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The genetic risks for Alzheimer’s Disease, explained

The former GMTV presenter Fiona Phillips has revealed today that she has a diagnosis of early-onset Alzheimer’s disease.

Phillips is 62, so would normally be classed as an “early-onset” Alzheimer’s patient – the majority of scientists working in this area consider an Alzheimer’s diagnosis before 65 to be in this category (though some apparently prefer to set the cutoff at 60). Early-onset Alzheimer’s is rare, making up only about 5% of cases of the disease.

Of course, any such age threshold is arbitrary – it’s not as if something suddenly switches in your body’s biology when you reach your 66th birthday and you suffer from an entirely different condition.

And in fact, many researchers think that the majority of early-onset patients aren’t in a qualitatively different category from those with a later-onset: they’re subject to the same genetic risks, but perhaps just have more of them.

What are the genetic risks?

We know that Alzheimer’s disease is very heritable – that is, a high percentage of the differences in Alzheimer’s risk between people, something like 60-80%, are due to genetics (that doesn’t, of course, rule out lifestyle factors like smoking, diet, and exercise making a difference as well).

“Genetic risk” can mean several different things. For very many health conditions, particularly those that affect the brain (schizophrenia, depression), there aren’t just a handful of DNA variations that affect your risk – there are thousands. Each little genetic variation adds a tiny bit to the probability that you might develop the disease in future – and even if you have a lot of them, there’s still a decent chance you’ll never get it.

At the other end of the spectrum is a disease like Huntington’s, which really is just about one gene. If you have a particular mutation in that relevant gene, you are certain to get the disease (which starts off with mood problems, then affects movement, and eventually results in dementia-like symptoms).

Alzheimer’s is somewhere in between these two poles. There are thousands of genetic variants that can raise or lower your risk of the disease by just a small amount, depending on which version—which “allele”—of each of them that you have. People with more of the risk-raising alleles are those who are more likely to get the disease. But there’s also one particular gene that has a major impact on your Alzheimer’s risk.

It’s a gene that produces the protein called Apolipoprotein E, and for that reason it’s called APOE (most scientists pronounce it “ah po ee”). There’s one particular allele of APOE that raises Alzheimer’s risk, called the epsilon 4, or e4, allele.

You might remember from high school genetics that you can have 0, 1, or 2 alleles of any particular genetic variant. The vast majority of people—around 70%—have zero APOE e4 alleles. But around 25% have one – and this puts them at roughly double the risk of Alzheimer’s compared to the zero-allele majority.

Having two alleles of e4 is much worse: those people, between 2 and 3% of the population, have somewhere from eight to twelve times the risk of developing the disease.

As well as raising the overall risk that you’ll develop Alzheimer’s, there’s also evidence that people who have more of these genetic risks will develop it earlier. And that brings us back to the idea that most cases of early-onset Alzheimer’s are simply the extreme end of the genetic risk – perhaps they have two e4 alleles plus many other genes that raise their risk and bring forward their timeline of getting the disease.

That’s not definite, though: the difficulties of measuring and diagnosing early-onset Alzheimer’s—it’s highly likely that many people have the early-onset version but don’t notice until they’re older than 65, and thus don’t get classified as early-onset—mean that we have smaller samples and a lot more uncertainty about what an early-onset case really looks like, genetically and in terms of the pathology in the brain.

“Familial” Alzheimer’s

There’s a final category of Alzheimer’s patients: sufferers of what’s known as “familial” Alzheimer’s. In these cases, the Alzheimer’s is less like one of the probabilistic diseases we discussed above, where lots of genes raise your risk by tiny amounts, and much more like Huntington’s, where a mutation in just one gene drastically raises your risk.

We know of three genes where a mutation can cause familial Alzheimer’s, called PSEN1, PSEN2, and APP (and since there are cases of families who clearly have familial Alzheimer’s but don’t have mutations in any of these genes, there must be some others that we don’t yet know about). People with mutations in these genes can see Alzheimer’s symptoms from as early as their 30s or 40s. This kind of Alzheimer’s is unusual, though: it accounts for only about 1% of Alzheimer’s cases overall, and only about 10% of early-onset cases.

The reason it’s called “familial” is that these mutations, which have a large effect on Alzheimer’s risk, are very easily passed on within families. That is, it’s not like the normal situation where you might pass a few of the small-effect genes to your kids, raising their risk by a tiny degree: familial Alzheimer’s is very noticeable, and geneticists can make “pedigree” maps of how the mutations are passed through families and which family members do and don’t get an Alzheimer’s diagnosis.

Fiona Phillips mentioned that several of her family members—her mother, father, and uncle—also had Alzheimer’s, though that doesn’t by itself mean that her diagnosis is a “familial” one by the definition used above.

With the generally disappointing results from clinical trials of Alzheimer’s drugs—even for the claimed “medical breakthroughs”—we’re still largely at a loss to know what to do to treat the disease. The drugs might cause a small reduction in the speed of the decline, but they don’t in any way reverse the damage.

All we can hope is that they’re just the beginning of better treatments – and that all the genetic research on late-onset, early-onset, and familial Alzheimer’s reveals new biology that points us to more effective drugs, or at least ways to predict or prevent the symptoms.

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