Our genome has a region that works like a control panel for immunity. The panel has three buttons, and every person has a different combination pressed. One button muffles the alarm signal, another switches it on too often, and a third keeps immune cells bustling for no apparent reason.

Scientists have long known that this region, the HLA-II region, is linked to Alzheimer's disease and to longevity. But they could not work out how, because signals from the different buttons got mixed together. In a new study, they took genetic data from 6053 people and broke the region down into three independent variants that are inherited together.

It turned out that the first variant, Hap-B, acts as a protector: people who carry it develop Alzheimer's disease less often and have less protein debris in the brain. The second variant, Hap-R, does the opposite, raising the risk of disease and lowering the odds of living to 100. The third, Hap-Y, is more common in healthy people, yet it pushes the brain's immune cells to work harder. It is as if the brain clears out the debris in advance, before there is too much of it.

Until now it was unclear how the different variants in this stretch of DNA affect the brain's immune cells. Now it is clear that there are three of them, and each has its own role. That explains why previous studies produced conflicting results: they looked at individual pieces rather than at whole combinations. Today this work could help in developing genetic tests to assess Alzheimer's risk and in selecting patients for treatments that target the immune system.

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