Early age-related progression of AD-like neuropathology in Down's syndrome

We have previously reported that increased numbers of Alz-50-reactive (apoptotic) neurons occurred in young DS subjects compared to controls, but increased in density with increasing age, and in advance of identifiable senile plaques (SP) in DS. The purpose of the study was to determine if there are further differences in Alzheimer's disease (AD)-like neuropathology with increasing age among individuals with Down's syndrome (DS) compared to cognitively normal age-matched controls. The two populations compared were age-matched normal controls (N = 14) between 11 months and 61 years of age and individuals with DS (N = 8) between 1 and 54 years of age. There were 7 cognitively intact DS and 10 control subjects under 35 years of age. The single demented 54 year old DS subject was compared to 4 non-demented controls between 48 and 61 years of age. 50 μm Vibratome sections of formalin fixed hippocampal formations were immunohistochemically stained for amyloid-β (6E10), APP (22C11) and phosphorylated tau (AT8) using standard methods. AT8 immunoreactive features were found only in the oldest DS subject. In contrast, the number and intensity of amyloid-β-immunoreactive neurons were maximal in the youngest DS subjects (1-24 years), reduced in the young adults (25-35 years) synchronous with the appearance of only diffuse-form SP, and were further reduced in the 54 year-old DS subject exhibiting abundant multiform SP. Distribution of APP immunoreactivity (22C11) was distinct from amyloid-β (6E10) in appearance and by location and age in both DS and normal controls. The data indicates that the earliest observable neuropathologic feature in DS may be neuronal accumulation of amyloid-β. Such accumulation of amyloid-β occurs decades in advance of deposition as SP, which in turn occurs decades before cognitive decline.