Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Defining Advance Care Planning for Adults: A Consensus Definition From a Multidisciplinary Delphi Panel

Context Despite increasing interest in advance care planning (ACP) and previous ACP descriptions, a consensus definition does not yet exist to guide clinical, research, and policy initiatives. Objective The aim of this study was to develop a consensus definition of ACP for adults. Methods We convened a Delphi panel of multidisciplinary, international ACP experts consisting of 52 clinicians, researchers, and policy leaders from four countries and a patient/surrogate advisory committee. We conducted 10 rounds using a modified Delphi method and qualitatively analyzed panelists’ input. Panelists identified several themes lacking consensus and iteratively discussed and developed a final consensus definition. Results Panelists identified several tensions concerning ACP concepts such as whether the definition should focus on conversations vs. written advance directives; patients’ values vs. treatment preferences; current shared decision making vs. future medical decisions; and who should be included in the process. The panel achieved a final consensus one-sentence definition and accompanying goals statement: “Advance care plannin