Alzheimer's disease (AD) is a devastating dementia of late life that is cor
related with a region-specific neuronal cell loss. Despite progress in unco
vering many of the factors that contribute to the etiology of the disease,
the cause of the nerve cell death remains unknown. One promising theory is
that the neurons degenerate because they reenter a lethal cell cycle. This
theory receives support from immunocytochemical evidence for the reexpressi
on of several cell cycle-related proteins. Direct proof for DNA replication
, however, has been lacking. We report here the use of fluorescent in situ
hybridization to examine the chromosomal complement of interphase neuronal
nuclei in the adult human brain. We demonstrate that a significant fraction
of the hippocampal pyramidal and basal forebrain neurons in AD have fully
or partially replicated four separate genetic loci on three different chrom
osomes. Cells in unaffected regions of the AD brain or in the hippocampus o
f nondemented age-matched controls show no such anomalies. We conclude that
the AD neurons complete a nearly full S phase, but because mitosis is not
initiated, the cells remain tetraploid. Quantitative analysis indicates tha
t the genetic imbalance persists for many months before the cells die, and
we propose that this imbalance is the direct cause of the neuronal loss in
Alzheimer's disease.