Alzheimer's disease is 70% heritable, yet it remains unclear how genetic variants in the most polymorphic region of the genome, the HLA-II region, translate into differences in the brain's immune function. Alongside this work, the archive holds studies linking brain folds, grip strength, breathing, and running to dementia risk, as well as maps of brain age and Alzheimer's genes via attention. This work stands apart: it does not hunt for new genome-wide associations but instead dissects one region where signals from different studies overlap, and ties them to microglia and neuropathology.
The authors took genetic data from 6053 people: 443 cognitively healthy long-lived individuals over 100 years old, 3219 healthy middle-aged people, and 2391 Alzheimer's patients. In a window of 1.15 million base pairs around two known disease-linked SNPs, they computed linkage disequilibrium for 24 651 variants. Then, using LD clumping and conditional joint analysis COJO, they identified seven independent haplotypes. Three of them, named Hap-B, Hap-R, and Hap-Y, matched previously published signals and were examined in detail. For each haplotype, the authors imputed HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles at two-field resolution and compared them with immunohistochemical markers of microglia in the temporal cortex of 96 brain donors.
Hap-B, carrying the protective variant rs35472547 and the DRB1*04 allele, was more common in healthy individuals and less common in Alzheimer's patients, with an odds ratio of 0.77 for the DRB1*04 allele when comparing long-lived individuals with patients. In an independent cohort from the Netherlands Brain Bank (513 patients and 248 controls), components of Hap-B were associated with a lower Braak stage for tau pathology (β=-0.49, FDR=0.042 for DQA1*03:01), as well as with less amyloid and α-synuclein pathology. Hap-R, carrying the risk variant rs9469112 and the DRB1*01 allele, was linked to increased Alzheimer's risk and a reduced likelihood of becoming long-lived. Hap-Y, carrying DRB1*15:01, unexpectedly turned out to be enriched in healthy individuals compared with patients at the two-field allele level (OR=0.79, P=0.0039 for DRB1*15:01), yet it was associated with increased HLA-II immunopositivity in microglia (β=1.67, FDR=7.59×10⁻⁵ for DRB1*15:01).
The work shows that the HLA-II region contains at least three independent haplotypes with different effects on Alzheimer's disease, longevity, and microglial activation. Unlike neighboring studies that either searched for genome-wide associations or examined individual SNPs, this one systematically resolves haplotypes at the level of HLA-II alleles and links them to brain immune states. This makes it possible to separate protective and risk variants within a single region and explains why previous studies produced conflicting results.
Further research could include long-read sequencing to uncover structural variants in the HLA-II region, especially in the DR1 structure, where the Hap-R effect was strongest at the level of the ancestral structure rather than a specific allele. Allele-resolved analyses of HLA expression in microglia and functional tests will also be needed to prove a causal link between HLA variants and tau protein clearance.
The results could influence patient stratification in clinical trials of Alzheimer's therapies, especially those targeting the immune system, and the development of genetic tests for assessing individual risk.
Test the associations of Hap-B, Hap-R, and Hap-Y in larger and more ancestrally diverse cohorts, and conduct functional experiments on microglia with different HLA-II alleles.
The work directly addresses an unsolved problem in neurogenetics: how polymorphisms in the HLA-II region, known from GWAS, translate into cellular phenotypes of microglia and neuropathology in Alzheimer's disease. It also touches on the question of why some people live to 100 without cognitive impairment despite having amyloid plaques.
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.