Regional tau burden tracks with lower microglial HLA class II transcription in the human brain

Human leukocyte antigen class II (HLA-II) genes mark several microglial states in Alzheimer's disease, but it remains unclear how their average transcription relates to tau measured in the same brain region.

We used a locked 13-gene HLA-II panel selected by biological function, cross-cohort detection, and variance, without considering effect estimates. The primary analysis was conducted using the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD): 361 donor-region observations from 79 donors across 6 cortical regions were modeled with within-donor pathology decomposition, region fixed effects, and a donor random intercept. A paired entorhinal-versus-somatosensory analysis in GSE160936 (11 donors) provided additional support for our findings. Sensitivity analyses addressed amyloid-β, RNA quality, neuronal-nuclei enrichment, microglial-state composition, published state annotations, alternative panels, region omission, and assay modality. Public human induced pluripotent stem cell (iPSC)-microglia data were used to provide a distinct tau-exposure context.

In the SEA-AD study, a higher local AT8-positive area within a donor was associated with a lower expanded HLA-II score (β = -0.174, 95% confidence interval [CI]: -0.297 to -0.052; p = 0.005). The estimate remained negative after adjusting for local amyloid-β, RNA integrity number, and the NeuN-positive fluorescence-activated nuclei sorting (FANS) fraction (β = -0.167, 95% CI: -0.289 to -0.045; p = 0.007). This result was consistent after adjusting for the proportion of a published Damage-Associated Microglia (DAM)-enriched state. A formal tau-minus-amyloid-β contrast was not significant. In GSE160936, the expanded-panel pTau coefficient was negative (β = -0.533); however, the primary exact test was not significant after the two-test correction (p = 0.083; q = 0.166). Fibrillar tau exposure lowered the score derived from the 12 detectable panel genes in iPSC-microglia (difference = -1.343; exact p = 0.029).

In a larger multi-region cohort and a smaller paired cohort, we observed that regional tau burden was associated with lower levels of pooled microglial HLA-II transcription. The association was not explained solely by the measured proportion of the DAM-like state. However, the data do not establish tau specificity, direct suppression, protein-level antigen presentation, or a causal mechanism.