Developmental deficits and staging of dynamics of age associated Alzheimer\u2019s disease neurodegeneration and neuronal loss in subjects with Down syndrome

Jerzy Wegiel,Michael Flory,Krzysztof Nowicki,Shuang Yong Ma,Teresa Wierzba Bobrowicz,Thomas Wisniewski,Florence Lai,Izabela Kuchna,Wayne P Silverman,Mony De Leon,Jarek Wegiel,Nanbert Zhong

doi:10.1186/s40478-021-01300-9

Abstract

The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21–linked early-onset Alzheimer’s disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26–72 years of age were to identify the magnitude of brain region–specific 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 26–41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43–49, 51–59, and 61–72-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 26–41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43–49 years of age; a 28.0% maximum neuronal loss at 51–59 years of age; and a 11.0% minimum neuronal loss at 61–72 years 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.

Highlights

Down syndrome (DS), caused by trisomy of chromosome 21 [31, 42], is the most common form of chromosomal abnormality; its prevalence increased between 1979 and 2003 from 9.0 to 11.8 per 10,000 live births
Braak/Braak staging of neurofibrillary degeneration detected with monoclonal antibody (mAb) Tau‐1 and Thal et al staging of topographic expansion of β‐amyloidosis detected with mAb 4G8 In DS subjects 26–41 years of age classified in this study as in the pre-Alzheimer’s disease (AD) stage and used for the estimation of developmental deficit without or with very limited AD neuronal loss, Braak stage I of early neurofibrillary degeneration with a few affected neurons was found in two individuals 26 and 28 years of age, whereas in two subjects 41 years of age, the pathology corresponded to stages II and IV (Table 1, Figs. 1 and 2)
In all DS subjects 51 or more years of age with prevalence of mild, moderately severe, and severe AD, the topographic pattern and severity of neurofibrillary degeneration corresponded to Braak final stage VI. β-amyloidosis was absent in a subject 26 years of age, whereas in all DS subjects 28 years of age or older, distribution of amyloid deposits matched that in Thal final phase 5

Summary

Introduction

Down syndrome (DS), caused by trisomy of chromosome 21 [31, 42], is the most common form of chromosomal abnormality; its prevalence increased between 1979 and 2003 from 9.0 to 11.8 per 10,000 live births. The life expectancy of the DS population increased from 9 years. Increase in life expectancy resulted in an increase of the DS population [26, 66]. Positive changes with a significant increase of life expectancy in the DS population are associated with an increased risk of early-onset Alzheimer’s disease (AD) and dementia, exceeding 50% prior to 60 years of age and continuing to rise thereafter [52]. Developmental abnormalities in the brain of DS subjects and developmental intellectual deficits That DS, the leading genetic cause of intellectual disability, is characterized by reduced brain size and a reduced number of neurons throughout development, points to altered neurogenesis as a major determinant of structural and functional anomalies. Neuropathological studies indicate that in DS, developmental defects of neurogenesis might be the main factor contributing to multiregional brain hypoplasia and functional abnormalities including cognitive impairment [57]

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