In the orchestra of our immunity there are three conductors, and each has a score of their own. One tells the musicians to play softer when a threat appears in the hall, another does the opposite and cranks up the noise, and the third conducts in such a way that the hall fills with sound, though nobody can say why.
These conductors live in one and the same spot in the genome, the HLA-II region, which governs how the immune system recognizes intruders. Scientists have long known that variants in this region are linked to Alzheimer's disease and to longevity, but they could not work out how. The signals overlapped, like the sounds of different instruments in a tutti.
Researchers took genetic data from 6053 people: long-lived individuals over a hundred years old, healthy middle-aged people, and patients with Alzheimer's disease. They analyzed 24 651 variants in a window 1.15 million base pairs across and identified seven independent haplotypes, that is, sets of variants inherited together. Three of them, named Hap-B, Hap-R, and Hap-Y, matched previously published signals and were examined in detail.
It turned out that Hap-B is a conductor that quiets the orchestra. It showed up more often in healthy people and less often in patients with Alzheimer's disease. In an independent cohort from the Netherlands Brain Bank, components of Hap-B were linked to less accumulation of tau protein in neurons and less amyloid pathology. In other words, this variant seems to help the brain avoid piling up protein junk.
Hap-R is a conductor that fans the flames instead. It was linked to a higher risk of Alzheimer's disease and a lower chance of living to a hundred. And Hap-Y proved the strangest of all: it appeared more often in healthy people than in patients, yet it was tied to stronger activation of the brain's immune cells, the microglia. As if the orchestra plays louder, but the music never turns alarming.
Previously it was unclear how the many genetic variants in the HLA-II region combine into haplotypes and affect the brain's immune cells. Now it is clear that the region holds three independent haplotypes with different effects. This explains why earlier studies produced contradictory results: they were looking at individual notes rather than at whole scores.
Today this work could help in developing genetic tests to assess Alzheimer's disease risk and in selecting patients for immunotherapy. Three conductors, three scores, and now we know which of them plays what music.
The HLA-II region spans 5 million base pairs and contains more than 200 immune-related genes, making it the most polymorphic part of the human genome.
The idea that immune gene variants can determine how the brain copes with neurodegeneration echoes Greg Egan's novel Quarantine, where genetic modifications affect cognitive abilities and disease resistance.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.