Citations 2
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
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Proceedings of the National Academy of Sciences | August 29, 2023 | Volume: 120 | Issue: 36 | Pages: No page available
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.
Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease
Dehghan, Abbas , Pinto, Rui , Karaman, İbrahim , Huang, Jian , Durainayagam, Brenan R., Ghanbari, Mohsen , Nazeer, Areesha , Zhong, Qi , Whiley, Luke , Mustafa, Rima , Solomon, Alina , Ngandu, Tiia , Kanekiyo, Takahisa , Aikawa, Tomonori , Radulescu, Carola I. , Graça, Gonçalo , Camuzeaux, Stéphane , Kaluarachchi, Manuja , Holmes, Elaine , Griffin, Julian L. , Whiley, Luke , Mustafa, Rima , Kanekiyo, Takahisa , Aikawa, Tomonori , Barnes, Samuel J , Chekmeneva, Elena , Kaluarachchi, Manuja R , Holmes, Elaine , Matthews, Paul M , Elliott, Paul , Zhong, Qi , Liggi, Sonia , Kivipelto, Miia , Lewis, Matthew R , Ikram, M. Arfan , Tzoulaki, Ioanna , Matthews, Paul M.
Proceedings of the National Academy of Sciences | October 21, 2022 | Volume: 119 | Issue: 43 | Pages: No page available
Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 ( P = 5.0 × 10 −5 to 1.3 × 10 −44 ). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) ( P = 0.049–1.4 × 10 −5 ), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.