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The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26\u201372\u00a0years of age were to identify the magnitude of brain region\u2013specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26\u201341-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43\u201349, 51\u201359, and 61\u201372-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26\u201341\u00a0years of age and 11.9% AD-associated neuronal loss in DS subjects 43\u201349\u00a0years of age; a 28.0% maximum neuronal loss at 51\u201359\u00a0years of age; and a 11.0% minimum neuronal loss at 61\u201372\u00a0years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.<\/jats:p>","DOI":"10.1186\/s40478-021-01300-9","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T13:02:50Z","timestamp":1641301370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Developmental deficits and staging of dynamics of age associated Alzheimer\u2019s disease neurodegeneration and neuronal loss in subjects with Down syndrome"],"prefix":"10.1186","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3685-0694","authenticated-orcid":false,"given":"Jerzy","family":"Wegiel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Flory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela","family":"Kuchna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Nowicki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarek","family":"Wegiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang Yong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanbert","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa Wierzba","family":"Bobrowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mony","family":"de Leon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne P.","family":"Silverman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wisniewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,4]]},"reference":[{"key":"1300_CR1","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/ana.21154","volume":"61","author":"C Amador-Ortiz","year":"2007","unstructured":"Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer\u2019s disease. 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Experimental protocols were approved by IBR\u2019s Institutional Review Board. The study was performed by using coded and anonymized brain tissue samples obtained from the tissue banks listed in the Acknowledgements. The anonymized extracts of clinical records were obtained from the New York State Brain and Tissue Bank for Developmental Disabilities and Aging at the New York State Institute for Basic Research in Developmental Disabilities.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2"}}