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

Abstract

BackgroundAlzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity and mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) and Amyloid‐β‐rich (amyloid plaques) aggregates in AD, α‐synuclein‐rich aggregates (Lewy bodies) in PD and TDP‐43 aggregates in ALS, although co‐presence of these aggregates may occur. Consensus is also growing that tau may also play a key role in PD and ALS.MethodUsing genome‐wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with PD or Alzheimer’s AD disease versus controls across ancestry groups.ResultA shared genetic association was observed across diseases 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), 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 tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA‐DRB1*04 subtypes strongly bound the aggregation‐prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation.ConclusionAn HLA‐DRB1*04‐mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

The association of microbial infection and adaptive immune cell activation in Alzheimer’s disease

“…More in-depth GWAS studies have discovered other specific antigens that could potentially serve as CAR targets. Here, novel-specific tau peptides have been shown to aggregate within AD patient cohorts that are dominant towards a specific patient’s MHC restriction [ 161 ]. These have not been investigated using CAR T-cell therapy to date, but could serve as a more specific target.…”