Intraneuronal Aβ42 accumulation in Down syndrome brain : Original Articles

Studies of the molecular basis of Alzheimer's disease exemplify the increasingly blurred distinction between basic and applied biomedical research. The four genes so far implicated in familial Alzheimer's disease have each been shown to elevate brain levels of the self-aggregating amyloid-beta protein, leading gradually to profound neuronal and glial alteration, synaptic loss and dementia. Progress in understanding this cascade has helped to identify specific therapeutic targets and provides a model for elucidating other neurodegenerative disorders.

One hundred brains of patients with Down's syndrome (DS) who died in institutions for chronic care were examined for clinicopathological correlation of Alzheimer's disease. Fifty-one were below and 49 were above age 30 years at death. Tissues from the right, prefrontal, and hippocampal cortices were processed for microscopy using H&E and Bodian-periodic acid-Schiff impregnation. Morphometric evaluations of plaques and tangles were carried out. Plaques or plaques and tangles were found in the brains of 56 patients with DS, 7 below age 30 and 49 above that age. A history of dementia was evident in the medical records of 15 of these patients; of these only 2 were below the age of 30. The brains of the patients with DS who also had clinical dementia had more than twenty plaques or plaques and tangles per 1.5 X 10(6) micron 2 of cortex. The numbers of plaques and tangles found in the brains of the patients with DS above the age of 30 greatly increased with age but varied from brain to brain. These observations suggest a correlation among dementia, the density of plaques and tangles, and age. All 100 brains studied showed early arrest of brain growth and brain atrophy, a condition that may have been due to prenatal arrest of neurogenesis mainly in the granular cell layers, prenatal and postnatal arrest of synaptogenesis, and early aging. Plaques and tangles developed twenty to thirty years earlier and dementia was clinically detected at least three times more frequently (20 to 30%) in DS than it is known to occur in the non-DS population.