While the cause for AD still remains to be determined, there is evidence to support what has been referred to as the “amyloid hypothesis”. This hypothesis states that the disease is caused by the build-up of the protein amyloid-β (Aβ) in the brain, forming “plaques” of this protein. This hypothesis is supported by the fact that the gene (APP) which codes for amyloid-β is located on chromosome 21, and people with Down’s Syndrome (caused by having three copies of chromosome 21 instead of 2) almostall suffer from early-onset Alzheimer’s. Although the cases of inherited AD are very few, those that do have the hereditary form often have a mutation in a gene called PSEN1, which is responsible for cleaving Aβ so that it can then be cleared from the brain. Also, studies have shown that people with two copies of the dysfunctional form (known as APOE4) of Apolipoprotein E (APOE), a protein that later clears Aβ deposits from the brain, are at high risk of developing AD.
The ApoE gene is regulated by other genes, like peroxisome proliferator activated receptor (PPARγ) and liver X receptors (LXR), in coordination with retinoid X receptors (RXR). This means that these genes work together to activate the transcription of APOE, which in turn goes ahead and helps clear these Aβ deposits from the brain. Therefore, the researchers in this case decided to get an already FDA-approved drug called bexarotene, which stimulates the gene RXR, and feed it a few different mouse models for AD.
First, they gave the drug to APP/PS1 mice. These are mice that overexpress the gene that produces AB (which is what we see in patients with Down’s Sydrome) as well as the mutant form of PSEN1. Administering the drug to these mice effectively reduced the Aβ in the brains of young and old mice with these mutations. Also, this treatment seemed to restore cognition and memory problems that these mutant mice have.
Next, these researchers tested this drug in two other mouse models for AD: APP PS1-21, which has similar mutations to the APP/PS1 mouse (only with higher levels of Aβ in the brain) and the Tg2576 mouse, which has a mutation in the APP gene and shows age-dependant memory loss. The drug worked in reducing both Aβ levels and restoring normal behaviour to these mutant mice
It was confirmed that this drug was effective in clearing Aβ from the brain by stimulating APOE production by administering it to mice that completely lacked the gene for APOE. In these mice Aβ levels remained the same, evidently because there was no APOE gene present to stimulate.
Now for the downside. These mutant mice have a genotype that are more applicable to patients with AD that have it because of too much APP protein, as in the case with Down’s Syndrome patients, or with a mutant form of PSEN1, as is the case of only 1-5% of all AD patients. These results seem far less applicable to patients that develop AD due to a defective form of APOE. This drug works by stimulating the transcription of APOE, thereby making the cells produce more protein that goes and clears the Aβ from the brain. However, in the case of people with a defective form of APOE, all this would do is make more defective protein. The question thus becomes this: how “defective” is APOE4? Is it just less good at doing its job, and therefore producing more of it would help the problem, or is it completely defective and not capable of clearing out the protein at all?
Yes, this is a promising study. However, the human trials that could come of this are trials for only a subset of people with AD. It is common to think that just because a disease has a name it means that there is one cause, one effect, one cure. If only it was that simple! There is no disease where this misconception is more evident than in cancer. Everyone wants “a cure for cancer”, as if there could ever be the one cure. There are hundreds of kinds of cancer each caused by multiple different factors and/or combinations of those factors. When someone comes up with one cure for a subset of one kind of cancer caused by one thing it barely makes news, despite the fact that it is a huge achievement.
Anyway, I’m not shitting all over the paper. It’s interesting, it’s promising and I would love to see how it does in human trials. The only downside is that this study is not so applicable to a significant fraction of patients with AD, so I doubt that it will be the “one and only” cure for it.