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The defining pathology of AD was described in 1906, yet it would take six more decades before it was recognized as a common disease affecting the elderly. Meanwhile, Struwe briefly mentioned the finding of senile plaques in a 37-year-old DS individual ("mongoloid") back in a 1929 monograph (Struwe 1929). More careful studies in the 1940s reported senile plaques, neurofibrillary changes, and loss of neurons in DS individuals in the fourth and fifth decades of life. In a study of three DS subjects, Jervis was apparently the first to note that these changes were accompanied by mental deterioration

1 Department of Neurosciences University of California, San Diego, La Jolla, CA USA

in these individuals in their fourth and fifth decades of life (Jervis 1948). While these changes were known to be present in aged individuals, the author noted the uniqueness of the extensive pathological changes in relatively young individuals. Indeed, his own unpublished observations led him to conclude that affected DS individuals older than 35 years of age were susceptible to "early senile dementia." Furthermore, he concluded with foresight that "the finding of this peculiar tendency of mongloloid idiots to develop premature senile dementia may offer some clue with regard to the problem of pathologic aging of the brain. It justifies the hypothesis that certain etiological factors which play a role in mongolism may be similar to those responsible for some of the senile changes... (Jervis 1948)."

Studies performed two decades later, particularly those by Nathan Malamud, established that AD changes in DS were seen in all individuals beyond the age of 40 (Malamud 1972). Moreover, the AD neuropathology in DS was unique to trisomy 21, as it was not seen in mental retardation in general without DS. In the 1970s, the similarity of AD pathology was extended to the ultrastructural level (Burger and Vogel 1973). Therefore, even before the recognition of AD as the most common neurodegenerative disorder with a high prevalence in the mid-1970s, it was well established that the neu-ropathology of AD was fully recapitulated in older DS individuals. Indeed, Malamud and Hirano suggested that "... the chromosomal abnormalities in Down's syndrome might predispose to development of the neuropathologic changes characteristic of Alzheimer's disease (Malamud and Hirano 1974)."

The next important milestone was the sequencing of the amyloid protein in meningeal vessels of adults with DS by Glenner in the early 1980s (Glenner and Wong 1984a). This study was published in the same year as the seminal paper reporting the isolation and identification of amyloid p-protein (Ap) from meningeal vessels of AD subjects. Equally prophetic in their second article was the statement in the abstract that "this is the first chemical evidence of a relationship between Down's syndrome and Alzheimer's disease. Assuming the beta protein [Ap] is a human gene product, it also suggests that the genetic defect in Alzheimer's disease is localized on chromosome 21" (Glenner and Wong 1984b). As readers all know, the latter prediction was fulfilled in 1987 with the cloning of APP gene by several laboratories virtually simultaneously, using strategies that depended on the initial sequence characterization of meningeal amyloid reported by George Glenner and plaque core amyloid reported by Konrad Beyreuther and Colin Masters. Upon the discovery that APP was located on chromosome 21, the link to DS was immediately obvious. In fact, a study the same year suggested that APP duplication was detected in AD individuals with sporadic onset, a finding that apparently was never replicated (Delabar et al. 1987). Nonetheless, the questions that remained to be clarified were whether it was indeed duplication of APP that resulted in the invariant AD pathology in trisomy 21 individuals and whether extra APP gene dosage could be pathogenic in non-trisomic 21 individuals.

Two more series of discoveries set the stage for the 2006 report by Rovelet-Lecrux and colleagues. The first was the finding of mutations within APP that result in a rare autosomal dominant form of AD, thus placing APP at the core of AD pathogenesis, if only in a small subset of inherited AD cases. Second, fine mapping of genes duplicated in several individuals with partial trisomy, where some but not all chromosome 21 genes were duplicated, excluded APP and SOD1 genes in generating classical features of DS (Korenberg et al. 1990). Subsequently, a remarkable case report described a 78-year-old woman with DS features due to partial trisomy 21 who at postmortem examination did not have any of the expected AD pathological changes in brain (Prasher et al. 1998). The segment of the chromosome that was duplicated in this individual excluded the APP gene, signifying that APP or possibly genes immediately adjacent to APP are necessary for the development of AD histopathology.

Finally, in January 2006, Rovelet-Lucrux and colleagues reported several independent duplications of the APP locus in different French families (Rovelet-Lecrux et al. 2006). Even more interesting was the finding that these families with variable autosomal dominant inheritance pattern showed neuropathology consistent with AD and severe congophilic amyloid angiopathy (CAA); the latter was likely the reason for the large lobar cerebral hemorrhages seen in some of the cases. In retrospect, it is ironic that the first APP mutation was not discovered in familial AD but in the hereditary cerebral hemorrhage with amyloid angiopathy, Dutch type, a particularly malignant form of amyloid angiopathy with early cerebral hemorrhages (Levy et al. 1990). With the finding of subsequent APP mutations, it is now known that these APP locus duplications can result in either classic AD or primarily CAA, or both. Taken together with studies of DS individuals, it can be concluded that duplication of the APP locus results in premature accumulation of Aß in brain causing AD and CAA. These findings also provide compelling evidence that the invariant AD pathology in trisomy 21 individuals is due to the third copy of the APP gene. Put another way, a modest 50% increase in gene dosage is sufficient to drive AD changes in individuals in their fourth to sixth decades of life.

Thus, in reviewing the history of the studies into the development of AD pathology in DS, it is apparent that in the last six decades, a number of remarkably prescient predictions have been made by those examining the brains of elderly DS individuals. It is fortuitous that the year when we commemorate the centennial of Alois Alzheimer's publication is also the year that compelling, perhaps even definitive, genetic evidence of the central role of APP and Aß in AD is reported. In turn, this brings to a satisfying conclusion the linkage between the development of AD pathology in DS individuals and the APP gene.

Acknowledgements. I wish to thank Drs. Peter Burger, Albert Heyman, and Stephen Vogel, who first introduced me to what has become a lifelong pursuit to understand the pathogenesis of Alzheimer's disease.

Takaomi C. Saido

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