ObjectiveTo explore genetic association between human leukocyte antigen (HLA) and neurodegenerative diseases and investigate mechanisms behind the association.BackgroundPathophysiology of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) involves accumulation of tau (neurofibrillary tangles) and amyloid-ß-rich (amyloid plaques) aggregates in AD, a-synuclein-rich aggregates (Lewy bodies) in PD and TDP-43 aggregates in ALS, although these aggregates may also co-occur. Likewise, consensus is growing that tau may play a key role in PD and ALS as well.Design/MethodsWe analyzed HLA associations in ∼176,000 individuals with PD or AD versus controls across ancestry groups. Pursuing this, we also compared postmortem brain density of neurofibrillary tangles and amyloid plaques in brain, tau and Aß42 levels in cerebrospinal fluid (CSF) of ∼8,000 individuals (controls and AD), and examined association of HLA in ∼2,500 patient with pathologically demonstrated Lewy Body Dementia. This was followed by HLA binding and tetramer T cell studies.ResultsA shared genetic association was observed across AD and PD 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]; p = 1.8 x 10-22) and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03 and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangle (but not neuritic plaque) density postmortem and was more associated with lower tau levels than Aß42 level changes in CSF. Furthermore, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. T cells recognizing this epitope were identified, showing relevance of this immune response in patients with neurodegenerative disorders.ConclusionsAn HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.