Regional tau burden tracks with lower microglial HLA class II transcription in the human brain
- 1Department of Neurology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University
- 2Department of Endocrinology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University
- 3Department of Pulmonary and Critical Care Medicine, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University
Abstract
Background: 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.
Methods: 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.
Results: 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).
Conclusion: 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.
Related
- Community-Level Wastewater Surveillance of Nicotine Biomarkers Tracks Cardiovascular Disease Burden and Myocardial Infarction
- Inflammatory Burden Shapes Antioxidant Adaptation and Immunometabolic Remodeling in LPS-Activated BV-2 Microglial Cells
- Diet-attributable colorectal cancer in Asia: Regional heterogeneity in burden and dietary intake
- Regional Perivascular Space Burden in Pediatric Idiopathic Intracranial Hypertension: A Case–Control MRI Study
- Quantitative MRI Characterization of Fluid-Related Phenotypes in Pediatric Epilepsy: Deep Learning-Assisted Assessment of Enlarged Perivascular Space Burden, Regional Distribution, and Clinical Associations
BibTeX
@article{li2026regional,
title = {{Regional tau burden tracks with lower microglial HLA class II transcription in the human brain}},
author = {Fan Li and Suqin Jin and Ping Wang and Hui Yang and Xianghua Zhuang and Feifei Feng and Peng Cheng},
journal = {Frontiers in Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnins.2026.1979981},
url = {https://www.frontiersin.org/articles/10.3389/fnins.2026.1979981/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regional tau burden tracks with lower microglial HLA class II transcription in the human brain
AU - Fan Li
AU - Suqin Jin
AU - Ping Wang
AU - Hui Yang
AU - Xianghua Zhuang
AU - Feifei Feng
AU - Peng Cheng
PY - 2026
DA - 2026/10/07
JO - Frontiers in Neuroscience
DO - 10.3389/fnins.2026.1979981
UR - https://www.frontiersin.org/articles/10.3389/fnins.2026.1979981/full
AB - Background: 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. Methods: 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. Results: 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). Conclusion: 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.
SN - 1662-453X
SN - 1662-4548
ER -