Citations 6
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.
Genome‐wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology
Nudelman, Kelly , Allen, Mariet , Hodges, Angela , Kim, Sungeun , Risacher, Shannon L. , Apostolova, Liana G. , Lin, Kuang, Lunnon, Katie , Wang, Xue , Burgess, Jeremy D. , Ertekin‐Taner, Nilüfer , Petersen, Ronald C. , Wang, Lisu, Qi, Zhenhao, He, Aiqing, Neuhaus, Isaac , Patel, Vishal , Faber, Kelley , Lovestone, Simon , Simmons, Andrew , Weiner, Michael W. , Initiative, for the Alzheimer's Disease Neuroimaging, Nudelman, Kelly N , Nho, Kwangsik T. , Neuhaus, Isaac, Foroud, Tatiana , Saykin, Andrew J. , Initiative, for the Alzheimer's Disease Neuroimaging
Alzheimer's & Dementia | August 5, 2020 | Volume: 16 | Issue: 9 | Pages: 1213-1223
AbstractIntroductionAbnormal gene expression patterns may contribute to the onset and progression of late‐onset Alzheimer's disease (LOAD).MethodsWe performed transcriptome‐wide meta‐analysis (N = 1440) of blood‐based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis.ResultsWe identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis‐expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10−8), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18F]Florbetapir positron emission tomography and CSF Aβ1‐42.DiscussionRNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
IC‐P‐074: Genome‐Wide Meta‐Analysis of Transcriptome Profiling Identifies Novel Dysregulated Genes Implicated in Alzheimer’s Disease
Apostolova, Liana G. , Lin, Kuang, Allen, Mariet , Wang, Xue , Ertekin‐Taner, Nilüfer , Petersen, Ronald , Soares, Holly , Wang, Lisu, Qi, Zhenhao, He, Aiqing, Neuhaus, Isaac , Patel, Vishal , Faber, Kelley, Simmons, Andrew , Weiner, Michael W. , Nho, Kwangsik T. , Kim, Sungeun , Risacher, Shannon L. , Keohane, Aoife , Lunnon, Katie , Hodges, Angela , Burgess, Jeremy D. , Singh, Parul , Foroud, Tatiana , Lovestone, Simon , Saykin, Andrew J.
Alzheimer's & Dementia | October 17, 2016 | Volume: 12 | Issue: 7S_Part_1 | Pages: No page available
P3‐087: Gene Expression of ABCA7 Dysregulated in Peripheral Blood is Associated With Decreased Metabolic Activity in Hippocampus
Kim, Sungeun , Horgousluoglu, Emrin, Apostolova, Liana G. , Lin, Kuang , Allen, Mariet , Wang, Xue , Ertekin‐Taner, Nilüfer , Petersen, Ronald , Soares, Holly , Singh, Parul , Wang, Lisu, Qi, Zhenhao, He, Aiqing, Neuhaus, Isaac , Patel, Vishal , Faber, Kelley, Simmons, Andrew , Weiner, Michael W. , Nho, Kwangsik T. , Risacher, Shannon L. , Keohane, Aoife , Lunnon, Katie , Hodges, Angela , Burgess, Jeremy D. , Foroud, Tatiana , Lovestone, Simon , Saykin, Andrew J.
Alzheimer's & Dementia | October 17, 2016 | Volume: 12 | Issue: 7S_Part_17 | Pages: No page available
IC‐P‐072: Gene Expression Of ABCA7 Dysregulated in Peripheral Blood is Associated With Decreased Metabolic Activity in Hippocampus
Kim, Sungeun , Horgousluoglu, Emrin, Apostolova, Liana G. , Lin, Kuang , Allen, Mariet , Wang, Xue , Ertekin‐Taner, Nilüfer , Petersen, Ronald , Soares, Holly , Singh, Parul , Wang, Lisu, Qi, Zhenhao, He, Aiqing, Neuhaus, Isaac , Patel, Vishal , Faber, Kelley, Simmons, Andrew , Weiner, Michael W. , Nho, Kwangsik T. , Risacher, Shannon L. , Keohane, Aoife , Lunnon, Katie , Hodges, Angela , Burgess, Jeremy D. , Foroud, Tatiana , Lovestone, Simon , Saykin, Andrew J.
Alzheimer's & Dementia | October 17, 2016 | Volume: 12 | Issue: 7S_Part_1 | Pages: No page available
O2‐06‐02: Genome‐Wide Meta‐Analysis of Transcriptome Profiling Identifies Novel Dysregulated Genes Implicated in Alzheimer's Disease
Apostolova, Liana G. , Lin, Kuang, Allen, Mariet , Wang, Xue , Ertekin‐Taner, Nilüfer , Petersen, Ronald , Soares, Holly , Wang, Lisu, Qi, Zhenhao, He, Aiqing, Neuhaus, Isaac , Patel, Vishal , Faber, Kelley, Simmons, Andrew , Weiner, Michael W. , Nho, Kwangsik T. , Kim, Sungeun , Risacher, Shannon L. , Keohane, Aoife , Lunnon, Katie , Hodges, Angela , Burgess, Jeremy D. , Singh, Parul , Foroud, Tatiana , Lovestone, Simon , Saykin, Andrew J.
Alzheimer's & Dementia | October 17, 2016 | Volume: 12 | Issue: 7S_Part_5 | Pages: No page available