Thoughts on APP Expression in AD

It’s well known that Down syndrome patients have a greatly increased incidence of early onset Alzheimers (around 75% by year 65), and this is usually attributed to the presence of the gene APP on chromosome 21, leading to its triplication and increased levels.*

If an increase in APP expression really is the cause of the early onset Alzheimers in Down syndrome patients, then we would also expect the following:

1) Triplications of APP should also lead to Alzheimers. Importantly, we do see this. Eg, see this paper reporting 19 such cases. This is strong evidence that APP is indeed the causative gene of the early dementia in Down syndrome patients. Caveat: based on this paper’s data, it seems possible, though pretty unlikely, that the causative gene is instead one of the others in the region that is also duplicated, such as GABPA. From their Figure 1C, a picture is worth a few hundo words:

Also, not a caveat, but to me a worthy question: why does Down syndrome associated early-onset AD start at ~ year 40 and the early-onset AD in these patients start at ~ year 52?

2) We’d expect to see cis-eQTLs near APP that likely regulate levels of APP expression and increase it in Alzheimers association studies. We do not see this; eg, see this paper, which does not mention APP in the main text nor mention it in the supplementary tables I checked. However, who knows: maybe there just aren’t any SNPs in the regions of the DNA that happen to control APP expression? This is only very weak, circumstantial evidence against APP being the causative gene.

3) Now, would we expect to see increased APP mRNA expression in Alzheimers patients vs controls? I think basically yes. And indeed, APP expression is increased in Down syndrome patients, by about 1.5-fold, which is around exactly what you’d expect based on the triplication. What makes this confusing is that its levels in Alzheimers are increased in some studies, such as this one, but not mentioned as upregulated in others. Confusing.

* = Interestingly, according to this article, nearly all Down syndrome patients have amyloid plaques in their brains by age 40, but by age 65, 25% still do not have Alzheimers dementia.