For the first time, researchers have identified duplications of the amyloid precursor protein (APP) gene locus as the cause of early onset Alzheimer disease in five families. The findings, from the laboratory of Dominique Campion of INSERM in Rouen and colleagues throughout France, establish increased APP gene copy number as a novel and relatively common genetic basis for autosomal dominant, early onset AD without mutations. Their discovery, reported in a paper published December 18 in Nature Genetics online, has importance for understanding sporadic AD, as well. Proof that an extra dose of the amyloid precursor protein is sufficient to cause AD strengthens the view that genetic variability in APP expression contributes to the risk of, and may even cause, late-onset AD.
In other genetics news this week, a new presenilin 1 mutation was reported by Joy Snider and colleagues at Washington University in St. Louis. The phenotype of this rare mutation includes a frighteningly early onset before age 30, and abundant and widespread α-synuclein-containing Lewy bodies, along with plaques and tangles. This unique phenotype should give researchers a new window into the relationship between the big three of AD neuropathology: β amyloid, tau, and α-synuclein.
Mutations in APP or the presenilin genes account for only half of the known cases of autosomal dominant early onset AD. In the French study, first author Anne Rovelet-Lecrux led the search for causes for the other half by analyzing APP expression in 12 unrelated patients with early onset familial AD. The patients had no mutations in APP or the presenilin genes, but the researchers found evidence for duplication of the APP locus in five of the group. The duplicated segments differed among the families, with lengths ranging from 0.58 to 6.37 Mb. All spanned the APP gene, and included an additional 4 to 11 genes. The locus duplication was present only in the affected members of the families, suggesting it was the causative lesion. Among this group of French families, the frequency of the APP locus duplication was roughly 8 percent, about the same incidence as APP mutations.
In the five original cases, the duplication resulted in a consistent phenotype. On autopsy, the brains of all five showed abundant amyloid deposits and neurofibrillary tangles, along with severe cerebral amyloid angiopathy, a pattern strikingly similar to that of cases of Down syndrome with trisomy 21. Campion’s data narrows the region responsible for the formation of amyloid deposits to a minimal chromosome 21 region, including APP and at most, four other genes.
The results have profound implications for the genetics of late-onset AD. Despite extensive searching, no mutations in APP or the presenilin have ever been found in late-onset AD, but genetic studies suggest that the APP locus does contribute to disease risk. In 1987, locus duplication was reported in three French patients with sporadic AD, but the results were never confirmed (Delabar et al., 1987). Despite this early misstep, the idea that even small increases in APP expression due to genetic variation could cause late-onset AD has steadily gained currency (see the “mass action” theory of John Hardy and colleagues, reviewed in Singleton et al., 2004). The new findings only add strength to the argument. The theory resonates with other neurodegenerative diseases, as well, given a recent report of an α-synuclein gene triplication in inherited Parkinson disease by Andrew Singleton and Hardy at the National Institute on Aging in Bethesda, Maryland (see ARF related news story). A discussion of this topic in a News and Views piece by Hardy will appear with the print version of Campion’s article in the January issue of Nature Genetics.
In some cases of AD, a wild-type APP gene becomes pathogenic under the influence of other mutations, such as those in the presenilin genes. The work of Snider and colleagues shows an extreme example of this phenomenon. The researchers identified a mutation in exon 6 of presenilin 1, resulting in an amino acid change in the third transmembrane domain of the protein. The woman carrying the mutation, her brother, and her father each started to display memory loss in their 20s, with a progression to death from AD at 43, 35, and 37 years old, respectively. At autopsy, the woman had extensive Lewy body accumulation, in addition to plaques and tangles. Further study will be needed to determine if Lewy body accumulation is a common feature of very early onset AD, which itself is most often associated with a presenilin 1 mutation. In an editorial accompanying the report in the December issue of the Archives of Neurology, Roger Rosenberg writes that the family “offers the unusual opportunity to understand more completely the linkages and mechanisms involved in the formation of the accumulated proteins Aβ (amyloid containing-plaques), hyperphosphorylated tau (neurofibrillary tangles), and α-synuclein (Lewy bodies).”—Pat McCaffrey