April 1995

Neuropathological Changes in Down's Syndrome Hippocampal FormationEffect of Age and Apolipoprotein E Genotype

Author Affiliations

From the Neurology Service, Massachusetts General Hospital, Harvard Medical School, Boston (Drs Hyman, Rebeck, and Lai and Mr West); the Shriver Center, Waltham, Mass (Dr Lai); and the Department of Pathological Sciences, University of Manchester (England) (Dr Mann).

Arch Neurol. 1995;52(4):373-378. doi:10.1001/archneur.1995.00540280059019

Background:  The neuropathological changes of Alzheimer's disease occur universally in individuals with Down's syndrome as they reach middle age and worsen with increasing age. Thus, evaluation of patients of various ages with Down's syndrome allows one to construct a life history of the development of neuropathological changes associated with Alzheimer's disease at various points in the disease process.

Methods:  We have used semiquantitative scales and quantitative computerized image analysis techniques to analyze the characteristics of neurofibrillary tangle formation and Aβ amyloid deposition in the hippocampal formation and inferior temporal gyrus in 36 individuals with Down's syndrome ranging in age from 4 to 73 years.

Results:  Neurofibrillary tangles occur in a hierarchical distribution in a circumscribed set of neuronal fields, affecting the entorhinal cortex, area CAl/subiculum, 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) ε4 genotype contained more than twice the amyloid burden of individuals who did not inherit the Apo E ε4 genotype.

Comment:  This large series of cases confirms earlier observations that had suggested early vulnerability of entorhinal cortex and CAl/subiculum for neurofibrillary tangles and a more widespread but specific topography of Aβ 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 Down's syndrome is higher than in sporadic Alzheimer's disease. Inheritance of the Apo E ε4 genotype appears to be an additional (independent) risk factor for developing higher levels of amyloid accumulation.