{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T12:34:13Z","timestamp":1771850053435,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T00:00:00Z","timestamp":1626739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004515","name":"Universiti Kebangsaan Malaysia","doi-asserted-by":"publisher","award":["Dana Fundamental PPUKM (PPUKM Fundamental Fund) FF-2020-013"],"award-info":[{"award-number":["Dana Fundamental PPUKM (PPUKM Fundamental Fund) FF-2020-013"]}],"id":[{"id":"10.13039\/501100004515","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Purpose: The olfactory system is particularly vulnerable in an ageing brain, both anatomically and functionally, and these brain changes are more pronounced among individuals with trisomy 21. Furthermore, the age of the system starts to deteriorate, and the mechanism involved is unclear in an individual with trisomy 21. Therefore, the present review aims to summarise the available information related to this topic and to suggest questions still unanswered which can be a subject of further research. Methods: A systematic literature search of trisomy 21 and olfactory dysfunction was conducted using PubMed\/MEDLINE and Scopus electronic database following PRISMA guidelines. References and citations were checked in the Google Scholar database. Reports were extracted for information on demographics and psychophysical evaluation. Then, the reports were systematically reviewed based on the effects of ageing on the three olfactory domains: threshold, discrimination, and identification. Results: Participants with trisomy 21 show an early onset of olfactory impairment, and the age effect of the olfactory deficit is fully expressed at age &gt; 30 years old. The three olfactory domains, threshold, discrimination, and identification, are suggested to be impaired in trisomy 21 participants with age &gt; 30 years old. Conclusions: Olfactory dysfunction in an individual with trisomy 21 commences at a relatively young age and affects the three olfactory domains. A challenge for the future is to quantitatively establish the olfactory function of an individual with trisomy 21 at all ages with more detailed measurements to further understand the pathophysiology of this brain deterioration.<\/jats:p>","DOI":"10.3390\/brainsci11070952","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T05:10:59Z","timestamp":1626757859000},"page":"952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Ageing and Olfactory Dysfunction in Trisomy 21: A Systematic Review"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6769-0603","authenticated-orcid":false,"given":"Hanani Abdul","family":"Manan","sequence":"first","affiliation":[{"name":"Makmal Pemprosesan Imej Kefungsian, Department of Radiology, Faculty of Medicine, Pusat Perubatan Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-6489","authenticated-orcid":false,"given":"Noorazrul","family":"Yahya","sequence":"additional","affiliation":[{"name":"Diagnostic Imaging & Radiotherapy Program, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12929-015-0138-y","article-title":"Down syndrome: An insight of the disease","volume":"22","author":"Asim","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1002\/bdr2.1589","article-title":"National population-based estimates for major birth defects, 2010\u20132014","volume":"111","author":"Mai","year":"2019","journal-title":"Birth Defects Res."},{"key":"ref_3","first-page":"246","article-title":"Incidence of Down\u2019s syndrome in a large Malaysian maternity hospital over an 18 month period","volume":"30","author":"Hoe","year":"1989","journal-title":"Singap. Med. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Roizen, N., and Myers, K. (2019). Down Syndrome. Encyclopedia of Infant and Early Childhood Development, Elsevier BV.","DOI":"10.1016\/B978-0-12-809324-5.23057-5"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1111\/j.1365-2788.2007.01013.x","article-title":"Hospitalizations of infants and young children with Down syndrome: Evidence from inpatient person-records from a statewide administrative database","volume":"51","author":"So","year":"2007","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_6","first-page":"76","article-title":"Down syndrome and leukemia: Insights into leukemogenesis and translational targets","volume":"4","author":"Mateos","year":"2015","journal-title":"Transl. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S1474-4422(10)70112-5","article-title":"Cognitive deficits and associated neurological complications in individuals with Down\u2019s syndrome","volume":"9","author":"Lott","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s00281-020-00804-1","article-title":"Down syndrome, accelerated aging and immunosenescence","volume":"42","author":"Gensous","year":"2020","journal-title":"Semin. Immunopathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/ddrr.1128","article-title":"Atypical aging in down syndrome","volume":"18","author":"Zigman","year":"2013","journal-title":"Dev. Disabil. Res. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1212\/WNL.44.2.232","article-title":"Cognitive impairment in adults with Down\u2019s syndrome: Similarities to early cognitive changes in Alzheimer\u2019s disease","volume":"44","author":"Brugge","year":"1994","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cecchini, M.P., Viviani, D., Sandri, M., H\u00e4hner, A., Hummel, T., and Zancanaro, C. (2016). Olfaction in People with Down Syndrome: A Comprehensive Assessment across Four Decades of Age. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0146486"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.otohns.2005.12.035","article-title":"Nasal health in Down syndrome: A cross-sectional study","volume":"134","author":"Chen","year":"2006","journal-title":"Otolaryngol. Neck Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/0028-3932(93)90152-P","article-title":"Olfactory identification deficits in down\u2019s syndrome and idiopathic mental retardation","volume":"31","author":"Hemdal","year":"1993","journal-title":"Neuropsychologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1136\/jnnp.61.4.412","article-title":"Olfactory function in young adolescents with Down\u2019s syndrome","volume":"61","author":"McKeown","year":"1996","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/0197-4580(90)90014-Q","article-title":"Olfactory thresholds are associated with degree of dementia in Alzheimer\u2019s disease","volume":"11","author":"Murphy","year":"1990","journal-title":"Neurobiol. Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/0197-4580(96)00008-5","article-title":"Olfactory dysfunction in down\u2019s syndrome","volume":"17","author":"Murphy","year":"1996","journal-title":"Neurobiol. Aging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1001\/jama.288.18.2307","article-title":"Prevalence of Olfactory Impairment in Older Adults","volume":"288","author":"Murphy","year":"2002","journal-title":"JAMA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0197-4580(01)00263-9","article-title":"Olfactory impairment increases as a function of age in persons with Down syndrome","volume":"23","author":"Nijjar","year":"2002","journal-title":"Neurobiol. Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"649","DOI":"10.3758\/BF03211788","article-title":"Smell and taste function in the visually impaired","volume":"54","author":"Smith","year":"1993","journal-title":"Percept. Psychophys."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"627","DOI":"10.2466\/pms.1994.78.2.627","article-title":"Olfactory Deficits in down Subjects: A Link with Alzheimer Disease","volume":"78","author":"Zucco","year":"1994","journal-title":"Percept. Mot. Ski."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1017\/S0033291700009120","article-title":"Down\u2019s Syndrome and Alzheimer\u2019s disease: A review","volume":"16","author":"Oliver","year":"1986","journal-title":"Psychol. Med."},{"key":"ref_22","first-page":"11","article-title":"Alzheimer\u2019s disease in premorbidly normal and Down\u2019s syndrome individuals: Selective involvement of hippocampus and neocortical asso-ciative brain regions","volume":"53","author":"Schapiro","year":"1988","journal-title":"Brain Dysfunct."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1093\/jnen\/63.7.679","article-title":"Trisomy 21 and the Brain","volume":"63","author":"Mrak","year":"2004","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"869","DOI":"10.2147\/NDT.S104886","article-title":"Olfactory dysfunction in Alzheimer\u2019s disease","volume":"12","author":"Zou","year":"2016","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrneurol.2012.80","article-title":"Olfactory dysfunction in Parkinson disease","volume":"8","author":"Doty","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1001\/archneurol.2008.521","article-title":"Olfactory Function in Corticobasal Syndrome and Frontotemporal Dementia","volume":"66","author":"Pardini","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/ana.21910","article-title":"Olfactory epithelium amyloid-\u03b2 and paired helical filament-tau pathology in Alzheimer disease","volume":"67","author":"Arnold","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/cne.903100307","article-title":"Human olfactory epithelium in normal aging, alzheimer\u2019s disease, and other neurodegenerative disorders","volume":"310","author":"Trojanowski","year":"1991","journal-title":"J. Comp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0165-0173(86)90008-1","article-title":"Maturation and plasticity in the olfactory system of vertebrates","volume":"11","author":"Brunjes","year":"1986","journal-title":"Brain Res. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/0301-0082(84)90008-X","article-title":"Perireceptor and receptor events in vertebrate olfaction","volume":"23","author":"Getchell","year":"1984","journal-title":"Prog. Neurobiol."},{"key":"ref_31","first-page":"375","article-title":"An autoradiographic study of the mouse olfactory epithelium: Evidence for long-lived receptors","volume":"210","author":"Hinds","year":"1984","journal-title":"Anat. Rec. Adv. Integr. Anat. Evol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mackay-Sim, A., Breipohl, W., and Kremer, M. (1988). Cell dynamics in the olfactory epithelium of the tiger salamander: A morphometric analysis. Exp. Brain Res., 71.","DOI":"10.1007\/BF00247534"},{"key":"ref_33","first-page":"736","article-title":"Pathological changes in olfactory neurons in patients with Alzheimer\u2019s disease","volume":"337","author":"Talamo","year":"1989","journal-title":"Nat. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3389\/fnins.2020.00440","article-title":"Alzheimer\u2019s Disease: What Can We Learn from the Peripheral Olfactory System?","volume":"14","author":"Dibattista","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2046-4053-4-1","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement","volume":"4","author":"Moher","year":"2015","journal-title":"Syst. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"n160","DOI":"10.1136\/bmj.n160","article-title":"PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1007\/s00066-018-1303-5","article-title":"Inclusion of dosimetric data as covariates in toxicity-related radiogenomic studies","volume":"194","author":"Yahya","year":"2018","journal-title":"Strahlenther. Onkol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e188","DOI":"10.1016\/j.wneu.2019.06.027","article-title":"Utilisation of Diffusion Tensor Imaging in Intracranial Radiotherapy and Radiosurgery Planning for White Matter Dose Optimization: A Systematic Review","volume":"130","author":"Yahya","year":"2019","journal-title":"World Neurosurg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.npbr.2020.03.003","article-title":"Functional connectivity changes in patients with brain tumours\u2014A systematic review on resting state-fMRI","volume":"36","author":"Manan","year":"2020","journal-title":"Neurol. Psychiatry Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00234-019-02322-w","article-title":"Utilization of functional MRI language paradigms for pre-operative mapping: A systematic review","volume":"62","author":"Manan","year":"2019","journal-title":"Neuroradiology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1007\/s00520-020-05808-z","article-title":"Neurocognitive impairment following proton therapy for paediatric brain tumour: A systematic review of post-therapy assessments","volume":"29","author":"Yahya","year":"2021","journal-title":"Support. Care Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e13329","DOI":"10.1111\/ecc.13329","article-title":"Diffusion tensor imaging indices to predict cognitive changes following adult radiotherapy","volume":"30","author":"Yahya","year":"2021","journal-title":"Eur. J. Cancer Care"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"del Barrio, V. (2017). Diagnostic and Statistical Manual of Mental Disorders. Reference Module in Neuroscience and Biobehavioral Psychology, Elsevier.","DOI":"10.1016\/B978-0-12-809324-5.05530-9"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1093\/chemse\/10.3.297","article-title":"Internal consistency and short-term test-retest reliability of the University of Pennsylvania Smell Identification Test","volume":"10","author":"Doy","year":"1985","journal-title":"Chem. Senses"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3758\/BF03210709","article-title":"Internal consistency reliability of the fractionated and whole University of Pennsylvania Smell Identification Test","volume":"45","author":"Doty","year":"1989","journal-title":"Percept. Psychophys."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/0031-9384(84)90269-5","article-title":"Development of the university of pennsylvania smell identification test: A sstandardised microencapsulated test of olfactory function","volume":"32","author":"Doty","year":"1984","journal-title":"Physiol. Behav."},{"key":"ref_47","unstructured":"Wechsler, D. (2002). Test de Inteligencia para Adultos: WAIS-III, Casa do Psic\u00f3logo."},{"key":"ref_48","unstructured":"Wechsler, D. (1974). Manual for the Wechsler Intelligence Scale for Children, Psychological Corporation."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1037\/10521-023","article-title":"Peabody Picture Vocabulary Test","volume":"Volume 6","author":"Naglieri","year":"2000","journal-title":"Encyclopedia of Psychology, Volume 6."},{"key":"ref_50","unstructured":"Becker, K. (2003). Stanford-Binet Intelligence Scales, Assessment Service Bulletin Number 1 History of the Stanford-Binet Intelligence Scales: Content and Psychometrics. Intelligence, 14."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/S0196-0709(83)80068-4","article-title":"Clinical evaluation of olfaction","volume":"4","author":"Cain","year":"1983","journal-title":"Am. J. Otolaryngol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/S1388-2457(99)00086-3","article-title":"Individuals with Down\u2019s syndrome demonstrate abnormal olfactory event-related potentials","volume":"110","author":"Wetter","year":"1999","journal-title":"Clin. Neurophysiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1001\/jamaneurol.2015.2952","article-title":"Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia","volume":"73","author":"Roberts","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_54","first-page":"1","article-title":"Olfactory Dysfunction","volume":"110","author":"Hummel","year":"2013","journal-title":"Dtsch. Aerzteblatt Online"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Fitzgerald, P., Leonard, H., Pikora, T.J., Bourke, J., and Hammond, G. (2013). Hospital Admissions in Children with Down Syndrome: Experience of a Population-Based Cohort Followed from Birth. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070401"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"842","DOI":"10.3389\/fnins.2019.00842","article-title":"Brain Structural Correlates of Odor Identification in Mild Cognitive Impairment and Alzheimer\u2019s Disease Revealed by Magnetic Resonance Imaging and a Chinese Olfactory Identification Test","volume":"13","author":"Wu","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41582-018-0097-5","article-title":"Olfactory and other sensory impairments in Alzheimer disease","volume":"15","author":"Murphy","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1111\/j.1749-6632.1998.tb10646.x","article-title":"Odor Memory in Normal Aging and Alzheimer\u2019s Diseasea","volume":"855","author":"Nordin","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1590\/1980-57642018dn12-020004","article-title":"Olfactory dysfunction in Alzheimer\u2019s disease Systematic review and meta-analysis","volume":"12","author":"Silva","year":"2018","journal-title":"Dement. Neuropsychol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3389\/fpsyg.2014.00020","article-title":"The influences of age on olfaction: A review","volume":"5","author":"Doty","year":"2014","journal-title":"Front. Psychol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3233\/JAD-2005-7208","article-title":"Olfactory involvement in aging and Alzheimer\u2019s disease: An autopsy study","volume":"7","author":"Attems","year":"2005","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1080\/13803390701415892","article-title":"Assessment of the influence of cognition and cognitive processing speed on three tests of olfaction","volume":"30","author":"Dulay","year":"2008","journal-title":"J. Clin. Exp. Neuropsychol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/7\/952\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:32:02Z","timestamp":1760164322000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/7\/952"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,20]]},"references-count":62,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["brainsci11070952"],"URL":"https:\/\/doi.org\/10.3390\/brainsci11070952","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,20]]}}}