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

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  1. This is a very exciting development that strongly supports the amyloid hypothesis of AD causation. It appears to be symmetrical with the discovery of α-synuclein duplication (and triplication) in otherwise phenotypically normal individuals in the causation of PD. It suggests that increased expression of wild-type APP—whether from enhanced gene dosage, as in these families, or perhaps from alterations in regulatory elements of the APP gene in other families yet to be discovered—can directly cause AD.

  2. A great discovery. I agree with John Hardy that this discovery shows, once and for all, the major role of APP dysfunction n Alzheimer disease.

    At first sight, the paper strongly reinforces the amyloid cascade hypothesis. However, in these familial cases, like in all other familial and sporadic AD cases, dementia occurs with a neocortical tauopathy, showing also that AD explanation is more likely an APP-tau deleterious interaction.

    View all comments by Andre Delacourte
  3. This is a very nice piece of work. First, it highlights the important issue of gene duplication in neurodegenerative disease.
    Second, the paper is very important for answering the question "Is duplication of APP alone (as in Down syndrome) sufficient to cause AD?" The authors have narrowed the AD region down to just four genes. This almost answers this question, but the genome may still have suprises up its sleeve, so it would be great for other labs to carry out similar analyses and see what the minimal duplicated region is to cause AD.

  4. The role of copy number polymorphisms in human genetic variation has only recently been appreciated and only investigated in a few diseases. This provides the first evidence that gene copy number abberations, in addition to being a mechanism of Parkinson disease, can be a cause of AD. So, the discovery about a decade ago of the CMT duplication may have been just the tip of the iceberg.

    View all comments by Daniel Geschwind
  5. This is a very interesting paper that is totally consistent with the Aβ hypothesis. The observation that duplication of APP causes early-onset AD and CAA is consistent with the observations in Down syndrome (DS) and confirms that AD pathology in DS is due to APP overexpression. The presence of CAA is also interesting and supports data from the transgenic mice, DS, and other FAD mutations that overproduction of Aβ40 leads to CAA, while increased Aβ42 is associated with parenchymal plaques. This also fits with the observations in PD, where duplication and triplication of α-synuclein have been associated with early-onset PD.

    I am surprised by the frequency of the duplications in their early-onset FAD samples (8 percent of FAD cases) and by the fact that each of the duplications is different but not associated with any other phenotype despite the presence of other genes in the duplicated region.

    Lastly, these studies really beg the question: Does variation in APP expression contribute to risk for late-onset AD? We posed this possibility in the first mutation papers back in 1991/1992 but I don't think the question has been adequately addressed yet. This new data makes it all the more important to tackle this question.

  6. This brief paper describes a rare genetic abnormality in five different families with autosomal dominant, early-onset Alzheimer disease with cerebral amyloid angiopathy. Using three different techniques, this research group was able to establish that a very small portion of chromosome 21 is duplicated in these families. The chromosomal region includes the locus for APP, as well as other genes. Because the duplicated region is slightly different among the five families but in all families the APP locus is included, the conclusion that overproduction of APP is responsible for the disease is compelling. The disease phenotype is similar in all five families. It consists of progressive AD with abundant dense-core and diffuse amyloid deposits as well as neurofibrillary tangles, giving support to the hypothesis that overproduction of the amyloid protein initiates a cascade of events that leads to both plaques and tangles.

    In addition, the patients studied by Rovelet-Lecrux et al. have severe cerebral amyloid angiopathy (CAA), and this vascular amyloid deposition is primarily composed of Aβ40. Mutations in Aβ have been discovered in several autosomal dominant cerebral amyloid angiopathies, leading to the hypothesis that amino acid substitutions within the Aβ sequence generate a peptide that has a propensity to aggregate in the microvasculature. However, CAA is also found in sporadic AD, as well as Down syndrome, and is now reported in these families with duplication of the APP locus. Thus, overproduction alone of wild-type Aβ can precipitate development of CAA.

    In the patients reported here, the parenchymal amyloid deposits are primarily composed of Aβ42, surrounded by Aβ40. A tendency of Aβ40 to aggregate in the vasculature versus primarily parenchymal deposition of Aβ42 suggests that these peptides are either produced or processed differently within different cell types. Distinct pathological structures characterize the brains of AD patients with mutations of the presenilins (PS1 and 2), where overproduction of Aβ42 is a consistent finding. The comparison of the nature of lesions within each of these genetic variations of AD may help us understand molecular events that are upstream of amyloid deposition.

  7. This study by Rovelet-Lecrux et al. is interesting in several aspects: It points out that gene duplication may be a more common cause of early-onset familial Alzheimer disease than previously suspected, and it highlights the coexistence of two forms of amyloid pathology, parenchymal and vascular.

    The authors did not comment on whether immunohistochemical stains for synuclein or ubiquitin were performed. It will be interesting to study the interactions between the pathological burden of amyloid (both parenchymal and vascular) and Lewy body pathology. Specifically, it will be interesting to determine whether the coexistence of Lewy body pathology with Alzheimer-type pathology in early-onset AD is limited to people harboring presenilin 1 mutations, or whether it is a more general feature seen in some patients independent of the gene mutation (or duplication).

  8. Obviously, the excitement of the paper derives from the fact that simple duplication of the APP gene can cause AD. Scientists had always assumed that it is the extra copy of APP that is responsible for the Alzheimer disease pathology that develops in virtually all individuals over the age of 40 with Down syndrome, but there was not definitive proof that this was the case. While this paper does not prove absolutely that it's the extra dose of APP in the duplicated segments that causes AD—the authors point out that the duplicated segments they studied in the families contained between five and 12 known genes—it certainly makes a good case for APP being the cause. If so, we can conclude that a simple overdose of the wild-type gene has the same clinical consequences as does one dose of the mutated FAD APP genes.

    There are precedents for this; for example, either overexpression of the wild-type EGF receptor or else expression of mutant EGF receptors can cause oncogenesis, while either overexpression of wild type α-synuclein or expression of specific mutants of α-synuclein can cause Parkinson disease (Singleton et al., 2003).

    The data in Rovelet-Lecrux et al. are consistent with the previous finding that overexpression of wild-type APP in neurons in vitro causes it to enter the cell cycle and then die via a signal transduction pathway that is very similar to, if not identical with, the pathway by which FAD APP causes neurons to die in vitro (McPhie et al., 2003). Dissecting the elements of this signal transduction pathway may explain why overexpression of APP, but usually not expression of FAD APP, causes cerebral amyloid angiopathy in addition to Alzheimer disease.

    References:

    . alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003 Oct 31;302(5646):841. PubMed.

    . DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci. 2003 Jul 30;23(17):6914-27. PubMed.

  9. This is a very interesting paper. As the daughter of an Alzheimer's patient it is very important to know that progress is being made. Well done.

References

News Citations

  1. Synuclein and Parkinson's—It's All in the Dose

Paper Citations

  1. . Beta amyloid gene duplication in Alzheimer's disease and karyotypically normal Down syndrome. Science. 1987 Mar 13;235(4794):1390-2. PubMed.
  2. . The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R123-6. PubMed.

Further Reading

Papers

  1. . Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer's disease. Neurobiol Aging. 2005 Nov-Dec;26(10):1329-41. PubMed.

Primary Papers

  1. . APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. PubMed.
  2. . Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol. 2005 Dec;62(12):1821-30. PubMed.
  3. . New presenilin 1 mutation with Alzheimer disease and Lewy bodies. Arch Neurol. 2005 Dec 1;62(12):1808. PubMed.