Protective Association of HLA-DRB1*04 Subtypes in Neurodegenerative Diseases Implicates Acetylated Tau PHF6 Sequences

Objective To explore genetic association between human leukocyte antigen (HLA) and neurodegenerative diseases investigate mechanisms behind the association. Background Pathophysiology of Alzheimer's disease (AD), Parkinson's (PD) amyotrophic lateral sclerosis (ALS) involves accumulation tau (neurofibrillary tangles) amyloid-ß-rich (amyloid plaques) aggregates in AD, a-synuclein-rich (Lewy bodies) PD TDP-43 ALS, although these may also co-occur. Likewise, consensus is growing that play a key role ALS as well. Design/Methods We analyzed HLA associations ∼176,000 individuals with or AD versus controls across ancestry groups. Pursuing this, we compared postmortem brain density neurofibrillary tangles amyloid plaques brain, Aß42 levels cerebrospinal fluid (CSF) ∼8,000 (controls AD), examined ∼2,500 patient pathologically demonstrated Lewy Body Dementia. This was followed by binding tetramer T cell studies. Results A shared observed at rs601945 (PD: odds ratio (OR) = 0.84; 95% confidence interval, [0.80; 0.88]; p 2.2 x 10-13; AD: OR 0.91[0.89; 0.93]; 1.8 10-22) protective recently reported ALS. Hierarchical effects HLA-DRB1*04 subtypes best accounted for 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 tangle (but not neuritic plaque) more lower than level changes CSF. Furthermore, strongly bound aggregation-prone PHF6 sequence, but only when acetylated K311, modification central to aggregation. cells recognizing this epitope were identified, showing relevance immune response patients disorders. Conclusions An HLA-DRB1*04-mediated adaptive response, potentially against tau, decreases PD, risk, offering possibility new therapeutic avenues.