neuropathological changes in downs syndrome hippocampal formation effect of age and apolipoprotein e genotype background the neuropathological changes of alzheimers disease occur universally in individuals with downs syndrome as they reach middle age and worsen with increasing age thus evaluation of patients of various ages with downs syndrome allows one to construct a life history of the development of neuropathological changes associated with alzheimers disease at various points in the disease processmethods we have used semiquantitative scales and quantitative computerized image analysis techniques to analyze the characteristics of neurofibrillary tangle formation and a beta amyloid deposition in the hippocampal formation and inferior temporal gyrus in 36 individuals with downs syndrome ranging in age from 4 to 73 yearsresults neurofibrillary tangles occur in a hierarchical distribution in a circumscribed set of neuronal fields affecting the entorhinal cortex area ca1subiculum then other hippocampal subfields although amyloid deposition occurs more evenly in a more widespread distribution it also accumulates over the years 30 to 50 surprisingly examination of the patients available older than 50 years showed no trend toward continued increased deposition of amyloid within this group however individuals who had inherited the apolipoprotein e apo e epsilon 4 genotype contained more than twice the amyloid burden of individuals who did not inherit the apo e epsilon 4 genotypecomment this large series of cases confirms earlier observations that had suggested early vulnerability of entorhinal cortex and ca1subiculum for neurofibrillary tangles and a more widespread but specific topography of a beta deposition moreover it demonstrates quantitatively that the lesions increase to a certain level and then apparently reach a plateau the level of amyloid deposition in downs syndrome is higher than in sporadic alzheimers disease inheritance of the apo e epsilon 4 genotype appears to be an additional independent risk factor for developing higher levels of amyloid accumulation