500 Varients of the genes for younger-onset Alzheimer's disease?

In Beating the Dementia Monster, we said that there were three variants of the gene most commonly associated with "sporadic" or late-onset Alzheimer's disease.  This is the most common type of Alzheimer's, but it arises in different ways.  It's only partially genetic.  The three variants of the gene are ApoE2, ApoE3, and ApoE4.  These are the genes 23&Me tests for to tell you your risk of developing the disease.  If you carry the E2 variant, you have some extra resistance to the disease, E3 seems to be neutral, but E4 is associated with a higher risk.  But this is a shallow analysis, since you can develop Alzheimer's disease even if you carry the E1, and you can miss it even if you carry the E4.  And, as we wrote earlier, researchers have now discovered as many as 72 genes that can contribute to you developing it.  

(The ApoE gene provides for a protein that is responsible for packaging cholesterol and other fats and carrying them through the bloodstream.)

But then there are the three genes associated with "familial," or younger-onset Alzheimer's disease.  There is a much stronger correlation between people who are gene carriers and those who develop the disease in their 50s, 40s, or even 30s.  Variants of the gene that produces the amyloid precursor protein (APP) as well as variants of the presenilin 1 (PSEN1), and presenilin 2 (PSEN 2) genes are strongly associated with familial disease.  

(We don't know what APP is good for, but the PSEN 1 and 2 proteins are associated with the function of calcium ions in neurotransmitters.  You can read up on this in the link above, but good luck...)

So if there are three primary variants of the ApoE gene, how many variants are there of the three genes associated with familial disease?  Between the three of them -- 500!

That's a lot of variants, but they do not all have the same level of influence over probability of developing the disease.  Since familial Alzheimer's disease is more strongly driven by genetics than the sporadic form, knowing how significant each variant is can help assess someone risk for developing the familial form.  So, thirty years ago researchers developed a database of the variants that assesses the strength of each, making such assessments possible.  

It's called the Alzforum Mutations database.  Alzforum is an organization that brings together many researchers and research organizations in a quest to find a cure for Alzheimer's disease.  (I'm an avid reader of their weekly newsletter.)  This week, Alzforum's newsletter described efforts to overhaul and improve the way they catalog and estimate the toxicity of each variant associated with familial Alzheimer's disease.  This was necessitated by the explosive growth in the number of variants of these three genes that have been found.