Abstract
Maintaining good health is crucial, and exercise plays a vital role in achieving this goal. It offers a range of positive benefits for cognitive function, regardless of age. However, as our population ages and life expectancy increases, cognitive impairment has become a prevalent issue, often coexisting with age-related neurodegenerative conditions. This can result in devastating consequences such as memory loss, difficulty speaking, and confusion, greatly hindering one’s ability to lead an ordinary life. In addition, the decrease in mental capacity has a significant effect on an individual’s physical and emotional well-being, greatly reducing their overall level of contentment and causing a significant financial burden for communities. While most current approaches aim to slow the decline of cognition, exercise offers a non-pharmacological, safe, and accessible solution. Its effects on cognition are intricate and involve changes in the brain’s neural plasticity, mitochondrial stability, and energy metabolism. Moreover, exercise triggers the release of cytokines, playing a significant role in the body–brain connection and its impact on cognition. Additionally, exercise can influence gene expression through epigenetic mechanisms, leading to lasting improvements in brain function and behavior. Herein, we summarized various genetic and epigenetic mechanisms that can be modulated by exercise in cognitive dysfunction.
Similar content being viewed by others
Data Availability
Not applicable.
References
Fisher GG, Chacon M, Chaffee DS (2019) Theories of cognitive aging and work. Work across the lifespan. Elsevier, pp. 17–45
Salthouse TA (1996) The processing-speed theory of adult age differences in cognition. Psychol Rev 103(3):403–428
van Hooren SA, Valentijn AM, Bosma H, Ponds RW, van Boxtel MP, Jolles J (2007) Cognitive functioning in healthy older adults aged 64-81: a cohort study into the effects of age, sex, and education. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 14(1):40–54
Orgeta V, Mukadam N, Sommerlad A, Livingston G (2019) The Lancet Commission on Dementia Prevention, Intervention, and Care: a call for action. Ir J Psychol Med 36(2):85–88
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D et al (2017) Dementia prevention, intervention, and care. Lancet 390(10113):2673–2734
Frankish H, Horton R (2017) Prevention and management of dementia: a priority for public health. Lancet 390(10113):2614–2615
Rao C, Bundhamcharoen K, Kelly M, Tangcharoensathien V (2021) Mortality estimates for WHO SEAR countries: problems and prospects. BMJ Glob Health 6(11). https://doi.org/10.1136/bmjgh-2021-007177
Committee on the Public Health Dimensions of Cognitive A, Board on Health Sciences P, Institute of M. The National Academies Collection: reports funded by National Institutes of Health. In: Blazer DG, Yaffe K, Liverman CT, editors. Cognitive Aging: Progress in Understanding and Opportunities for Action. Washington (DC): National Academies Press (US) Copyright 2015 by the National Academy of Sciences. All rights reserved.; 2015.
Yang R, Wang H, Edelman LS, Tracy EL, Demiris G, Sward KA et al (2020) Loneliness as a mediator of the impact of social isolation on cognitive functioning of Chinese older adults. Age Ageing 49(4):599–604
Falck RS, Landry GJ, Best JR, Davis JC, Chiu BK, Liu-Ambrose T (2017) Cross-sectional relationships of physical activity and sedentary behavior with cognitive function in older adults with probable mild cognitive impairment. Phys Ther 97(10):975–984
Kooistra M, Boss HM, van der Graaf Y, Kappelle LJ, Biessels GJ, Geerlings MI (2014) Physical activity, structural brain changes and cognitive decline. The SMART-MR study. Atherosclerosis 234(1):47–53
Makizako H, Liu-Ambrose T, Shimada H, Doi T, Park H, Tsutsumimoto K et al (2015) Moderate-intensity physical activity, hippocampal volume, and memory in older adults with mild cognitive impairment. J Gerontol A Biol Sci Med Sci 70(4):480–486
O'Sullivan M, Jones DK, Summers PE, Morris RG, Williams SC, Markus HS (2001) Evidence for cortical “disconnection” as a mechanism of age-related cognitive decline. Neurology 57(4):632–638
Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A et al (2005) Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 15(11):1676–1689
Voss MW, Vivar C, Kramer AF, van Praag H (2013) Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci 17(10):525–544
Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25(6):295–301
Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L et al (2011) Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A 108(7):3017–3022
Gomez-Pinilla F, Hillman C (2013) The influence of exercise on cognitive abilities. Compr Physiol 3(1):403–428
Lista I, Sorrentino G (2010) Biological mechanisms of physical activity in preventing cognitive decline. Cell Mol Neurobiol 30(4):493–503
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 96(23):13427–13431
Cassilhas RC, Viana VA, Grassmann V, Santos RT, Santos RF, Tufik S et al (2007) The impact of resistance exercise on the cognitive function of the elderly. Med Sci Sports Exerc 39(8):1401–1407
Colcombe SJ, Kramer AF, McAuley E, Erickson KI, Scalf P (2004) Neurocognitive aging and cardiovascular fitness: recent findings and future directions. J Mol Neurosci 24(1):9–14
Heyn PC, Johnson KE, Kramer AF (2008) Endurance and strength training outcomes on cognitively impaired and cognitively intact older adults: a meta-analysis. J Nutr Health Aging 12(6):401–409
Yaffe K, Fiocco AJ, Lindquist K, Vittinghoff E, Simonsick EM, Newman AB et al (2009) Predictors of maintaining cognitive function in older adults: the Health ABC study. Neurology 72(23):2029–2035
Sibley BA, Etnier JL (2003) The relationship between physical activity and cognition in children: a meta-analysis. Pediatr Exerc Sci 15(3):243–256
Ludyga S, Gerber M, Brand S, Holsboer-Trachsler E, Pühse U (2016) Acute effects of moderate aerobic exercise on specific aspects of executive function in different age and fitness groups: a meta-analysis. Psychophysiology 53(11):1611–1626
Siette J, Reichelt AC, Westbrook RF (2014) A bout of voluntary running enhances context conditioned fear, its extinction, and its reconsolidation. Learn Mem 21(2):73–81
Fernandes J, Soares JC, do Amaral Baliego LG, Arida RM (2016) A single bout of resistance exercise improves memory consolidation and increases the expression of synaptic proteins in the hippocampus. Hippocampus 26(8):1096–1103
Kvam S, Kleppe CL, Nordhus IH, Hovland A (2016) Exercise as a treatment for depression: a meta-analysis. J Affect Disord 202:67–86
Rethorst CD, Trivedi MH (2013) Evidence-based recommendations for the prescription of exercise for major depressive disorder. J Psychiatr Pract 19(3):204–212
Chin LM, Keyser RE, Dsurney J, Chan L (2015) Improved cognitive performance following aerobic exercise training in people with traumatic brain injury. Arch Phys Med Rehabil 96(4):754–759
de Almeida AA, Gomes da Silva S, Lopim GM, Vannucci Campos D, Fernandes J, Cabral FR et al (2017) Resistance exercise reduces seizure occurrence, attenuates memory deficits and restores BDNF signaling in rats with chronic epilepsy. Neurochem Res 42(4):1230–1239
Grealy MA, Johnson DA, Rushton SK (1999) Improving cognitive function after brain injury: the use of exercise and virtual reality. Arch Phys Med Rehabil 80(6):661–667
Intlekofer KA, Cotman CW (2013) Exercise counteracts declining hippocampal function in aging and Alzheimer’s disease. Neurobiol Dis 57:47–55
Jayakody K, Gunadasa S, Hosker C (2014) Exercise for anxiety disorders: systematic review. Br J Sports Med 48(3):187–196
Matura S, Carvalho AF, Alves GS, Pantel J (2016) Physical exercise for the treatment of neuropsychiatric disturbances in Alzheimer’s dementia: possible mechanisms, current evidence and future directions. Curr Alzheimer Res 13(10):1112–1123
Peixinho-Pena LF, Fernandes J, de Almeida AA, Novaes Gomes FG, Cassilhas R, Venancio DP et al (2012) A strength exercise program in rats with epilepsy is protective against seizures. Epilepsy Behav 25(3):323–328
Reynolds GO, Otto MW, Ellis TD, Cronin-Golomb A (2016) The therapeutic potential of exercise to improve mood, cognition, and sleep in Parkinson’s disease. Mov Disord 31(1):23–38
Shu HF, Yang T, Yu SX, Huang HD, Jiang LL, Gu JW et al (2014) Aerobic exercise for Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials. PLoS One 9(7):e100503
Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss HO (2005) Exercise treatment for depression: efficacy and dose response. Am J Prev Med 28(1):1–8
Blumenthal JA, Babyak MA, Moore KA, Craighead WE, Herman S, Khatri P et al (1999) Effects of exercise training on older patients with major depression. Arch Intern Med 159(19):2349–2356
van Praag H (2008) Neurogenesis and exercise: past and future directions. Neuromolecular Med 10(2):128–140
van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2(3):266–270
Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30(9):464–472
Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20(10):2580–2590
Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM et al (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12(16):2499–2509
Boppart MD, Asp S, Wojtaszewski JF, Fielding RA, Mohr T, Goodyear LJ (2000) Marathon running transiently increases c-Jun NH2-terminal kinase and p38 activities in human skeletal muscle. J Physiol 526(Pt 3):663–669
Yu M, Blomstrand E, Chibalin AV, Krook A, Zierath JR (2001) Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle. J Physiol 536(Pt 1):273–282
Aronson D, Boppart MD, Dufresne SD, Fielding RA, Goodyear LJ (1998) Exercise stimulates c-Jun NH2 kinase activity and c-Jun transcriptional activity in human skeletal muscle. Biochem Biophys Res Commun 251(1):106–110
Widegren U, Wretman C, Lionikas A, Hedin G, Henriksson J (2000) Influence of exercise intensity on ERK/MAP kinase signalling in human skeletal muscle. Pflugers Arch 441(2-3):317–322
Murgia M, Serrano AL, Calabria E, Pallafacchina G, Lomo T, Schiaffino S (2000) Ras is involved in nerve-activity-dependent regulation of muscle genes. Nat Cell Biol 2(3):142–147
Higginson J, Wackerhage H, Woods N, Schjerling P, Ratkevicius A, Grunnet N et al (2002) Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture. Pflugers Arch 445(3):437–443
Goncalves RL, Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Brand MD (2015) Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise. J Biol Chem 290(1):209–227
Sakellariou GK, Vasilaki A, Palomero J, Kayani A, Zibrik L, McArdle A et al (2013) Studies of mitochondrial and nonmitochondrial sources implicate nicotinamide adenine dinucleotide phosphate oxidase(s) in the increased skeletal muscle superoxide generation that occurs during contractile activity. Antioxid Redox Signal 18(6):603–621
Gomez-Cabrera MC, Close GL, Kayani A, McArdle A, Viña J, Jackson MJ (2010) Effect of xanthine oxidase-generated extracellular superoxide on skeletal muscle force generation. Am J Physiol Regul Integr Comp Physiol 298(1):R2–R8
Ameziane-El-Hassani R, Schlumberger M, Dupuy C (2016) NADPH oxidases: new actors in thyroid cancer? Nat Rev Endocrinol 12(8):485–494
Henríquez-Olguín C, Boronat S, Cabello-Verrugio C, Jaimovich E, Hidalgo E, Jensen TE (2019) The emerging roles of nicotinamide adenine dinucleotide phosphate oxidase 2 in skeletal muscle redox signaling and metabolism. Antioxid Redox Signal 31(18):1371–1410
Ji LL, Gomez-Cabrera MC, Steinhafel N, Vina J (2004) Acute exercise activates nuclear factor (NF)-kappaB signaling pathway in rat skeletal muscle. FASEB J 18(13):1499–1506
Merry TL, Ristow M (2016) Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. J Physiol 594(18):5195–5207
Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M et al (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106(21):8665–8670
Vasilaki A, Mansouri A, Van Remmen H, van der Meulen JH, Larkin L, Richardson AG et al (2006) Free radical generation by skeletal muscle of adult and old mice: effect of contractile activity. Aging Cell 5(2):109–117
McMahon M, Itoh K, Yamamoto M, Hayes JD (2003) Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 278(24):21592–21600
Zhang DD, Hannink M (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23(22):8137–8151
Lukosz M, Jakob S, Büchner N, Zschauer TC, Altschmied J, Haendeler J (2010) Nuclear redox signaling. Antioxid Redox Signal 12(6):713–742
Wright DC, Han DH, Garcia-Roves PM, Geiger PC, Jones TE, Holloszy JO (2007) Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. J Biol Chem 282(1):194–199
Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V et al (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1):115–124
Bouviere J, Fortunato RS, Dupuy C, Werneck-de-Castro JP, Carvalho DP, Louzada RA (2021) Exercise-stimulated ROS sensitive signaling pathways in skeletal muscle. Antioxidants 10(4):537. https://doi.org/10.3390/antiox10040537
Colcombe S, Kramer AF (2003) Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci 14(2):125–130
Colzato LS, Kramer AF, Bherer L (2018) Editorial special topic: enhancing brain and cognition via physical exercise. Springer, pp. 135–136
Hillman CH, Erickson KI, Kramer AF (2008) Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 9(1):58–65
Raichlen DA, Alexander GE (2017) Adaptive capacity: an evolutionary neuroscience model linking exercise, cognition, and brain health. Trends Neurosci 40(7):408–421
Roig M, Nordbrandt S, Geertsen SS, Nielsen JB (2013) The effects of cardiovascular exercise on human memory: a review with meta-analysis. Neurosci Biobehav Rev 37(8):1645–1666
ten Brinke LF, Hsu CL, Best JR, Barha CK, Liu-Ambrose T (2018) Increased aerobic fitness is associated with cortical thickness in older adults with mild vascular cognitive impairment. J Cogn Enhanc 2:157–169
Frith E, Loprinzi PD (2018) Physical activity and individual cognitive function parameters: Unique exercise-induced mechanisms. JCBPR 7:92–106
Cheval B, Daou M, Cabral DA, Bacelar MF, Parma JO, Forestier C et al (2020) Higher inhibitory control is required to escape the innate attraction to effort minimization. Psychol Sport Exerc 51:101781
Cheval B, Rebar AL, Miller MW, Sieber S, Orsholits D, Baranyi G et al (2019) Cognitive resources moderate the adverse impact of poor perceived neighborhood conditions on self-reported physical activity of older adults. Prev Med 126:105741
Choi KW, Chen CY, Stein MB, Klimentidis YC, Wang MJ, Koenen KC et al (2019) Assessment of bidirectional relationships between physical activity and depression among adults: a 2-sample Mendelian randomization study. JAMA Psychiatry 76(4):399–408
Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22(3):123–131
Yamada K, Nabeshima T (2003) Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 91(4):267–270
Lindsay RM, Wiegand SJ, Altar CA, DiStefano PS (1994) Neurotrophic factors: from molecule to man. Trends Neurosci 17(5):182–190
Groot C, Hooghiemstra AM, Raijmakers PG, van Berckel BN, Scheltens P, Scherder EJ et al (2016) The effect of physical activity on cognitive function in patients with dementia: a meta-analysis of randomized control trials. Ageing Res Rev 25:13–23
Gomez-Pinilla F, Vaynman S, Ying Z (2008) Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition. Eur J Neurosci 28(11):2278–2287
Vilela TC, Muller AP, Damiani AP, Macan TP, da Silva S, Canteiro PB et al (2017) Strength and aerobic exercises improve spatial memory in aging rats through stimulating distinct neuroplasticity mechanisms. Mol Neurobiol 54(10):7928–7937
Maejima H, Kanemura N, Kokubun T, Murata K, Takayanagi K (2018) Exercise enhances cognitive function and neurotrophin expression in the hippocampus accompanied by changes in epigenetic programming in senescence-accelerated mice. Neurosci Lett 665:67–73
Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T et al (2016) Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife 5:e15092. https://doi.org/10.7554/eLife.15092
Adachi N, Numakawa T, Richards M, Nakajima S, Kunugi H (2014) New insight in expression, transport, and secretion of brain-derived neurotrophic factor: implications in brain-related diseases. World J Biol Chem 5(4):409–428
Kennedy KM, Reese ED, Horn MM, Sizemore AN, Unni AK, Meerbrey ME et al (2015) BDNF val66met polymorphism affects aging of multiple types of memory. Brain Res 1612:104–117
Toh YL, Ng T, Tan M, Tan A, Chan A (2018) Impact of brain-derived neurotrophic factor genetic polymorphism on cognition: a systematic review. Brain Behav 8(7):e01009
Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P et al (2008) Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly. Genes Brain Behav 7(4):411–417
Ward DD, Summers MJ, Saunders NL, Janssen P, Stuart KE, Vickers JC (2014) APOE and BDNF Val66Met polymorphisms combine to influence episodic memory function in older adults. Behav Brain Res 271:309–315
Huang R, Huang J, Cathcart H, Smith S, Poduslo SE (2007) Genetic variants in brain-derived neurotrophic factor associated with Alzheimer’s disease. J Med Genet 44(2):e66
Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39(1):17–23
Matyi J, Tschanz JT, Rattinger GB, Sanders C, Vernon EK, Corcoran C et al (2017) Sex differences in risk for Alzheimer’s disease related to neurotrophin gene polymorphisms: the Cache County Memory Study. J Gerontol A Biol Sci Med Sci 72(12):1607–1613
Barrett GL, Reid CA, Tsafoulis C, Zhu W, Williams DA, Paolini AG et al (2010) Enhanced spatial memory and hippocampal long-term potentiation in p75 neurotrophin receptor knockout mice. Hippocampus 20(1):145–152
Buhusi M, Etheredge C, Granholm AC, Buhusi CV (2017) Increased hippocampal ProBDNF contributes to memory impairments in aged mice. Front Aging Neurosci 9:284
Murphy M, Wilson YM, Vargas E, Munro KM, Smith B, Huang A et al (2015) Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer’s disease. Neurobiol Aging 36(2):740–752
Simmons DA, Knowles JK, Belichenko NP, Banerjee G, Finkle C, Massa SM et al (2014) A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer’s disease mouse models with mid- to late-stage disease progression. PLoS One 9(8):e102136
Chen Z, Simmons MS, Perry RT, Wiener HW, Harrell LE, Go RC (2008) Genetic association of neurotrophic tyrosine kinase receptor type 2 (NTRK2) with Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 147(3):363–369
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43(8):1467–1472
Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10(3):241–252
Rawle MJ, Davis D, Bendayan R, Wong A, Kuh D, Richards M (2018) Apolipoprotein-E (Apoe) ε4 and cognitive decline over the adult life course. Transl Psychiatry 8(1):18
Ritchie SJ, Hill WD, Marioni RE, Davies G, Hagenaars SP, Harris SE et al (2020) Polygenic predictors of age-related decline in cognitive ability. Mol Psychiatry 25(10):2584–2598
Wisdom NM, Callahan JL, Hawkins KA (2011) The effects of apolipoprotein E on non-impaired cognitive functioning: a meta-analysis. Neurobiol Aging 32(1):63–74
Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L (1999) The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA 282(1):40–46
Deeny SP, Poeppel D, Zimmerman JB, Roth SM, Brandauer J, Witkowski S et al (2008) Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in epsilon4 carriers. Biol Psychol 78(2):179–187
Etnier JL, Caselli RJ, Reiman EM, Alexander GE, Sibley BA, Tessier D et al (2007) Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness. Med Sci Sports Exerc 39(1):199–207
Krell-Roesch J, Pink A, Roberts RO, Stokin GB, Mielke MM, Spangehl KA et al (2016) Timing of physical activity, apolipoprotein E ε4 genotype, and risk of incident mild cognitive impairment. J Am Geriatr Soc 64(12):2479–2486
Luck T, Riedel-Heller SG, Luppa M, Wiese B, Köhler M, Jessen F et al (2014) Apolipoprotein E epsilon 4 genotype and a physically active lifestyle in late life: analysis of gene-environment interaction for the risk of dementia and Alzheimer’s disease dementia. Psychol Med 44(6):1319–1329
Niti M, Yap KB, Kua EH, Tan CH, Ng TP (2008) Physical, social and productive leisure activities, cognitive decline and interaction with APOE-epsilon 4 genotype in Chinese older adults. Int Psychogeriatr 20(2):237–251
Pizzie R, Hindman H, Roe CM, Head D, Grant E, Morris JC et al (2014) Physical activity and cognitive trajectories in cognitively normal adults: the adult children study. Alzheimer Dis Assoc Disord 28(1):50–57
Podewils LJ, Guallar E, Kuller LH, Fried LP, Lopez OL, Carlson M et al (2005) Physical activity, APOE genotype, and dementia risk: findings from the cardiovascular health cognition study. Am J Epidemiol 161(7):639–651
Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J et al (2005) Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol 4(11):705–711
Schuit AJ, Feskens EJ, Launer LJ, Kromhout D (2001) Physical activity and cognitive decline, the role of the apolipoprotein e4 allele. Med Sci Sports Exerc 33(5):772–777
Law CK, Lam FM, Chung RC, Pang MY (2020) Physical exercise attenuates cognitive decline and reduces behavioural problems in people with mild cognitive impairment and dementia: a systematic review. J Physiother 66(1):9–18
Vanhoutte PM, Shimokawa H, Feletou M, Tang EH (2017) Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol 219(1):22–96
He XF, Liu DX, Zhang Q, Liang FY, Dai GY, Zeng JS et al (2017) Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice. Front Mol Neurosci 10:144
de Senna PN, Xavier LL, Bagatini PB, Saur L, Galland F, Zanotto C et al (2015) Physical training improves non-spatial memory, locomotor skills and the blood brain barrier in diabetic rats. Brain Res 1618:75–82
Chupel MU, Minuzzi LG, Furtado G, Santos ML, Hogervorst E, Filaire E et al (2018) Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women. Appl Physiol Nutr Metab 43(7):733–741
Pang R, Wang X, Pei F, Zhang W, Shen J, Gao X et al (2019) Regular exercise enhances cognitive function and intracephalic GLUT expression in Alzheimer’s disease model mice. J Alzheimers Dis 72(1):83–96
Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K et al (2018) Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175(7):1756–68.e17
Chen K, Wang K, Wang T (2022) Protective effect of irisin against Alzheimer’s disease. Front Psych 13:967683
Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC et al (2019) Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med 25(1):165–175
Lu Y, Bu FQ, Wang F, Liu L, Zhang S, Wang G et al (2023) Recent advances on the molecular mechanisms of exercise-induced improvements of cognitive dysfunction. Transl Neurodegener 12(1):9
Lee B, Shin M, Park Y, Won SY, Cho KS (2021) Physical exercise-induced myokines in neurodegenerative diseases. Int J Mol Sci 22(11):5795. https://doi.org/10.3390/ijms22115795
Campbell SC, Wisniewski PJ, Noji M, McGuinness LR, Häggblom MM, Lightfoot SA et al (2016) The effect of diet and exercise on intestinal integrity and microbial diversity in mice. PLoS One 11(3):e0150502
Kim MS, Kim Y, Choi H, Kim W, Park S, Lee D et al (2020) Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut 69(2):283–294
Jackson A, Forsyth CB, Shaikh M, Voigt RM, Engen PA, Ramirez V et al (2019) Diet in Parkinson’s disease: critical role for the microbiome. Front Neurol 10:1245
Shin HE, Kwak SE, Zhang DD, Lee J, Yoon KJ, Cho HS et al (2020) Effects of treadmill exercise on the regulation of tight junction proteins in aged mice. Exp Gerontol 141:111077
Huang B, Chen K, Li Y (2023) Aerobic exercise, an effective prevention and treatment for mild cognitive impairment. Front Aging Neurosci 15:1194559
Pareja-Galeano H, Sanchis-Gomar F, García-Giménez JL (2014) Physical exercise and epigenetic modulation: elucidating intricate mechanisms. Sports Med 44(4):429–436
Sanchis-Gomar F, Garcia-Gimenez JL, Perez-Quilis C, Gomez-Cabrera MC, Pallardo FV, Lippi G (2012) Physical exercise as an epigenetic modulator: eustress, the “positive stress” as an effector of gene expression. J Strength Cond Res 26(12):3469–3472
Santos-Rebouças CB, Pimentel MM (2007) Implication of abnormal epigenetic patterns for human diseases. Eur J Hum Genet 15(1):10–17
Taniguchi S, Sagara J (2007) Regulatory molecules involved in inflammasome formation with special reference to a key mediator protein, ASC. Semin Immunopathol 29(3):231–238
Radom-Aizik S, Zaldivar F Jr, Leu SY, Adams GR, Oliver S, Cooper DM (2012) Effects of exercise on microRNA expression in young males peripheral blood mononuclear cells. Clin Transl Sci 5(1):32–38
Radom-Aizik S, Zaldivar F Jr, Oliver S, Galassetti P, Cooper DM (2010) Evidence for microRNA involvement in exercise-associated neutrophil gene expression changes. J Appl Physiol 109(1):252–261
Nakajima K, Takeoka M, Mori M, Hashimoto S, Sakurai A, Nose H et al (2010) Exercise effects on methylation of ASC gene. Int J Sports Med 31(9):671–675
Bopp T, Radsak M, Schmitt E, Schild H (2010) New strategies for the manipulation of adaptive immune responses. Cancer Immunol Immunother 59(9):1443–1448
Franks AL, Slansky JE (2012) Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res 32(4):1119–1136
Ntanasis-Stathopoulos J, Tzanninis JG, Philippou A, Koutsilieris M (2013) Epigenetic regulation on gene expression induced by physical exercise. J Musculoskelet Neuronal Interact 13(2):133–146
Dimauro I, Scalabrin M, Fantini C, Grazioli E, Beltran Valls MR, Mercatelli N et al (2016) Resistance training and redox homeostasis: correlation with age-associated genomic changes. Redox Biol 10:34–44
McGee SL, Hargreaves M (2011) Histone modifications and exercise adaptations. J Appl Physiol 110(1):258–263
Zimmer P, Baumann FT, Bloch W, Schenk A, Koliamitra C, Jensen P et al (2014) Impact of exercise on pro inflammatory cytokine levels and epigenetic modulations of tumor-competitive lymphocytes in non-Hodgkin-lymphoma patients-randomized controlled trial. Eur J Haematol 93(6):527–532
Philp A, Rowland T, Perez-Schindler J, Schenk S (2014) Understanding the acetylome: translating targeted proteomics into meaningful physiology. Am J Physiol Cell Physiol 307(9):C763–C773
Lavratti C, Dorneles G, Pochmann D, Peres A, Bard A, de Lima SL et al (2017) Exercise-induced modulation of histone H4 acetylation status and cytokines levels in patients with schizophrenia. Physiol Behav 168:84–90
Flowers E, Won GY, Fukuoka Y (2015) MicroRNAs associated with exercise and diet: a systematic review. Physiol Genomics 47(1):1–11
Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102(39):13944–13949
Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz LA Jr, Sjoblom T et al (2006) The colorectal microRNAome. Proc Natl Acad Sci U S A 103(10):3687–3692
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435(7043):828–833
Michael MZ, O'Connor SM, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1(12):882–891
Rowlands DS, Page RA, Sukala WR, Giri M, Ghimbovschi SD, Hayat I et al (2014) Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in Type 2 diabetic obesity. Physiol Genomics 46(20):747–765
Denham J, O'Brien BJ, Marques FZ, Charchar FJ (2015) Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise. J Appl Physiol 118(4):475–488
Lindahl T (1981) DNA methylation and control of gene expression. Nature 290(5805):363–364
Ziller MJ, Gu H, Müller F, Donaghey J, Tsai LT, Kohlbacher O et al (2013) Charting a dynamic DNA methylation landscape of the human genome. Nature 500(7463):477–481
Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10(5):295–304
Sakuma K, Yamaguchi A (2012) Novel intriguing strategies attenuating to sarcopenia. J Aging Res 2012:251217
Horsburgh S, Robson-Ansley P, Adams R, Smith C (2015) Exercise and inflammation-related epigenetic modifications: focus on DNA methylation. Exerc Immunol Rev 21:26–41
Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49(2):359–367
Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14(10):R115
Horvath S, Raj K (2018) DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19(6):371–384
Gale CR, Marioni RE, Čukić I, Chastin SF, Dall PM, Dontje ML et al (2018) The epigenetic clock and objectively measured sedentary and walking behavior in older adults: the Lothian Birth Cohort 1936. Clin Epigenetics 10:4
Marioni RE, Shah S, McRae AF, Ritchie SJ, Muniz-Terrera G, Harris SE et al (2015) The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936. Int J Epidemiol 44(4):1388–1396
Angevaren M, Aufdemkampe G, Verhaar HJ, Aleman A, Vanhees L (2008) Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev (2):CD005381. https://doi.org/10.1002/14651858.CD005381
Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E et al (2006) Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci 61(11):1166–1170
Voss MW, Erickson KI, Prakash RS, Chaddock L, Kim JS, Alves H et al (2013) Neurobiological markers of exercise-related brain plasticity in older adults. Brain Behav Immun 28:90–99
Zoladz JA, Pilc A (2010) The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies. J Physiol Pharmacol 61(5):533–541
Heyn P, Abreu BC, Ottenbacher KJ (2004) The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 85(10):1694–1704
Nagamatsu LS, Handy TC, Hsu CL, Voss M, Liu-Ambrose T (2012) Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med 172(8):666–668
Coelho FG, Vital TM, Stein AM, Arantes FJ, Rueda AV, Camarini R et al (2014) Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease. J Alzheimers Dis 39(2):401–408
Etgen T, Sander D, Huntgeburth U, Poppert H, Förstl H, Bickel H (2010) Physical activity and incident cognitive impairment in elderly persons: the INVADE study. Arch Intern Med 170(2):186–193
Nouchi R, Taki Y, Takeuchi H, Sekiguchi A, Hashizume H, Nozawa T et al (2014) Four weeks of combination exercise training improved executive functions, episodic memory, and processing speed in healthy elderly people: evidence from a randomized controlled trial. Age 36(2):787–799
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC et al (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328(5979):753–756
Zhong T, Ren F, Huang CS, Zou WY, Yang Y, Pan YD et al (2016) Swimming exercise ameliorates neurocognitive impairment induced by neonatal exposure to isoflurane and enhances hippocampal histone acetylation in mice. Neuroscience 316:378–388
de Meireles LC, Bertoldi K, Cechinel LR, Schallenberger BL, da Silva VK, Schröder N et al (2016) Treadmill exercise induces selective changes in hippocampal histone acetylation during the aging process in rats. Neurosci Lett 634:19–24
Cechinel LR, Basso CG, Bertoldi K, Schallenberger B, de Meireles LCF, Siqueira IR (2016) Treadmill exercise induces age and protocol-dependent epigenetic changes in prefrontal cortex of Wistar rats. Behav Brain Res 313:82–87
de Meireles LC, Bertoldi K, Elsner VR, Moysés Fdos S, Siqueira IR (2014) Treadmill exercise alters histone acetylation differently in rats exposed or not exposed to aversive learning context. Neurobiol Learn Mem 116:193–196
Chwang WB, O'Riordan KJ, Levenson JM, Sweatt JD (2006) ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn Mem 13(3):322–328
Koshibu K, Gräff J, Beullens M, Heitz FD, Berchtold D, Russig H et al (2009) Protein phosphatase 1 regulates the histone code for long-term memory. J Neurosci 29(41):13079–13089
Koshibu K, Gräff J, Mansuy IM (2011) Nuclear protein phosphatase-1: an epigenetic regulator of fear memory and amygdala long-term potentiation. Neuroscience 173:30–36
Collins A, Hill LE, Chandramohan Y, Whitcomb D, Droste SK, Reul JM (2009) Exercise improves cognitive responses to psychological stress through enhancement of epigenetic mechanisms and gene expression in the dentate gyrus. PLoS One 4(1):e4330
Chen WQ, Viidik A, Skalicky M, Höger H, Lubec G (2007) Hippocampal signaling cascades are modulated in voluntary and treadmill exercise rats. Electrophoresis 28(23):4392–4400
Li T, Tao X, Sun R, Han C, Li X, Zhu Z et al (2023) Cognitive-exercise dual-task intervention ameliorates cognitive decline in natural aging rats via inhibiting the promotion of LncRNA NEAT1/miR-124-3p on caveolin-1-PI3K/Akt/GSK3β Pathway. Brain Res Bull 202:110761
Liu B, Li J, Cairns MJ (2014) Identifying miRNAs, targets and functions. Brief Bioinform 15(1):1–19
Dong J, Liu Y, Zhan Z, Wang X (2018) MicroRNA-132 is associated with the cognition improvement following voluntary exercise in SAMP8 mice. Brain Res Bull 140:80–87
Valenti MT, Deiana M, Cheri S, Dotta M, Zamboni F, Gabbiani D et al (2019) Physical exercise modulates miR-21-5p, miR-129-5p, miR-378-5p, and miR-188-5p expression in progenitor cells promoting osteogenesis. Cells 8(7):742. https://doi.org/10.3390/cells8070742
Vo N, Klein ME, Varlamova O, Keller DM, Yamamoto T, Goodman RH et al (2005) A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci 102(45):16426–16431
Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng H-YM et al (2008) An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci 105(26):9093–9098
Da Silva FC, Rode MP, Vietta GG, Iop RDR, Creczynski-Pasa TB, Martin AS et al (2021) Expression levels of specific microRNAs are increased after exercise and are associated with cognitive improvement in Parkinson's disease. Mol Med Rep 24(2):618. https://doi.org/10.3892/mmr.2021.12257
Liu SX, Zheng F, Xie KL, Xie MR, Jiang LJ, Cai Y (2019) Exercise reduces insulin resistance in type 2 diabetes mellitus via mediating the lncRNA MALAT1/microrna-382-3p/resistin axis. Mol Ther Nucleic Acids 18:34–44
Sun X, Shen H, Liu S, Gao J, Zhang S (2020) Long noncoding RNA SNHG14 promotes the aggressiveness of retinoblastoma by sponging microRNA-124 and thereby upregulating STAT3. Int J Mol Med 45(6):1685–1696
Zhang LM, Wang MH, Yang HC, Tian T, Sun GF, Ji YF et al (2019) Dopaminergic neuron injury in Parkinson’s disease is mitigated by interfering lncRNA SNHG14 expression to regulate the miR-133b/ α-synuclein pathway. Aging 11(21):9264–9279
Huaying C, Xing J, Luya J, Linhui N, Di S, Xianjun D (2020) A signature of five long non-coding RNAs for predicting the prognosis of Alzheimer’s disease based on competing endogenous RNA networks. Front Aging Neurosci 12:598606
He Y, Qiang Y (2021) Mechanism of autonomic exercise improving cognitive function of Alzheimer’s disease by regulating lncRNA SNHG14. Am J Alzheimers Dis Other Demen 36:15333175211027681
Johnson R (2012) Long non-coding RNAs in Huntington’s disease neurodegeneration. Neurobiol Dis 46(2):245–254
Wang J, Niu Y, Tao H, Xue M, Wan C (2020) Knockdown of lncRNA TUG1 inhibits hippocampal neuronal apoptosis and participates in aerobic exercise-alleviated vascular cognitive impairment. Biol Res 53(1):53
Patnode CD, Perdue LA, Rossom RC, Rushkin MC, Redmond N, Thomas RG et al (2020) Screening for cognitive impairment in older adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 323(8):764–785
Russ TC, Morling JR (2012) Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev 2012(9):CD009132. https://doi.org/10.1002/14651858.CD009132
Brehmer Y, Kalpouzos G, Wenger E, Lövdén M (2014) Plasticity of brain and cognition in older adults. Psychol Res 78:790–802
Joubert C, Chainay H (2018) Aging brain: the effect of combined cognitive and physical training on cognition as compared to cognitive and physical training alone–a systematic review. Clin Interv Aging 13:1267–1301
Lauenroth A, Ioannidis AE, Teichmann B (2016) Influence of combined physical and cognitive training on cognition: a systematic review. BMC Geriatr 16:1–14
Bradburn S, Murgatroyd C, Ray N (2019) Neuroinflammation in mild cognitive impairment and Alzheimer’s disease: a meta-analysis. Ageing Res Rev 50:1–8
Fjell AM, McEvoy L, Holland D, Dale AM, Walhovd KB, Initiative AsDN (2014) What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Prog Neurobiol 117:20–40
Maren S, Phan KL, Liberzon I (2013) The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 14(6):417–428
Li X-L, Tao X, Li T-C, Zhu Z-M, Huang P-L, Gong W-J (2022) Cognitive–exercise dual-task intervention ameliorates cognitive decline in natural aging rats through reducing oxidative stress and enhancing synaptic plasticity. Exp Gerontol 169:111981
Grasso M, Piscopo P, Confaloni A, Denti MA (2014) Circulating miRNAs as biomarkers for neurodegenerative disorders. Molecules 19(5):6891–6910
Hansen KF, Karelina K, Sakamoto K, Wayman GA, Impey S, Obrietan K (2013) miRNA-132: a dynamic regulator of cognitive capacity. Brain Struct Funct 218:817–831
Gao J, Wang W-Y, Mao Y-W, Gräff J, Guan J-S, Pan L et al (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466(7310):1105–1109
Earls LR, Westmoreland JJ, Zakharenko SS (2014) Non-coding RNA regulation of synaptic plasticity and memory: implications for aging. Ageing Res Rev 17:34–42
Xie S-P, Zhou F, Li J, Duan S-j (2019) NEAT1 regulates MPP+-induced neuronal injury by targeting miR-124 in neuroblastoma cells. Neurosci Lett 708:134340
Butler AA, Johnston DR, Kaur S, Lubin FD (2019) Long noncoding RNA NEAT1 mediates neuronal histone methylation and age-related memory impairment. Sci Signal 12(588):eaaw9277
Nwosu ZC, Ebert MP, Dooley S, Meyer C (2016) Caveolin-1 in the regulation of cell metabolism: a cancer perspective. Mol Cancer 15(1):1–12
Cha S-H, Choi YR, Heo C-H, Kang S-J, Joe E-H, Jou I et al (2015) Loss of parkin promotes lipid rafts-dependent endocytosis through accumulating caveolin-1: implications for Parkinson’s disease. Mol Neurodegener 10(1):1–13
Kang Q, Xiang Y, Li D, Liang J, Zhang X, Zhou F et al (2017) MiR-124-3p attenuates hyperphosphorylation of Tau protein-induced apoptosis via caveolin-1-PI3K/Akt/GSK3β pathway in N2a/APP695swe cells. Oncotarget 8(15):24314
Ikezu T, Trapp BD, Song KS, Schlegel A, Lisanti MP, Okamoto T (1998) Caveolae, plasma membrane microdomains for α-secretase-mediated processing of the amyloid precursor protein. J Biol Chem 273(17):10485–10495
Van Helmond Z, Miners J, Bednall E, Chalmers K, Zhang Y, Wilcock G et al (2007) Caveolin-1 and-2 and their relationship to cerebral amyloid angiopathy in Alzheimer’s disease. Neuropathol Appl Neurobiol 33(3):317–327
Maqbool M, Mobashir M, Hoda N (2016) Pivotal role of glycogen synthase kinase-3: a therapeutic target for Alzheimer’s disease. Eur J Med Chem 107:63–81
Qi Y, Dou D-Q, Jiang H, Zhang B-B, Qin W-Y, Kang K et al (2017) Arctigenin attenuates learning and memory deficits through PI3k/Akt/GSK-3β pathway reducing tau hyperphosphorylation in Aβ-induced AD mice. Planta Med 83(01/02):51–56
Acknowledgements
The authors would like to thank the Shanxi Province Higher Education Reform and Innovation Project (project number: J20221160) and the Shanxi Province Education Science “14th Five-Year Plan” 2021 annual project (project number: GH-21269).
Author information
Authors and Affiliations
Contributions
Runhong Zhang and Shangwu Liu involved in manuscript drafting and data collection. All authors approved the final paper. Seyed Mojtaba Mousavi oversaw the study.
Corresponding authors
Ethics declarations
Ethics Approval and Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhang, R., Liu, S. & Mousavi, S.M. Cognitive Dysfunction and Exercise: From Epigenetic to Genetic Molecular Mechanisms. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03970-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12035-024-03970-7