Genes R US — Rare genetic variation protects against Alzheimer’s disease
Posted: Wednesday, July 18, 2012 5:00 pm
A diagnosis of cancer strikes great fear into the hearts of my parents’ generation. My most dreaded diagnosis is Alzheimer’s disease, definitely not cancer. There are treatment strategies for cancer.
Every week Missy, Zorra, Punkin and I visit residents at several local nursing homes. Some of the residents are obviously afflicted with this mind-robbing disease. Some of these residents (mostly women) are just confused; others are lost in time or space; and some are in that final trance-like state where possibility of communication is questionable.
Last week I was saddened to hear about a high school classmate disabled by early onset Alzheimer’s. At the same time, I was encouraged to read about a newly-identified genetic mutation that protects against late onset Alzheimer’s and aging associated intellectual decline. The discovery of this mutation was made by deCODE, a biomedical company in Iceland.
Since 1998, Iceland has allowed genealogical, genetic, and complete medical history to be catalogued for its entire population. Using this data, deCODE scientists observed that the elderly (80-100) with a particular mutation in their APP gene had no incidence of Alzheimer’s disease and that this protected group had less cognitive decline than their aged counterparts.
So what is this APP gene? This gene codes for the amyloid precursor protein. This is protein that accumulates between nerve cells in the brain of Alzheimer’s patients. Nobody knows what amyloid precursor protein does but it is found in large quantities in the brain and spinal column as well as in lower amounts throughout the body.
My classmate could have any one of more than 50 mutations in her APP gene-any one of which could have caused her disease. There are two presenilin genes (PSEN1 and PSEN2) that have mutations known to guarantee early onset Alzheimer’s. But even these familial forms account for less than 10 percent of the total cases of early onset Alzheimer’s, and less than 1 percent Alzheimer’s cases overall.
Most Alzheimer’s cases are what are called sporadic. Scientists do believe that genes have a bigger role in developing Alzheimer’s than does our environment. In sporadic cases, there are genetic vulnerabilities — but unlike familial forms — scientists still can’t pinpoint, with accuracy, which people will develop the disease.
The most well-known genetic vulnerability depends on which version of the APOE gene one carries. But even having the high risk variant of APOE does not guarantee that one will definitely develop AD. Half of those with Alzheimer’s do not have the risky version of APOE! I have the risk-neutral version of APOE.
Scientists have been unclear if the deposits of amyloid precursor protein between nerve cells, and the concomitant tangles of the tau protein within the nerve cells themselves, are symptoms or the actual cause of Alzheimer’s.
This is why the observation from the Iceland study is so important. The particular mutation of APP found in the cognitive “sharpies”, aged 80 to 100, prevents another protein, BACE1, from cutting (or cleaving off) part of the amyloid protein. The cleaved proteins accumulate in the brain between those nerve cells. So stopping BACE1 appears to be a good thing.
A drug company, Genentech, quickly latched onto the significance of deCODE’s finding. In their biochemistry labs, using cells some with and some without the mutant version of APP. They found significantly less amyloid deposition in their cellular assays with the mutant version of APP.
Now there has been much research and even a vaccine developed to clear out amyloid proteins — pretty much to no avail. The scientific community has known about amyloid plaques for several decades. So what is different here?
By focusing on reducing the efficacy of BACE1, scientists will be attacking the process early on prior to deposition. That is the big difference: prevention.
It is simple to check if one has this extraordinarily protective version of the APP gene. A single DNA variation (or SNP) determines if one has the good mutant. We get two versions of the gene; one from each parent. Even having a single version of the protective SNP confers a hugely protective effect.
Unfortunately, only around 1 in 10,000 people will have this rare and protective SNP. I am not one of them. My chance of developing Alzheimer’s is pretty much like the average Josephine. That is, my risk doubles by the time I am 65. And should I make it to 90 then I have a one in four chance of developing the disease.
Nancy@Nancy MillerLatimer.com has worked in scientific research and development for 27 years. She blogs at NeuronalBeauty.BlogSpot.com. Published in The Messenger 7.18.12