HLA-II variants show distinct associations with Alzheimer’s disease, longevity, and microglial activity

HLA-II variants show distinct associations with Alzheimer’s disease, longevity, and microglial activity

In a preprint published on August 27, researchers compared HLA-II, a group of immune genes, in 6 053 people: 443 cognitively healthy people over 100 years old, 3 219 control participants, and 2 391 patients with Alzheimer’s disease. They identified seven sets of genetic variants that are usually inherited together. Three of these sets overlapped with previously reported signals associated with disease or longevity.

HLA-II is a group of immune genes whose proteins present fragments of other proteins to T-cells, allowing the immune system to recognize a target and mount a response. The HLA-II region is highly variable, and neighboring variants within it are often inherited together. A single DNA variant can therefore indicate the presence of an entire inherited set. The authors grouped 24 651 DNA variants and tested each group across the three groups of people and in postmortem donated brain tissue.

A biological hypothesis already existed for Hap-B, which is associated with the DRB1*04 variant. Some DRB1*04 subtypes may bind a fragment of tau protein, which forms pathological deposits in the brain. In the new analysis, Hap-B was more common among control participants and cognitively healthy people over 100 years old than among patients. In an independent Dutch collection of donated brain tissue, some Hap-B variants were associated with a lower Braak stage of tau pathology. The Braak scale measures how far pathologically altered tau protein has spread. After the researchers accounted for the extent of amyloid pathology, the association with a lower tau stage remained for DR4, a broader inherited set of HLA variants that includes DRB1*04.

The other two groups showed different associations. Hap-R, which is associated with DRB1*01:01, was more common among patients and less common among cognitively healthy people over 100 years old and control participants. Hap-Y, which is associated with DRB1*15:01, was linked to a larger area of HLA-II staining in microglia, the immune cells of the brain, in postmortem tissue. This measure reflects the immune state of microglia. The authors assessed the spread of tau pathology using a separate scale.