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The modern era of Alzheimer's disease research really begins with Glenner and Wong's identification of the amyloid sequence in the congophilic angiopathy of Alzheimer's disease and Down's syndrome (1984a, b). Indeed, much of what we now know about Alzheimer's disease is implicit in the abstract of the second of their two papers from 1984:

"The cerebrovascular amyloid protein from a case of adult Down's syndrome was isolated and purified. Amino acid sequence analysis showed it to be homologous to that of the g protein of Alzheimer's disease. This is the first chemical evidence of a relationship between Down's syndrome and Alzheimer's disease. It suggests that Down's syndrome may be a predictable model for Alzheimer's disease. Assuming the g protein is a human gene product, it also suggests that the genetic defect in Alzheimer's disease is localized on chromosome 21."

With the realization that the plaque was largely made of the same peptide (Masters et al. 1985) and the cloning of the APP gene (Kang et al, 1987, Goldgaber et al. 1987, Robakis et al. 1987, Tanzi et al. 1987) the stage was set for the finding of APP mutations in Alzheimer's disease. However, the genetics of Alzheimer's disease was more complicated than previously delineated diseases and the analysis of families was hampered by the poor informativity of genetic markers, the paucity of family material and the unexpected complexity of the problem: these complexities led to missteps. An erroneous report of a gene duplication of the amyloid gene in AD (Delabar et al. 1987), together with the fact that the original report of genetic linkage to the region was a type 1 (false positive) error (St. George Hyslop et al. 1987) as well as the incorrect assumption that all autosomal dominant AD was caused by lesions in a single gene, led to the dismissal of the APP gene as the site of lesions in AD (Van Broeckhoven et al. 1987, Tanzi et al. 1987).

Two lines of research, continuing in parallel, led to the re-evaluation of the APP gene in AD: the first was the study of the rare disorder, Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch type (HCHWA-D). Pioneering work on this stroke disorder had shown that this disorder is caused by amyloid deposition in the brain blood vessels (van Duinen et al. 1987). Linkage studies in this disease showed that the APP gene was the site of the pathogenic mutations (Van Broeckhoven et al 1990) and a segregating mutation, E693Q (Levy, et al., 1990), was discovered: this work showed unequivocally that mutations in APP could lead to amyloid deposition, albeit not in the brain parenchyma. In parallel with this, further genetic analysis of more families led to a more complete understanding of the complexities of the problem and the realization that the disease was genetically heterogeneous (Schellenberg et al. 1988, St. George Hyslop et al. 1990).

With this background, with the newly developed technology of PCR, our group decided to sequence the APP gene in a family in which we had good evidence for linkage to chromosome 21 (Goate et al. 1989) and we found a mutation, I717V (Goate et al. 1991). Initially, we found no mutations in our other families, but confirmed the occurrence of the mutation in a sample from Duke in a family which also had prior evidence for linkage to chromosome 21 (Pericak Vance et al. 1988). Immediately after this success, we and others went out looking for families with similar clinical characteristics (in particular, age at onset seemed an important variable) and other mutations were quickly identified (Murrell et al. 1991, Chartier Harlin et al. 1991). The next two mutations were both to the same residue (I717F, I717G) suggesting that the effects on APP metabolism were key to pathogenicity: it was of particular note that residue 717 is close to the Ag-secretase site (Chartier Harlin et al. 1991). This suspicion was confirmed with the identification of the Flemish (Hendricks et al 1992) and Swedish mutations (Mullan et al 1992 ) which are adjacent to the alpha- and g-secretase sites respectively (see figure). These mutations are summarized on the accompanying diagram and table. It is now clear that all the pathogenic mutations affect processing (Citron et al. 1992, Suzuki et al. 1994). The effects of these mutations are summarized on the Amyloid Cascade Hypothesis Diagram.

After this spurt of activity, APP sequencing essentially stopped as genetic groups hunted for the other pathogenic loci (the presenilins: Sherrington et al. 1995) although several polymorphisms were identified (table). After the presenilins were identified, other mutations were identified (V716I: V715M) (Eckman et al. 1997: Ancolio et al. 1999) which all appear to share the characteristic of altering APP processing such that a more depositable peptide is produced.

Although it is often stated that APP mutations do not cause late onset Alzheimer's disease, it is suprising how infrequently the whole APP open reading frame has been sequenced and recent data strongly suggest that genetic variability within the whole locus (though more likely in the promoter than the open reading frame) does indeed contribute to risk of developing disease (Wavrant DeVrieze et al. 1999).

View APP Mutations Diagram
View APP Mutations Table
View Amyloid Cascade Hypothesis Diagram
Note: The diagram and table are freely available for use by our colleagues in their own slide lectures. Please credit John Hardy, Richard Crook and the Alzheimer Research Forum as the source.

In his discussion accompanying the "APP Mutations Directory," John Hardy describes the V715M mutation discovered by Ancolio et al. as creating a situation where "more depositable peptide is produced." With all due respect, I believe this characterization is based on assumptions that make it somewhat misleading. What the investigators reported is an increase only in the ratio of Ab(x-42):Ab(x-40); Ab(1-42) does not change, and total Ab production is actually DECREASED by this mutation. Presumably, Dr. Hardy would argue that because Ab(1-42) aggregates faster than Ab(1-40) in vitro, his statement is factually correct. However, the band showing an increase in the report by Ancolio et al. has a mobility consistent with p3(17-42) rather than Ab(1-42). While the p3 peptide was shown by Pike et al. (J Biol Chem. 270:23895) to aggregate quite readily, its common presence in diffuse plaques of non-symptomatic persons (and other species) leads one to question its contribution to disease. Furthermore, the complex environment in which plaques form in vivo may render the in vitro aggregation properties of various peptides overly simplistic. Perhaps, more attention should be given to the fact that the V715M mutation increases release of sAPP than to any speculative leaps about the significance of creating more p3(17-42), itself an expected outcome of elevated sAPP production.

See References

Comment by Rudy Tanzi (tanzi@helix.mgh.harvard.edu) -- Posted 14 July 2001

I strongly disagree with the statement that the APP gene was dismissed as a candidate AD gene back in 1987 after the chromosome 21 linkage was found to be a type I error and the APP duplication results were refuted. In my Science paper, showing lack of linkage of APP to FAD, I had simply ruled out APP as the AD locus in the original four FAD pedigrees that were reported earleir that year to be linked to chromosome 21. However, I had left open the possiblity that it could carry mutations in other families.

Reply from John Hardy -- Posted 14 July 2001

Entertaining nonsense... this is called post hoc rationalization Rudy!!! You had four families in which you had published linkage to ch21 (OK.. so you were wrong, but that is another story), and there was nothing in APP. It is always possible that the gene is important in another family.. but at the time we (the field) did not realise the disease was genetically heterogenous....

I quote: "The future is there for anyone to change, but sometimes you know it seems, it would be easier to change the past"

If Rudy can name that song, he gets a pint next time I see him.

Reply by Rudy Tanzi -- Posted 14 July 2001

Not realizing heterogeneity is not the same as saying we "dismissed" APP.

It will take some time to figure out those lyrics but in reply I quote what famous singer below?

Still we try to make it right;
We've seen the light, we've seen the broken dreams;
It's something in between.
It's not the right or wrong,
It's just the things you do.
It's not the black and white,
It's just the shade you choose.
It's not the in and out,
It's how you make the move.
It's not just come and go,
It's what it means to you.

Comment by Rudy Tanzi (tanzi@helix.mgh.harvard.edu) -- Posted 24 July 2001

Well John, it looks like you owe about 30 people pints based on how many emails I have received telling me who wrote those lyrics! But, regarding the other story -the original linkage of FAD on chromosome 21 (St.George-Hyslop et al, Science, 1987), you would really need to take up the type I error issue with the person who ran those linkage analyses! But, also consider the question that Ann Parson and I raise in our recent book, "Decoding Darkness: The Search for the Genetic Causes of AD", in which we recount those wonderful and crazy early days of AD research: Would you have looked for (and found!) an APP mutation in your British family if the erroneous chromosome 21 FAD linkage paper was never published?

So, one last lyric in return (and no prize for this one as it's too easy!):

"You can't always get what you want,
But if you try sometimes you just might find
You'll get what you need."

Response by Laurin Mancour laurin.mancour@duke.edu -- Posted 24 July 2001

In regards to the new comments on APP mutations by Rudy Tanzi and John Hardy, here is a response to the challenge for readers to identify mystery song lyrics...

"The future is there for anyone to change, but sometimes you know it seems, it would be easier to change the past" I believe that this is an excerpt from the song "Fountain of Sorrow" by Jackson Brown.

Still we try to make it right;
We've seen the light, we've seen the broken dreams;
It's something in between.
It's not the right or wrong,
It's just the things you do.
It's not the black and white,
It's just the shade you choose.
It's not the in and out,
It's how you make the move.
It's not just come and go,
It's what it means to you.

I believe that this is taken from the song "Something in Between" by Future Music (or some other British group).

References

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