Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants
Abstract Introduction The role of TOMM40‐APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Methods We dissected genetic profiles within the TOMM40‐APOE region in 451...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-01-01
|
| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| Subjects: | |
| Online Access: | https://doi.org/10.1016/j.trci.2019.08.005 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849688380991864832 |
|---|---|
| author | Inga Prokopenko Gentaro Miyakawa Bang Zheng Jani Heikkinen Daniela Petrova Quayle Chinedu Udeh‐Momoh Annique Claringbould Juliane Neumann Hazal Haytural Marika A. Kaakinen Elena Loizidou Esther Meissner Lars Bertram BIOS consortium Djordje O. Gveric Steve M. Gentleman Johannes Attems Robert Perneczky Thomas Arzberger Pierandrea Muglia Christina M. Lill Laura Parkkinen Lefkos T. Middleton |
| author_facet | Inga Prokopenko Gentaro Miyakawa Bang Zheng Jani Heikkinen Daniela Petrova Quayle Chinedu Udeh‐Momoh Annique Claringbould Juliane Neumann Hazal Haytural Marika A. Kaakinen Elena Loizidou Esther Meissner Lars Bertram BIOS consortium Djordje O. Gveric Steve M. Gentleman Johannes Attems Robert Perneczky Thomas Arzberger Pierandrea Muglia Christina M. Lill Laura Parkkinen Lefkos T. Middleton |
| author_sort | Inga Prokopenko |
| collection | DOAJ |
| description | Abstract Introduction The role of TOMM40‐APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Methods We dissected genetic profiles within the TOMM40‐APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD‐related pathology and healthy controls. Results TOMM40‐L/APOE‐ε4 alleles were associated with DLB (ORTOMM40‐L = 3.61; P value = 3.23 × 10−9; ORAPOE‐ε4 = 3.75; P value = 4.90 × 10−10) and earlier age at onset of DLB (HRTOMM40‐L = 1.33, P value = .031; HRAPOE‐ε4 = 1.46, P value = .004), but not with PDD. The TOMM40‐L/APOE‐ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (ORTOMM40‐L = 4.40, P value = 1.15 × 10−6; ORAPOE‐ε4 = 5.65, P value = 2.97 × 10−8) but was not significant in DLB without AD. Meta‐analyses combining all APOE‐ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10−99; ORDLB+AD = 5.36, P value = 1.56 × 10−47). Discussion APOE‐ε4/TOMM40‐L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD‐related pathology. These findings have important implications in future drug discovery and development efforts in DLB. |
| format | Article |
| id | doaj-art-b22b19304c254efa8a72ee1ffb54cf24 |
| institution | DOAJ |
| issn | 2352-8737 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj-art-b22b19304c254efa8a72ee1ffb54cf242025-08-20T03:22:00ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372019-01-015181482410.1016/j.trci.2019.08.005Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variantsInga Prokopenko0Gentaro Miyakawa1Bang Zheng2Jani Heikkinen3Daniela Petrova Quayle4Chinedu Udeh‐Momoh5Annique Claringbould6Juliane Neumann7Hazal Haytural8Marika A. Kaakinen9Elena Loizidou10Esther Meissner11Lars Bertram12BIOS consortiumDjordje O. Gveric13Steve M. Gentleman14Johannes Attems15Robert Perneczky16Thomas Arzberger17Pierandrea Muglia18Christina M. Lill19Laura Parkkinen20Lefkos T. Middleton21Section of Genomics of Common Disease Department of MedicineImperial College LondonLondonUKGenetic and Molecular Epidemiology Group, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA)University of LübeckLübeckGermanyNeuroepidemiology and Ageing Research UnitSchool of Public Health, Imperial College LondonLondonUKSection of Genomics of Common Disease Department of MedicineImperial College LondonLondonUKNeuroepidemiology and Ageing Research UnitSchool of Public Health, Imperial College LondonLondonUKNeuroepidemiology and Ageing Research UnitSchool of Public Health, Imperial College LondonLondonUKDepartment of GeneticsUniversity Medical Centre GroningenGroningenThe NetherlandsNuffield Department of Clinical Neuroscience, Neuropathology and Oxford Parkinson's Disease CentreUniversity of OxfordOxfordUKNuffield Department of Clinical Neuroscience, Neuropathology and Oxford Parkinson's Disease CentreUniversity of OxfordOxfordUKSection of Genomics of Common Disease Department of MedicineImperial College LondonLondonUKSection of Genomics of Common Disease Department of MedicineImperial College LondonLondonUKMax Planck Institute for Molecular GeneticsBerlinGermanyNeuroepidemiology and Ageing Research UnitSchool of Public Health, Imperial College LondonLondonUKMultiple Sclerosis and Parkinson's Tissue BankImperial College LondonLondonUKNeuropathology Unit Department of MedicineImperial College LondonLondonUKInstitute of Neuroscience, Newcastle UniversityNewcastle upon TyneUKNeuroepidemiology and Ageing Research UnitSchool of Public Health, Imperial College LondonLondonUKDepartment of Psychiatry and PsychotherapyLudwig‐Maximilians‐Universität MünchenMunichGermanyNeuroscience Discovery Medicine, UCB Pharma, Brussels AreaBelgiumGenetic and Molecular Epidemiology Group, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA)University of LübeckLübeckGermanyNuffield Department of Clinical Neuroscience, Neuropathology and Oxford Parkinson's Disease CentreUniversity of OxfordOxfordUKNeuroepidemiology and Ageing Research UnitSchool of Public Health, Imperial College LondonLondonUKAbstract Introduction The role of TOMM40‐APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Methods We dissected genetic profiles within the TOMM40‐APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD‐related pathology and healthy controls. Results TOMM40‐L/APOE‐ε4 alleles were associated with DLB (ORTOMM40‐L = 3.61; P value = 3.23 × 10−9; ORAPOE‐ε4 = 3.75; P value = 4.90 × 10−10) and earlier age at onset of DLB (HRTOMM40‐L = 1.33, P value = .031; HRAPOE‐ε4 = 1.46, P value = .004), but not with PDD. The TOMM40‐L/APOE‐ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (ORTOMM40‐L = 4.40, P value = 1.15 × 10−6; ORAPOE‐ε4 = 5.65, P value = 2.97 × 10−8) but was not significant in DLB without AD. Meta‐analyses combining all APOE‐ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10−99; ORDLB+AD = 5.36, P value = 1.56 × 10−47). Discussion APOE‐ε4/TOMM40‐L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD‐related pathology. These findings have important implications in future drug discovery and development efforts in DLB.https://doi.org/10.1016/j.trci.2019.08.005Parkinson's diseaseAlzheimer's diseaseParkinson's disease dementiaDementia with Lewy bodiesApolipoprotein EAPOE |
| spellingShingle | Inga Prokopenko Gentaro Miyakawa Bang Zheng Jani Heikkinen Daniela Petrova Quayle Chinedu Udeh‐Momoh Annique Claringbould Juliane Neumann Hazal Haytural Marika A. Kaakinen Elena Loizidou Esther Meissner Lars Bertram BIOS consortium Djordje O. Gveric Steve M. Gentleman Johannes Attems Robert Perneczky Thomas Arzberger Pierandrea Muglia Christina M. Lill Laura Parkkinen Lefkos T. Middleton Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants Alzheimer’s & Dementia: Translational Research & Clinical Interventions Parkinson's disease Alzheimer's disease Parkinson's disease dementia Dementia with Lewy bodies Apolipoprotein E APOE |
| title | Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants |
| title_full | Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants |
| title_fullStr | Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants |
| title_full_unstemmed | Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants |
| title_short | Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants |
| title_sort | alzheimer s disease pathology explains association between dementia with lewy bodies and apoe ε4 tomm40 long poly t repeat allele variants |
| topic | Parkinson's disease Alzheimer's disease Parkinson's disease dementia Dementia with Lewy bodies Apolipoprotein E APOE |
| url | https://doi.org/10.1016/j.trci.2019.08.005 |
| work_keys_str_mv | AT ingaprokopenko alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT gentaromiyakawa alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT bangzheng alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT janiheikkinen alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT danielapetrovaquayle alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT chineduudehmomoh alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT anniqueclaringbould alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT julianeneumann alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT hazalhaytural alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT marikaakaakinen alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT elenaloizidou alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT esthermeissner alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT larsbertram alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT biosconsortium alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT djordjeogveric alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT stevemgentleman alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT johannesattems alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT robertperneczky alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT thomasarzberger alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT pierandreamuglia alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT christinamlill alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT lauraparkkinen alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants AT lefkostmiddleton alzheimersdiseasepathologyexplainsassociationbetweendementiawithlewybodiesandapoee4tomm40longpolytrepeatallelevariants |