Down's Can Escape Alzheimer's
ABSTRACT & COMMENTARY
Source: Prasher VP, et al. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol 1998;43: 380-383.
Patients with down's syndrome (ds) usually develop progressive cognitive decline as adults and almost always have Alzheimer's disease (AD) neuropathology at autopsy. It has long been suspected that triplication of the amyloid precursor protein (APP) gene on the long arm of chromosome 21 is responsible for the occurrence of an AD-like dementia syndrome in DS. An intriguing report from the United Kingdom provides further evidence that the APP gene or a near neighbor is the actual culprit in this process. Prasher et al now describe a patient with Down's who was found to have partial trisomy of chromosome 21, causing her to possess three copies of the obligate Down's region but only two of the APP gene. This patient had physical stigmata consistent with Down's syndrome, and a mild learning disability. She was assessed periodically throughout her life for signs of cognitive decline, and lived to age 78 without developing signs of dementia. After her death from Mycoplasma pneumonia, a post-mortem examination was carried out. Her brain was of small size (950 g), as is often the case in DS, but it had no obvious gyral abnormalities. Microscopic analysis revealed only mild chronic ischemic changes and no indication of AD or other neurodegenerative disorders. The dissociation of the Down's from the AD phenotype in this patient suggests that extra copies of the APP gene may be required for the expression of AD pathology in DS patients.
COMMENTARY
The occurrence of AD in Down's patients was among the first identified clues that a gene on chromosome 21 might cause AD. The APP gene is, in fact, found on chromosome 21 near the region that must be triplicated for the Down's phenotype to develop (the obligate Down's region). A mutation in the APP gene was the first identified genetic cause for early onset familial AD, but no APP mutations have been found in the vast majority of DS cases. The dissociation between AD and DS phenotypes in this patient with partial trisomy 21 strongly suggests that triplication of the APP gene is the relevant factor in the development of AD in Down's. Mutations in the APP gene promote excessive production of the amyloid protein or disproportionate formation of the species of beta-amyloid that are prone to form deposits in the brain. However, only 20-30 families throughout the world are known to have AD-causing APP mutations, which has engendered some doubts about the importance of amyloid processing as a primary pathogenetic mechanism for AD. Implicating the APP gene as the locus for AD in Down's, however, extends the relevance of this amyloid-related gene to several hundred thousand cases of AD associated with DS worldwide. It is still possible that another gene in this region of chromosome 21 is involved, and further research will be needed to rule out this possibility. Given recent findings that the presenilin mutations causing early-onset AD affect amyloid processing, there is growing evidence that abnormalities in amyloid are a key element in the development of Alzheimer's disease. -nrr
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