Development of Alzheimer’s disease in Down syndrome

Abstract

Down syndrome (DS), caused by trisomy 21, is strongly associated with an increased risk of early-onset Alzheimer’s disease (AD). This work explores the cellular, genetic, epigenetic, and neuropsychological mechanisms that underlie the accelerated development of AD in individuals with DS. We review key contributors such as amyloid-β accumulation, mitochondrial dysfunction, oxidative stress, tau pathology, neuroinflammation, and chromosomal and epigenetic instability in the neuropathology of AD in DS. Particular attention is given to genes, microRNAs, and chromatin remodeling factors encoded by human chromosome 21 (Hsa21) that regulate these pathological processes. We also highlight the roles of non-coding RNAs and altered DNA methylation patterns in modulating gene expression and neuronal vulnerability. Additionally, the writing evaluates current pharmacological and non-pharmacological interventions and addresses the critical need for inclusive, person-centered health services. Integrating molecular biology with clinical perspectives, the review emphasizes the importance of early diagnosis and coordinated care strategies for individuals with DS at risk for AD.

Keywords

Down syndrome / Alzheimer’s disease / aging / chromosome 21 / genes

References

[1] Ballard C,Mobley W,Hardy J,Williams G,Corbett A.Dementia in Down’s syndrome.Lancet Neurol.2016;15:622-36.

[2] Lauricella S.Challenges and Prospects for the Future: Down syndrome.J Down Syndr Chromosome Abnorm.2021;7:160.

[3] Kazemi M,Salehi M,Kheirollahi M.Down Syndrome: Current Status, Challenges and Future Perspectives.Int J Mol Cell Med.2016;5:125-33.

[4] Antonarakis SE,Skotko BG,Rafii MS,Strydom A,Pape SE,Bianchi DW,et al.Down syndrome.Nat Rev Dis Primers.2020;6:9.

[5] Söylemez F.Phenotypes Associated with Down Syndrome and Causative Genes. In: Dey SK. editors.Down Syndrome and Other Chromosome Abnormalities.Rijeka:IntechOpen2022

[6] Coppedè F.Risk factors for Down syndrome.Arch Toxicol.2016;90:2917-29.

[7] Ghosh S,Hong C,Feingold E,Ghosh P,Ghosh P,Bhaumik P,et al.Epidemiology of Down syndrome: new insight into the multidimensional interactions among genetic and environmental risk factors in the oocyte.Am J Epidemiol.2011;174:1009-16.

[8] Bull MJ.Down Syndrome.N Engl J Med.2020;382:2344-52.

[9] Chapman RS,Hesketh LJ.Behavioral phenotype of individuals with Down syndrome.Ment Retard Dev Disabil Res Rev.2000;6:84-95.

[10] Daunhauer LA,Fidler DJ.The down syndrome behavioral phenotype: implications for practice and research in occupational therapy.Occup Ther Health Care.2011;25:7-25.

[11] Maure-Blesa L,Carmona-Iragui M,Lott I,Head E,Wisniewski T,Rafii MS,et al.The history of Down syndrome–associated Alzheimer’s disease; past, present, and future.Alzheimers Dement.2025;21:e70158.

[12] Salehi A,Ashford JW,Mufson EJ.Editorial (Thematic Issue: The Link between Alzheimer’s Disease and Down Syndrome. A Historical Perspective).Curr Alzheimer Res.2016;13:2-6.

[13] Holland AJ,Oliver C.Down’s syndrome and the links with Alzheimer’s disease.J Neurol Neurosurg Psychiatry.1995;59:111-4.

[14] Fortea J,Zaman SH,Hartley S,Rafii MS,Head E,Carmona-Iragui M.Alzheimer’s disease associated with Down syndrome: a genetic form of dementia.Lancet Neurol.2021;20:930-42.

[15] Fortea J,Vilaplana E,Carmona-Iragui M,Benejam B,Videla L,Barroeta I,et al.Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study.Lancet.2020;395:1988-97.

[16] Zigman WB.Atypical aging in Down syndrome.Dev Disabil Res Rev.2013;18:51-67.

[17] Mann DM.The pathological association between Down syndrome and Alzheimer disease.Mech Ageing Dev.1988;43:99-136.

[18] Wiseman FK,Al-Janabi T,Hardy J,Karmiloff-Smith A,Nizetic D,Tybulewicz VLJ,et al.A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.Nat Rev Neurosci.2015;16:564-74.

[19] Devenny DA,Krinsky-McHale SJ,Sersen G,Silverman WP.Sequence of cognitive decline in dementia in adults with Down’s syndrome.J Intellect Disabil Res.2000;44 :654-65.

[20] Head E,Lott IT,Wilcock DM,Lemere CA.Aging in Down Syndrome and the Development of Alzheimer’s Disease Neuropathology.Curr Alzheimer Res.2016;13:18-29.

[21] Iulita MF,Chavez DG,Christensen MK,Tamayo NV,Plana-Ripoll O,Rasmussen SA,et al.Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome.JAMA Netw Open.2022;5:e2212910.

[22] Lott IT.Neurological phenotypes for Down syndrome across the life span.Prog Brain Res.2012;197:101-21.

[23] Iacono T,Torr J,Wong HY.Relationships amongst age, language and related skills in adults with Down syndrome.Res Dev Disabil.2010;31:568-76.

[24] Wilcock DM,Griffin WST.Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis.J Neuroinflammation.2013;10:84.

[25] Rujeedawa T,Félez EC,Clare ICH,Fortea J,Strydom A,Rebillat A,et al.The Clinical and Neuropathological Features of Sporadic (Late-Onset) and Genetic Forms of Alzheimer’s Disease.J Clin Med.2021;10:4582.

[26] Ilacqua A,Benedict J,Shoben A,Skotko BG,Matthews T,Benson B,et al.Alzheimer’s disease development in adults with Down syndrome: Caregivers’ perspectives.Am J Med Genet A.2020;182:104-14.

[27] van Allen MI,Fung J,Jurenka SB.Health care concerns and guidelines for adults with Down syndrome.Am J Med Genet.1999;89:100-10.

[28] Verma IC,Lall M,Puri RD.Down syndrome in India—diagnosis, screening, and prenatal diagnosis.Clin Lab Med.2012;32:231-48.

[29] Manzano Vela MP,Manzano Vela DR,Flores Mancheno AC,Parra Chávez MV.Genetic and Molecular Tools for the Clinical Diagnosis of Down Syndrome.Salud, Cienc Tecnol.2025;5:1027.

[30] Colak C,Yagin FH,Yagin B,Alkhateeb A,Al-Rawi MBA,Akhloufi MA,et al.Identification of metabolomics-based biomarker discovery in individuals with down syndrome utilizing kernel-tree model-enhanced explainable artificial intelligence methodology.Front Mol Biosci.2025;12:1567199.

[31] Rafii MS,Wishnek H,Brewer JB,Donohue MC,Ness S,Mobley WC,et al.The down syndrome biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer’s disease biomarkers in down syndrome.Front Behav Neurosci.2015;9:239.

[32] Lee N,Yang S,Chieh J,Huang P,Chang L,Chiu Y,et al.Blood Beta-Amyloid and Tau in Down Syndrome: A Comparison with Alzheimer’s Disease.Front Aging Neurosci.2017;8:316.

[33] Handen BL.The Search for Biomarkers of Alzheimer’s Disease in Down Syndrome.Am J Intellect Dev Disabil.2020;125:97-9.

[34] Handen BL,Mapstone M,Hartley S,Andrews H,Christian B,Lee JH,et al.The Alzheimer’s Biomarker Consortium–Down Syndrome (ABC-DS): A 10-year report.Alzheimers Dement.2025;21:e70294.

[35] Qu H,Liu Y,Connolly JJ,Mentch FD,Kao C,Hakonarson H.Risk of Alzheimer’s disease in Down syndrome: Insights gained by multi-omics.Alzheimers Dement.2025;21:e14604.

[36] McCarron M,McCallion P,Reilly E,Mulryan N.A prospective 14-year longitudinal follow-up of dementia in persons with Down syndrome.J Intellect Disabil Res.2014;58:61-70.

[37] Vaughan RM,McGee C,Guerin S,Tyrrell J,Dodd P.The challenges of diagnosis and treatment of dementia in Down’s syndrome.Ir J Psychol Med.2016;33:151-8.

[38] Grotteschi N,Rochat MJ,Pollarini V,Ghezzo A,Pellegrini C,Calandra-Buonaura G,et al.Neurological findings in a cohort of adults with down syndrome.Neurol Sci.2025;46:3639-49.

[39] Singh SG,Das D,Barman U,Saikia MJ.Early Alzheimer’s Disease Detection: A Review of Machine Learning Techniques for Forecasting Transition from Mild Cognitive Impairment.Diagnostics (Basel).2024;14:1759.

[40] Arya AD,Verma SS,Chakarabarti P,Chakrabarti T,Elngar AA,Kamali A,et al.A systematic review on machine learning and deep learning techniques in the effective diagnosis of Alzheimer’s disease.Brain Inform.2023;10:17.

[41] Shaikh MA,Al-Rawashdeh HS,Sait ARW.A Review of Artificial Intelligence-Based Down Syndrome Detection Techniques.Life (Basel).2025;15:390.

[42] Conti E,Galimberti G,Piazza F,Raggi ME,Ferrarese C.Increased soluble APPalpha, Abeta 1-42, and anti-Abeta 1-42 antibodies in plasma from Down syndrome patients.Alzheimer Dis Assoc Disord.2010;24:96-100.

[43] Coppus AM,Schuur M,Vergeer J,Janssens AC,Oostra BA,Verbeek MM,et al.Plasma β amyloid and the risk of Alzheimer’s disease in Down syndrome.Neurobiol Aging.2012;33:1988-94.

[44] Coppus A,Berger M,Szabo P,Relkin N,Janssens AC,van Duijn C,et al.P2-225: Association of plasma amyloid beta peptide and anti-amyloid antibodies with risk of dementia in individuals with down syndrome.Alzheimer’s Dementia.2011;7:S369-404.

[45] Johannesson M,Sahlin C,Söderberg L,Basun H,Fälting J,Möller C,et al.Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer’s disease.Mol Cell Neurosci.2021;114:103641.

[46] Costa ACS.On the Therapeutic Use of Monoclonal Antibodies Against Amyloid Plaques in Older Adults with Down Syndrome: A Narrative Review and Perspective.Brain Sci.2024;14:1084.

[47] Lott IT,Dierssen M.Cognitive deficits and associated neurological complications in individuals with Down’s syndrome.Lancet Neurol.2010;9:623-33.

[48] Caoimh RO,Clune Y,Molloy D W.Screening for Alzheimer’s Disease in Downs Syndrome.J Alzheimers Dis Parkinsonism.2013;S7:001.

[49] Krinsky-McHale SJ,Silverman W.Dementia and mild cognitive impairment in adults with intellectual disability: issues of diagnosis.Dev Disabil Res Rev.2013;18:31-42.

[50] Beresford-Webb JA,Mak E,Grigorova M,Daffern SJ,Holland AJ,Zaman SH.Establishing diagnostic thresholds for Alzheimer’s disease in adults with Down syndrome: the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX-DS).BJPsych Open.2021;7:e79.

[51] Krinsky-McHale SJ,Hartley S,Hom C,Pulsifer M,Clare ICH,Handen BL,et al.Alzheimer’s Biomarker Consortium—Down Syndrome (ABC-DS) Investigators.A modified Cued Recall Test for detecting prodromal AD in adults with Down syndrome.Alzheimers Dement (Amst).2022;14:e12361.

[52] Grieco J,Pulsifer M,Seligsohn K,Skotko B,Schwartz A.Down syndrome: Cognitive and behavioral functioning across the lifespan.Am J Med Genet C Semin Med Genet.2015;169:135-49.

[53] Annus T,Wilson LR,Hong YT,Acosta-Cabronero J,Fryer TD,Cardenas-Blanco A,et al.The pattern of amyloid accumulation in the brains of adults with Down syndrome.Alzheimers Dement.2016;12:538-45.

[54] Hartley SL,Handen BL,Devenny D,Mihaila I,Hardison R,Lao PJ,et al.Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome.Neurobiol Aging.2017;58:68-76.

[55] Hartley SL,Handen BL,Devenny D,Tudorascu D,Piro-Gambetti B,Zammit MD,et al.Cognitive indicators of transition to preclinical and prodromal stages of Alzheimer’s disease in Down syndrome.Alzheimers Dement (Amst).2020;12:e12096.

[56] Ghezzo A,Salvioli S,Solimando MC,Palmieri A,Chiostergi C,Scurti M,et al.Age-related changes of adaptive and neuropsychological features in persons with Down Syndrome.PLoS One.2014;9:e113111.

[57] Figueroa M,Darbra S.Language and Ageing in Adults With Down Syndrome: An Analysis of Receptive and Expressive Language Measures.J Appl Res Intellect Disabil.2025;38:e13330.

[58] Nelson LD,Orme D,Osann K,Lott IT.Neurological changes and emotional functioning in adults with Down Syndrome.J Intellect Disabil Res.2001;45:450-6.

[59] Baddeley A,Jarrold C.Working memory and Down syndrome.J Intellect Disabil Res.2007;51:925-31.

[60] Lanfranchi S,Cornoldi C,Vianello R.Verbal and visuospatial working memory deficits in children with Down syndrome.Am J Ment Retard.2004;109:456-66.

[61] Carlesimo GA,Marotta L,Vicari S.Long-term memory in mental retardation: evidence for a specific impairment in subjects with Down’s syndrome.Neuropsychologia.1997;35:71-9.

[62] Vicari S,Bellucci S,Carlesimo GA.Implicit and explicit memory: a functional dissociation in persons with Down syndrome.Neuropsychologia.2000;38:240-51.

[63] Krasuski JS,Alexander GE,Horwitz B,Rapoport SI,Schapiro MB.Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down’s syndrome: implications for the prodromal phase of Alzheimer’s disease.Am J Psychiatry.2002;159:74-81.

[64] Pinter JD,Eliez S,Schmitt JE,Capone GT,Reiss AL.Neuroanatomy of Down’s syndrome: a high-resolution MRI study.Am J Psychiatry.2001;158:1659-65.

[65] Blok JB,Scheirs JGM,Thijm NS.Personality and behavioural changes do not precede memory problems as possible signs of dementia in ageing people with Down syndrome.Int J Geriatr Psychiatry.2017;32:1257-63.

[66] Costanzo F,Varuzza C,Menghini D,Addona F,Gianesini T,Vicari S.Executive functions in intellectual disabilities: a comparison between Williams syndrome and Down syndrome.Res Dev Disabil.2013;34:1770-80.

[67] Cristofori I,Cohen-Zimerman S,Grafman J.Executive functions.Handb Clin Neurol.2019;163:197-219.

[68] Lee NR,Fidler DJ,Blakeley-Smith A,Daunhauer L,Robinson C,Hepburn SL.Caregiver report of executive functioning in a population-based sample of young children with Down syndrome.Am J Intellect Dev Disabil.2011;116:290-304.

[69] Miezah D,Porter M,Batchelor J,Gavria P,Boulton K,Reeve J.Everyday Executive Functioning Profiles in Adults with Down Syndrome.J Autism Dev Disord.2024;[Epub ahead of print]

[70] Hamadelseed O,Chan MKS,Wong MBF,Skutella T.Distinct neuroanatomical and neuropsychological features of Down syndrome compared to related neurodevelopmental disorders: a systematic review.Front Neurosci.2023;17:1225228.

[71] Rodrigues M,Nunes J,Figueiredo S,Martins de Campos A,Geraldo AF.Neuroimaging assessment in Down syndrome: a pictorial review.Insights Imaging.2019;10:52.

[72] Teipel SJ,Hampel H.Neuroanatomy of Down syndrome in vivo: a model of preclinical Alzheimer’s disease.Behav Genet.2006;36:405-15.

[73] Pujol J,Fenoll R,Ribas-Vidal N,Martínez-Vilavella G,Blanco-Hinojo L,García-Alba J,et al.A longitudinal study of brain anatomy changes preceding dementia in Down syndrome.Neuroimage Clin.2018;18:160-6.

[74] Mullins D,Daly E,Simmons A,Beacher F,Foy CM,Lovestone S,et al.Dementia in Down’s syndrome: an MRI comparison with Alzheimer’s disease in the general population.J Neurodev Disord.2013;5:19.

[75] Pennington BF,Moon J,Edgin J,Stedron J,Nadel L.The neuropsychology of Down syndrome: evidence for hippocampal dysfunction.Child Dev.2003;74:75-93.

[76] de Graaf G,Buckley F,Skotko BG.Estimation of the number of people with Down syndrome in the United States.Genet Med.2017;19:439-47.

[77] de Graaf G,Buckley F,Skotko BG.Estimation of the number of people with Down syndrome in Europe.Eur J Hum Genet.2021;29:402-10.

[78] Yang Q,Rasmussen SA,Friedman JM.Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study.Lancet.2002;359:1019-25.

[79] Franceschi C,Garagnani P,Gensous N,Bacalini MG,Conte M,Salvioli S.Accelerated bio-cognitive aging in Down syndrome: State of the art and possible deceleration strategies.Aging Cell.2019;18:e12903.

[80] Ishihara K,Kawashita E,Akiba S.Bio-Metal Dyshomeostasis-Associated Acceleration of Aging and Cognitive Decline in Down Syndrome.Biol Pharm Bull.2023;46:1169-75.

[81] Peng L,Baradar AA,Aguado J,Wolvetang E.Cellular senescence and premature aging in Down Syndrome.Mech Ageing Dev.2023;212:111824.

[82] Carfì A,Liperoti R,Fusco D,Giovannini S,Brandi V,Vetrano DL,et al.Bone mineral density in adults with Down syndrome.Osteoporos Int.2017;28:2929-34.

[83] Kinnear D,Morrison J,Allan L,Henderson A,Smiley E,Cooper S.Prevalence of physical conditions and multimorbidity in a cohort of adults with intellectual disabilities with and without Down syndrome: cross-sectional study.BMJ Open.2018;8:e018292.

[84] Vis JC,de Bruin-Bon RH,Bouma BJ,Backx AP,Huisman SA,Imschoot L,et al.‘The sedentary heart’: physical inactivity is associated with cardiac atrophy in adults with an intellectual disability.Int J Cardiol.2012;158:387-93.

[85] Xu K,Li S,Muskens IS,Elliott N,Myint SS,Pandey P,et al.Accelerated epigenetic aging in newborns with Down syndrome.Aging Cell.2022;21:e13652.

[86] Horvath S,Garagnani P,Bacalini MG,Pirazzini C,Salvioli S,Gentilini D,et al.Accelerated epigenetic aging in Down syndrome.Aging Cell.2015;14:491-5.

[87] Alldred MJ,Martini AC,Patterson D,Hendrix J,Granholm A.Aging with Down Syndrome—Where Are We Now and Where Are We Going?J Clin Med.2021;10:4687.

[88] Scheltens P,Strooper BD,Kivipelto M,Holstege H,Chételat G,Teunissen CE,et al.Alzheimer’s disease.Lancet.2021;397:1577-90.

[89] Knopman DS,Amieva H,Petersen RC,Chételat G,Holtzman DM,Hyman BT,et al.Alzheimer disease.Nat Rev Dis Primers.2021;7:33.

[90] 2024 Alzheimer’s disease facts and figures.Alzheimers Dement.2024;20:3708-821.

[91] Chen X,Zuo X.New insights into the effects of APP gene dose on synapse in Down syndrome.Neural Regen Res.2024;19:961-2.

[92] Mori C,Spooner ET,Wisniewsk KE,Wisniewski TM,Yamaguch H,Saido TC,et al.Intraneuronal Abeta42 accumulation in Down syndrome brain.Amyloid.2002;9:88-102.

[93] Gomez W,Morales R,Maracaja-Coutinho V,Parra V,Nassif M.Down syndrome and Alzheimer’s disease: common molecular traits beyond the amyloid precursor protein.Aging (Albany NY).2020;12:1011-33.

[94] Martínez-Cué C,Rueda N.Signalling Pathways Implicated in Alzheimer’s Disease Neurodegeneration in Individuals with and without Down Syndrome.Int J Mol Sci.2020;21:6906.

[95] Carmona-Iragui M,Balasa M,Benejam B,Alcolea D,Fernández S,Videla L,et al.Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer’s disease.Alzheimers Dement.2017;13:1251-60.

[96] Lott IT,Head E,Doran E,Busciglio J.Beta-amyloid, oxidative stress and Down syndrome.Curr Alzheimer Res.2006;3:521-8.

[97] Iannello RC,Crack PJ,de Haan JB,Kola I.Oxidative stress and neural dysfunction in Down syndrome.J Neural Transm Suppl.1999;57:257-67.

[98] Cenini G,Dowling ALS,Beckett TL,Barone E,Mancuso C,Murphy MP,et al.Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome.Biochim Biophys Acta.2012;1822:130-8.

[99] Cordeiro AMT,Singulani MP,Talib LL,Forlenza OV.Down syndrome and Alzheimer’s disease: Oxidative stress in the neurodegenerative process.J Alzheimers Dis.2025;105:258-67.

[100] Zis P,Dickinson M,Shende S,Walker Z,Strydom A.Oxidative stress and memory decline in adults with Down syndrome: longitudinal study.J Alzheimers Dis.2012;31:277-83.

[101] Murakami K,Murata N,Noda Y,Tahara S,Kaneko T,Kinoshita N,et al.SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer disease.J Biol Chem.2011;286:44557-68.

[102] Busciglio J,Yankner BA.Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro.Nature.1995;378:776-9.

[103] Tan K,Lee H,Cheah P,Ling K.Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy.Neuroscience.2023;511:1-12.

[104] Zuo X.Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?Aging Dis.2025;[Epub ahead of print]

[105] Beresford-Webb JA,McAllister CJ,Sleigh A,Walpert MJ,Holland AJ,Zaman SH.Mitochondrial Dysfunction Correlates with Brain Amyloid Binding, Memory, and Executive Function in Down Syndrome: Implications for Alzheimer’s Disease in Down Syndrome.Brain Sci.2025;15:130.

[106] Ganguly BB,Kadam NN.Triplication of HSA21 on alterations in structure and function of mitochondria.Mitochondrion.2022;65:88-101.

[107] Coskun PE,Wyrembak J,Derbereva O,Melkonian G,Doran E,Lott IT,et al.Systemic mitochondrial dysfunction and the etiology of Alzheimer’s disease and down syndrome dementia.J Alzheimers Dis.2010;20:S293-310.

[108] Coskun PE,Busciglio J.Oxidative Stress and Mitochondrial Dysfunction in Down’s Syndrome: Relevance to Aging and Dementia.Curr Gerontol Geriatr Res.2012;2012:383170.

[109] Helguera P,Seiglie J,Rodriguez J,Hanna M,Helguera G,Busciglio J.Adaptive downregulation of mitochondrial function in Down syndrome.Cell Metab.2013;17:132-40.

[110] Busciglio J,Pelsman A,Wong C,Pigino G,Yuan M,Mori H,et al.Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down’s syndrome.Neuron.2002;33:677-88.

[111] Thirumalai S,Livesey FJ,Patani R,Hung C.APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes.Alzheimers Dement.2025;21:e14560.

[112] Ma X,Li W,Ma J,Han Z,Deng S,Wang S.Autophagy is a promising process for linking inflammation and redox homeostasis in Down syndrome.Front Pharmacol.2024;15:1491563.

[113] Drachman DA,Smith TW,Alkamachi B,Kane K.Microvascular changes in Down syndrome with Alzheimer’s-type pathology: Insights into a potential vascular mechanism for Down syndrome and Alzheimer’s disease.Alzheimers Dement.2017;13:1389-96.

[114] Head E,Phelan MJ,Doran E,Kim RC,Poon WW,Schmitt FA,et al.Cerebrovascular pathology in Down syndrome and Alzheimer disease.Acta Neuropathol Commun.2017;5:93.

[115] Reed-Cossairt A,Zhu X,Lee H,Reed C,Perry G,Petersen RB.Alzheimer’s disease and vascular deficiency: lessons from imaging studies and Down syndrome.Curr Gerontol Geriatr Res.2012;2012:929734.

[116] Edwards NC,Lao PJ,Alshikho MJ,Ericsson OM,Rizvi B,Petersen ME,et al.Cerebrovascular disease is associated with Alzheimer’s plasma biomarker concentrations in adults with Down syndrome.Brain Commun.2024;6:fcae331.

[117] Lao P,Edwards N,Flores-Aguilar L,Alshikho M,Rizvi B,Tudorascu D,et al.Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome.Sci Rep.2024;14:12334.

[118] Carmona-Iragui M,Videla L,Lleó A,Fortea J.Down syndrome, Alzheimer disease, and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis.Dev Neurobiol.2019;79:716-37.

[119] Smith EE,Greenberg SM.β-amyloid, blood vessels, and brain function.Stroke.2009;40:2601-6.

[120] Martini AC,Gross TJ,Head E,Mapstone M.Beyond amyloid: Immune, cerebrovascular, and metabolic contributions to Alzheimer disease in people with Down syndrome.Neuron.2022;110:2063-79.

[121] Karlsen AS,Pakkenberg B.Total numbers of neurons and glial cells in cortex and basal ganglia of aged brains with Down syndrome—a stereological study.Cereb Cortex.2011;21:2519-24.

[122] Karlsen AS,Korbo S,Uylings HBM,Pakkenberg B.A stereological study of the mediodorsal thalamic nucleus in Down syndrome.Neuroscience.2014;279:253-9.

[123] Uguagliati B,Grilli M.Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation.Cells.2024;13:2037.

[124] García O,Flores-Aguilar L.Astroglial and microglial pathology in Down syndrome: Focus on Alzheimer’s disease.Front Cell Neurosci.2022;16:987212.

[125] Wilcock DM,Hurban J,Helman AM,Sudduth TL,McCarty KL,Beckett TL,et al.Down syndrome individuals with Alzheimer’s disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer’s disease.Neurobiol Aging.2015;36:2468-74.

[126] Garcia O,Torres M,Helguera P,Coskun P,Busciglio J.A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down’s syndrome.PLoS One.2010;5:e14200.

[127] Torres MD,Garcia O,Tang C,Busciglio J.Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome.Free Radic Biol Med.2018;114:10-4.

[128] Garcia O,Villegas-Piña JA.Thrombospondin-1 (TSP-1) and Neuronal Plasticity: Implications in Down Syndrome.Med Res Arch.2022;10:1-14.

[129] Son SM,Nam DW,Cha M,Kim KH,Byun J,Ryu H,et al.Thrombospondin-1 prevents amyloid beta-mediated synaptic pathology in Alzheimer’s disease.Neurobiol Aging.2015;36:3214-27.

[130] Rao KVR,Curtis KM,Johnstone JT,Norenberg MD.Amyloid-β inhibits thrombospondin 1 release from cultured astrocytes: effects on synaptic protein expression.J Neuropathol Exp Neurol.2013;72:735-44.

[131] Isenberg JS,Roberts DD.Thrombospondin-1 in maladaptive aging responses: a concept whose time has come.Am J Physiol Cell Physiol.2020;319:C45-63.

[132] Habib N,McCabe C,Medina S,Varshavsky M,Kitsberg D,Dvir-Szternfeld R,et al.Disease-associated astrocytes in Alzheimer’s disease and aging.Nat Neurosci.2020;23:701-6.

[133] Head E,Azizeh BY,Lott IT,Tenner AJ,Cotman CW,Cribbs DH.Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down Syndrome.Neurobiol Dis.2001;8:252-65.

[134] Veteleanu A,Pape S,Davies K,Kodosaki E,Hye A,Zelek WM,et al.Complement dysregulation and Alzheimer’s disease in Down syndrome.Alzheimers Dement.2023;19:1383-92.

[135] Parodi-Rullán RM,Javadov S,Fossati S.Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer’s Disease.Cells.2021;10:2903.

[136] Fernández-Blanco Á,Sierra C,Tejido C,Dierssen M.Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome.Int J Mol Sci.2024;25:3289.

[137] Pinto B,Morelli G,Rastogi M,Savardi A,Fumagalli A,Petretto A,et al.Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome.Neuron.2020;108:887-904.e12.

[138] Jin M,Xu R,Wang L,Alam MM,Ma Z,Zhu S,et al.Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer’s disease.Cell Stem Cell.2022;29:1135-53.e8.

[139] Streit WJ,Braak H,Xue Q,Bechmann I.Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease.Acta Neuropathol.2009;118:475-85.

[140] Xue Q,Streit WJ.Microglial pathology in Down syndrome.Acta Neuropathol.2011;122:455-66.

[141] Reiche L,Küry P,Göttle P.Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?Cells.2019;8:1591.

[142] Olmos-Serrano JL,Kang HJ,Tyler WA,Silbereis JC,Cheng F,Zhu Y,et al.Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.Neuron.2016;89:1208-22.

[143] Rosas HD,Hsu E,Mercaldo ND,Lai F,Pulsifer M,Keator D,et al.Alzheimer-related altered white matter microstructural integrity in Down syndrome: A model for sporadic AD?Alzheimers Dement (Amst).2020;12:e12040.

[144] Ferrer I,Gullotta F.Down’s syndrome and Alzheimer’s disease: dendritic spine counts in the hippocampus.Acta Neuropathol.1990;79:680-5.

[145] Buée L,Hof PR,Roberts DD,Delacourte A,Morrison JH,Fillit HM.Immunohistochemical identification of thrombospondin in normal human brain and in Alzheimer’s disease.Am J Pathol.1992;141:783-8.

[146] Martinez JL,Zammit MD,West NR,Christian BT,Bhattacharyya A.Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease.Front Aging Neurosci.2021;13:703876.

[147] Wegiel J,Flory M,Kuchna I,Nowicki K,Wegiel J,Ma SY,et al.Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome.Acta Neuropathol Commun.2022;10:2.

[148] Antonarakis SE.Down syndrome and the complexity of genome dosage imbalance.Nat Rev Genet.2017;18:147-63.

[149] Sukreet S,Rafii MS,Rissman RA.From understanding to action: Exploring molecular connections of Down syndrome to Alzheimer’s disease for targeted therapeutic approach.Alzheimers Dement (Amst).2024;16:e12580.

[150] Hunter S,Hendrix J,Freeman J,Dowell RD,Allen MA.Transcription dosage compensation does not occur in Down syndrome.BMC Biol.2023;21:228.

[151] Starbuck JM,Cole TM 3rd,Reeves RH,Richtsmeier JT.Trisomy 21 and facial developmental instability.Am J Phys Anthropol.2013;151:49-57.

[152] Ovod V,Ramsey KN,Mawuenyega KG,Bollinger JG,Hicks T,Schneider T,et al.Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.Alzheimers Dement.2017;13:841-9.

[153] George A,Venkatesan S,Ashok N,Saraswathy R,Hande MP.Assessment of genomic instability and proliferation index in cultured lymphocytes of patients with Down syndrome, congenital anomalies and aplastic anaemia.Mutat Res Genet Toxicol Environ Mutagen.2018;836:98-103.

[154] Rafferty K,Archer KJ,Turner K,Brown R,Jackson-Cook C.Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome.PLoS One.2021;16:e0254806.

[155] Lightfoot DA,Höög C.Low level chromosome instability in embryonic cells of primary aneuploid mice.Cytogenet Genome Res.2004;107:95-8.

[156] Hampel H,Hardy J,Blennow K,Chen C,Perry G,Kim SH,et al.The Amyloid-β Pathway in Alzheimer’s Disease.Mol Psychiatry.2021;26:5481-503.

[157] Shukla R,Kumar A,Kelvin DJ,Singh TR.Disruption of DYRK1A-induced hyperphosphorylation of amyloid-beta and tau protein in Alzheimer’s disease: An integrative molecular modeling approach.Front Mol Biosci.2023;9:1078987.

[158] Wegiel J,Kaczmarski W,Barua M,Kuchna I,Nowicki K,Wang K,et al.Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome.J Neuropathol Exp Neurol.2011;70:36-50.

[159] Lee S,Ahnn J.Regulator of Calcineurin (RCAN): Beyond Down Syndrome Critical Region.Mol Cells.2020;43:671-85.

[160] Wong H,Buck JM,Borski C,Pafford JT,Keller BN,Milstead RA,et al.RCAN1 knockout and overexpression recapitulate an ensemble of rest-activity and circadian disruptions characteristic of Down syndrome, Alzheimer’s disease, and normative aging.J Neurodev Disord.2022;14:33.

[161] Zussy C,Loustalot F,Junyent F,Gardoni F,Bories C,Valero J,et al.Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity.J Neurosci.2016;36:9558-71.

[162] Zhou M,Huang T,Collins N,Zhang J,Shen H,Dai X,et al.APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice.Curr Alzheimer Res.2016;13:1048-55.

[163] Helguera P,Pelsman A,Pigino G,Wolvetang E,Head E,Busciglio J.ets-2 promotes the activation of a mitochondrial death pathway in Down’s syndrome neurons.J Neurosci.2005;25:2295-303.

[164] Wolvetang EW,Bradfield OM,Tymms M,Zavarsek S,Hatzistavrou T,Kola I,et al.The chromosome 21 transcription factor ETS2 transactivates the β-APP promoter: implications for Down syndrome.Biochim Biophys Acta.2003;1628:105-10.

[165] Perdomo-Sabogal A,Nowick K,Piccini I,Sudbrak R,Lehrach H,Yaspo M,et al.Human Lineage-Specific Transcriptional Regulation through GA-Binding Protein Transcription Factor Alpha (GABPa).Mol Biol Evol.2016;33:1231-44.

[166] Norambuena A,Sun X,Wallrabe H,Cao R,Sun N,Pardo E,et al.SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers.Neurobiol Dis.2022;169:105737.

[167] Patel A,Rees SD,Kelly MA,Bain SC,Barnett AH,Thalitaya D,et al.Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer’s disease in subjects with Down syndrome.Neurosci Lett.2011;487:144-8.

[168] Liu Y,Zhang Y,Ren Z,Zeng F,Yan J.RUNX1 Upregulation Causes Mitochondrial Dysfunction via Regulating the PI3K-Akt Pathway in iPSC from Patients with Down Syndrome.Mol Cells.2023;46:219-30.

[169] Malle L,Bogunovic D.Down syndrome and type I interferon: not so simple.Curr Opin Immunol.2021;72:196-205.

[170] Pellegrini-Calace M,Tramontano A.Identification of a novel putative mitogen-activated kinase cascade on human chromosome 21 by computational approaches.Bioinformatics.2006;22:775-8.

[171] Miranda AM,Herman M,Cheng R,Nahmani E,Barrett G,Micevska E,et al.Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer’s Disease.Cell Rep.2018;23:2967-75.

[172] Hwang R Jr,Dang L,Chen J,Lee JH,Marquer C.Triplication of Synaptojanin 1 in Alzheimer’s Disease Pathology in Down Syndrome.Curr Alzheimer Res.2022;19:795-807.

[173] Martin SB,Dowling ALS,Lianekhammy J,Lott IT,Doran E,Murphy MP,et al.Synaptophysin and synaptojanin-1 in Down syndrome are differentially affected by Alzheimer’s disease.J Alzheimers Dis.2014;42:767-75.

[174] Voronov SV,Frere SG,Giovedi S,Pollina EA,Borel C,Zhang H,et al.Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down’s syndrome.Proc Natl Acad Sci U S A.2008;105:9415-20.

[175] Gurses MS,Ural MN,Gulec MA,Akyol O,Akyol S.Pathophysiological Function of ADAMTS Enzymes on Molecular Mechanism of Alzheimer’s Disease.Aging Dis.2016;7:479-90.

[176] Ichinohe A,Kanaumi T,Takashima S,Enokido Y,Nagai Y,Kimura H.Cystathionine β-synthase is enriched in the brains of Down’s patients.Biochem Biophys Res Commun.2005;338:1547-50.

[177] Cheng JS,Dubal DB,Kim DH,Legleiter J,Cheng IH,Yu G,et al.Collagen VI protects neurons against Aβ toxicity.Nat Neurosci.2009;12:119-21.

[178] Pérez-Villarreal JM,Aviña-Padilla K,Beltrán-López E,Guadrón-Llanos AM,López-Bayghen E,Magaña-Gómez J,et al.Profiling of circulating chromosome 21-encoded microRNAs, miR-155, and let-7c, in down syndrome.Mol Genet Genomic Med.2022;10:e1938.

[179] Lehmann SM,Krüger C,Park B,Derkow K,Rosenberger K,Baumgart J,et al.An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration.Nat Neurosci.2012;15:827-35.

[180] Alexandrov PN,Percy ME,Lukiw WJ.Chromosome 21-Encoded microRNAs (mRNAs): Impact on Down’s Syndrome and Trisomy-21 Linked Disease.Cell Mol Neurobiol.2018;38:769-74.

[181] Chaves JCS,Machado FT,Almeida MF,Bacovsky TB,Ferrari MFR.microRNAs expression correlates with levels of APP, DYRK1A, hyperphosphorylated Tau and BDNF in the hippocampus of a mouse model for Down syndrome during ageing.Neurosci Lett.2020;714:134541.

[182] Lepagnol-Bestel A,Zvara A,Maussion G,Quignon F,Ngimbous B,Ramoz N,et al.DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.Hum Mol Genet.2009;18:1405-14.

[183] Farley SJ,Grishok A,Zeldich E.Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain.Epigenetics Chromatin.2022;15:39.

[184] Fulton SL,Wenderski W,Lepack AE,Eagle AL,Fanutza T,Bastle RM,et al.Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome.Nat Commun.2022;13:6384.

[185] Tafazoli A,Behjati F,Farhud DD,Abbaszadegan MR.Combination of Genetics and Nanotechnology for Down Syndrome Modification: A Potential Hypothesis and Review of the Literature.Iran J Public Health.2019;48:371-8.

[186] González Molina LA,Dekker AD,De Deyn PP,Dolga AM,Rots MG.Epigenetics and Down syndrome. In: Peedicayil J,Grayson DR,Tollefsbol T. editors.Neuropsychiatric Disorders and Epigenetics (Second Edition).Boston:Academic Press2024.pp. 139–81.

[187] Jones MJ,Farré P,McEwen LM,Macisaac JL,Watt K,Neumann SM,et al.Distinct DNA methylation patterns of cognitive impairment and trisomy 21 in Down syndrome.BMC Med Genomics.2013;6:58.

[188] Do C,Xing Z,Yu YE,Tycko B.Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models.Epigenomics.2017;9:189-207.

[189] Pal S,Tyler JK.Epigenetics and aging.Sci Adv.2016;2:e1600584.

[190] Sanchez-Mut JV,Gräff J.Epigenetic Alterations in Alzheimer’s Disease.Front Behav Neurosci.2015;9:347.

[191] Plano LMD,Saitta A,Oddo S,Caccamo A.Navigating Alzheimer’s Disease Mouse Models: Age-Related Pathology and Cognitive Deficits.Biomolecules.2024;14:1405.

[192] Haertle L,Müller T,Lardenoije R,Maierhofer A,Dittrich M,Riemens RJM,et al.Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer’s disease-related dysregulation.Clin Epigenetics.2019;11:195.

[193] Lu J,Mccarter M,Lian G,Esposito G,Capoccia E,Delli-Bovi LC,et al.Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression.Hum Mol Genet.2016;25:1714-27.

[194] Epping MT,Meijer LAT,Krijgsman O,Bos JL,Pandolfi PP,Bernards R.TSPYL5 suppresses p53 levels and function by physical interaction with USP7.Nat Cell Biol.2011;13:102-8.

[195] Fonseca LM,Navatta ACR,Bottino CMC,Miotto EC.Cognitive Rehabilitation of Dementia in Adults with Down Syndrome: A Review of Non-Pharmacological Interventions.Dement Geriatr Cogn Dis Extra.2015;5:330-40.

[196] Rubin DA,Clark B,Lam J,Vuong V,Brito J,Fisher KL.Is an Online Asynchronous Progressive Resistance Training Programme Feasible for Individuals With Down Syndrome?J Appl Res Intellect Disabil.2025;38:e70040.

[197] Cherni A,Ouerghi N,Jebabli N,Ghouili H,Bougrine H,Bragazzi NL,et al.A Tai Chi Program Improves Physical Performance Measures in Adolescents With Down Syndrome and Enhances Their Parents’ Psychological Well-Being: A Randomized Controlled Trial.Adapt Phys Activ Q.2025;42:228-46.

[198] Suire K,Helsel BC,Bowling A,Staiano AE,Sherman JR,Rice A,et al.The adaptation of the GameSquad exergaming intervention for young adults with Down syndrome: A pilot feasibility study.Disabil Health J.2025;18:101766.

[199] Giuriato M,Gatti A,Pellino VC,Bianchi A,Zanelli S,Pirazzi A,et al.A Tele-Coaching Pilot Study: An Innovative Approach to Enhance Motor Skills in Adolescents With Down Syndrome.J Appl Res Intellect Disabil.2025;38:e70036.

[200] Timaná LCR,García JFC,Filho TB,González AAO,Monsalve NRH,Jimenez NJV.Use of Serious Games in Interventions of Executive Functions in Neurodiverse Children: Systematic Review.JMIR Serious Games.2024;12:e59053.

[201] Dorris JL,Rodakowski J,Caldwell A.Understanding Music Participation for Adults With Down Syndrome.J Intellect Disabil Res.2025;69:527-32.

[202] Keeling LA,Spiridigliozzi GA,Hart SJ,Baker JA,Jones HN,Kishnani PS.Challenges in measuring the effects of pharmacological interventions on cognitive and adaptive functioning in individuals with Down syndrome: A systematic review.Am J Med Genet A.2017;173:3058-66.

[203] Golan-Tripto I,Dor O,Arwas N,Hazan I,Hazan G,Goldbart A.The effect of azithromycin treatment on respiratory morbidity in children with down syndrome.BMC Pediatr.2025;25:53.

[204] Emili M,Stagni F,Russo C,Angelozzi L,Guidi S,Bartesaghi R.Reversal of neurodevelopmental impairment and cognitive enhancement by pharmacological intervention with the polyphenol polydatin in a Down syndrome model.Neuropharmacology.2024;261:110170.

[205] de la Torre R,de Sola S,Hernandez G,Farré M,Pujol J,Rodriguez J,et al.TESDAD study group.Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down’s syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial.Lancet Neurol.2016;15:801-10.

[206] Stagni F,Giacomini A,Guidi S,Ciani E,Ragazzi E,Filonzi M,et al.Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice.Neurobiol Dis.2015;74:204-18.

[207] Martínez-Cué C,Bartesaghi R.Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?Nutrients.2022;14:2880.

[208] Dalal D,Singh L,Singh A.Mechanistic insight unrevealing the potential of Diadzein in ameliorating the Alzheimer’s disease.Front Health Inf.2024;13:7898-906.

[209] Kaur M,Singh S,Singh A,Singh A.Mechanisms of action of formononetin, an extract from Astragalus membranaceus medicinal plant, in ameliorating Alzheimer’s disease.Explor Neurosci.2025;4:100682.

[210] Iacono T,Bigby C,Carling-Jenkins R,Torr J.Taking each day as it comes: staff experiences of supporting people with Down syndrome and Alzheimer’s disease in group homes.J Intellect Disabil Res.2014;58:521-33.

[211] Carling-Jenkins R,Torr J,Iacono T,Bigby C.Experiences of supporting people with Down syndrome and Alzheimer’s disease in aged care and family environments.J Intellect Dev Disabil.2012;37:54-60.

[212] Fredericksen J,Fabbre V.Down Syndrome and Alzheimer’s Disease: Issues and Implications for Social Work Practice.J Gerontol Soc Work.2018;61:4-10.

[213] Shorey S,Seow JSL,Mahendran R,Wee GH,Goh LG,Kua EH.Peer Volunteers’ Journeys Through Training and Engagement in Older Adult Communities: Descriptive Qualitative Study.JMIR Aging.2025;8:e71810.

[214] Kendall L.Supporting all children to reach their potential: practitioner perspectives on creating an inclusive school environment.Education 3-13.2018;47:678-91.

[215] Darla S,Bhat D.Health-related quality of life and coping strategies among families with Down syndrome children in South India.Med J Armed Forces India.2021;77:187-93.

[216] Baumer NT,Becker ML,Capone GT,Egan K,Fortea J,Handen BL,et al.Conducting clinical trials in persons with Down syndrome: summary from the NIH INCLUDE Down syndrome clinical trials readiness working group.J Neurodev Disord.2022;14:22.

[217] Long R,Drawbaugh ML,Davis CM,Goodlett CR,Williams JR,Roper RJ.Usage of and attitudes about green tea extract and Epigallocathechin-3-gallate (EGCG) as a therapy in individuals with Down syndrome.Complement Ther Med.2019;45:234-41.