Love S, Kehoe PG. Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2006;65(10):1012–21.

Article  CAS  Google Scholar 

Grundke-Iqbal I, Iqbal K, Tung YC. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83:4913–7.

Article  CAS  Google Scholar 

Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019;76(8):915–24.

Article  Google Scholar 

Gratuze M, Julien J, Morin F, Marette A, Planel E. Differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in a mouse model of Alzheimer’s disease-like tau pathology fed with Western diet. Prog Neuro Psychopharmacol Biol Psychiatry. 2017;79(August):452–61. https://doi.org/10.1016/j.pnpbp.2017.08.001.

Article  CAS  Google Scholar 

Baker LD, Bayer-Carter JL, Skinner J, Montine TJ, Cholerton BA, Callaghan M, et al. High-intensity physical activity modulates diet effects on cerebrospinal amyloid-β levels in normal aging and mild cognitive impairment. J Alzheimers Dis. 2012;28(1):137–46.

Article  CAS  Google Scholar 

Quintanilla RA, Orellana DI, González-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res. 2004;295(1):245–57.

Article  CAS  Google Scholar 

Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA. Association of APOE with tau-tangle pathology with and without β-amyloid. Neurobiol Aging. 2016;37:19–25. https://doi.org/10.1016/j.neurobiolaging.2015.09.011.

Article  CAS  Google Scholar 

Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7. https://doi.org/10.1038/nature24016.

Article  CAS  Google Scholar 

Hou TT, Han YD, Cong L, Liu CC, Liang XY, Xue FZ, et al. Apolipoprotein E facilitates amyloid-β oligomer-induced tau phosphorylation. J Alzheimers Dis. 2020;74(2):521–34.

Article  CAS