Despite a common set of hallmark neuropathological lesions and clinical symptoms, Alzheimer’s disease has an apparently complex etiology. The disease can be caused by autosomal dominant mutations in at least three genes (encoding the amyloid precursor protein (APP) and the two presenilins). In addition, it can be influenced by certain allelic variants of at least three “risk factor” genes (apolipoprotein E, antichymotrypsin, and interleukin-1), or may arise “sporadically” with no evident genetic component. In the end, as many as 30–40% of individuals over the age of 85 may have some symptoms of Alzheimer’s—underscoring the fact that age itself is the strongest risk factor for the disease.
It has been known for almost twenty years that individuals with trisomy 21 (Down syndrome) exhibit Alzheimer neuropathology by the time they are 30–40 years old. Somewhat later, they also develop dementia, and eventually die of Alzheimer’s disease. Because the gene for amyloid precursor protein (APP) resides on chromosome 21, its consequent overexpression in trisomy 21 cells presumably contributes to the development of Alzheimer’s disease in Down syndrome individuals.
The connection between Down syndrome and Alzheimer’s disease and the application of Occam’s Razor led me to hypothesize that many cases of classical Alzheimer’s disease—both of the genetic and late-onset, sporadic forms—might similarly be caused by chromosome mis-segregation leading to a small number of trisomy 21 cells developing during the life of the affected individual.
In this chapter, I will consider evidence from several laboratories that defects in mitosis, and particularly in chromosome segregation, may be a part of the Alzheimer disease process. In particular, mutations in the presenilin genes that cause Alzheimer’s disease also cause chromosome instability. By generating a mosaic population of trisomy 21 and other aneuploid cells, such a mitotic defect could lead to Alzheimer pathology and dementia by inducing inflammation, apoptosis, and/or altered processing of the APP protein into the neurotoxic amyloid β-protein—all characteristic features of the disease. The possibility that many cases of Alzheimer’s disease are mosaic for trisomy 21 suggests novel approaches to diagnosis and therapy.