Protective association of <i>HLA‐DRB1</i> *04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences

Background Alzheimer’s disease (AD), Parkinson’s (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) Amyloid-β-rich (amyloid plaques) aggregates in AD, α-synuclein-rich (Lewy bodies) PD TDP-43 ALS, although co-presence may occur. Consensus is that play key role ALS. Method Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations over 176,000 individuals or AD versus controls across ancestry groups. Result A shared genetic was observed at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), protective HLA recently reported Hierarchical effects HLA-DRB1*04 subtypes best accounted the association, strongest HLA-DRB1*04:04 HLA-DRB1*04:07, intermediary HLA-DRB1*04:01 HLA-DRB1*04:03, absent HLA-DRB1*04:05. The same signal associated decreased neurofibrillary tangles (but not neuritic plaque density) postmortem brains more strongly levels than Aβ42 cerebrospinal fluid. Finally, bound aggregation-prone PHF6 sequence, but only when acetylated K311, modification central to aggregation. Conclusion An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, ALS risk, offering possibility new therapeutic avenues.