A subset of aged individuals with Down syndrome (DS) exhibits the clinical
features of Alzheimer's disease (AD) but our ability to detect dementia in
this population is hampered by developmental differences as well as the sen
sitivity of existing test tools. Despite the apparent clinical heterogeneit
y in aged individuals with DS, age-associated neuropathology is a consisten
t feature. This is due to the fact that trisomy 21 leads to a dose-dependen
t increase in the production of the amyloid precursor protein and subsequen
tly the production of the amyloidogenic fragments leading to early and pred
ominant senile plaque formation. A review of the existing literature indica
tes that oxidative damage and neuroinflammation may interact to accelerate
the disease process particularly in individuals with DS over the age of 40
years. By combining clinical information with measures of brain-region spec
ific neuropathology we can "work backwards" and identify the earliest and m
ost sensitive clinical change that may signal the onset of AD. For the past
50 years, investigators in the fields of mental retardation, developmental
disabilities, and aging have been interested in the curious link between A
D and DS. The morphologic and biochemical origins of AD are seen in the ear
ly years of the lifespan for individuals with DS. Study of the process by w
hich AD evolves in DS affords an opportunity to understand an important lin
k between development and aging. This review will focus on advances in the
molecular and clinical basis of this association. (C) 2001 Wiley Liss, Inc.