Abstract
Down's syndrome (DS, trisomy 21) represents a complex genetic abnormality that leads to pathology in later life that is similar to Alzheimer's disease (AD). We compared two cases of DS with APOE ε3/3 genotypes, a similar age at death, and comparable amyloid-beta 42 peptide (Aβ42) burdens in the brain but that differed markedly in the severity of AD-like pathology. One exhibited extensive neurofibrillary pathology whereas the other showed minimal features of this type. Comparable loads of Aβ42 could relate to the cases' similar life-time accumulation of Aβ due to trisomy 21-enhanced metabolism of amyloid precursor protein (APP). The cases' significant difference in AD-like pathology, however, suggests that parenchymal deposition of Aβ42, even when extensive, may not inevitably trigger AD-like tau pathology (though it may be necessary). Thus, these observations of a natural experiment may contribute to understanding the nuances of the amyloid cascade hypothesis of AD pathogenesis.
Highlights
Down’s syndrome (DS), caused by an additional chromosome 21, most commonly underlies genetic mental retardation
Routine neurohistological sections were prepared at the University of Cincinnati Hospital and additional immunohistochemical studies and determination of the APOE genotypes were carried out at the University of Indiana’s Alzheimer’s Disease Center
Tissue was processed according to standard protocols for embedding the brain in paraffin and each block was stained with hematoxylin and eosin (H&E)
Summary
Down’s syndrome (DS), caused by an additional chromosome 21, most commonly underlies genetic mental retardation. Alzheimer’s disease (AD) is the most common neurodegenerative disease causing dementia. DS is a strong risk factor for dementia that is very similar to AD. DS’ prevalence of dementia increases with age: 8% before age of 50, 55% before age of 60, and 75% after age of 60 years. Sporadic AD manifests increasingly after age of 60 years to affect 1 in 4 at age of 85 years [1]. AD-like pathology develops inevitably in DS brains after age of 40 and stages similar to sporadic AD are recapitulated and accelerated in DS brains [2]. The earliest changes in young DS brains (
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