TY - JOUR
T1 - Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants
AU - BIOS Consortium
AU - Prokopenko, Inga
AU - Miyakawa, Gentaro
AU - Zheng, Bang
AU - Heikkinen, Jani
AU - Petrova Quayle, Daniela
AU - Udeh-Momoh, Chinedu
AU - Claringbould, Annique
AU - Neumann, Juliane
AU - Haytural, Hazal
AU - Kaakinen, Marika A.
AU - Loizidou, Elena
AU - Meissner, Esther
AU - Bertram, Lars
AU - Gveric, Djordje O.
AU - Gentleman, Steve M.
AU - Attems, Johannes
AU - Perneczky, Robert
AU - Arzberger, Thomas
AU - Muglia, Pierandrea
AU - Lill, Christina M.
AU - Parkkinen, Laura
AU - Middleton, Lefkos T.
N1 - Funding Information:
I.P. was funded by the European Union's Horizon 2020 research , and innovation programme (LONGITOOLS, H2020- SC1-2019-874739 ; DYNAhealth, H2020- PHC-2014-633595 ); and the Wellcome Trust ( WT205915 ). M.A.K. was funded by the European Commission under the Marie Curie Intra-European Fellowship, project MARVEL (PIEF-GA-2013-626461). E.L. was supported by MRC CASE studentship. Further support came from the ERC (as part of the EMIF-AD project to LB, the Possehl foundation , the Renate Maaβ foundation , the German Research Foundation (FOR2488/1, GZ LI 2654/2-1) and the University of Lübeck (medical section, grant number: J21-2016 ) to C.M.L. L.P. is supported by a grant from Monument Trust Discovery Award ( J-1403 ) from Parkinson's UK .
Funding Information:
The authors are grateful to the patients who have made this study possible by donating brain tissue to the collaborating Brain banks of our study. Tissue material and associated clinical and neuropathological data were obtained from the following brain banks: the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) ( Alzheimer Society and Alzheimer Research UK), Autistica UK and the NIHR Oxford Biomedical Research Centre ; the Parkinson's UK Tissue Bank , funded by Parkinson's UK , a charity registered in England and Wales ( 258197 ) and Scotland ( SCO37554 ); the Newcastle Brain Tissue Resource , which is funded in part by a grant from the UK Medical Research Council ( G0400074 ) and by Brains for Dementia research , a joint venture between Alzheimer's Society and Alzheimer's Research UK.
Funding Information:
The study was supported by grants from Parkinson's UK ( G0909 ), the Michael J Fox Foundation and UCB Pharmaceuticals to LTM.
Funding Information:
The authors are grateful to the patients who have made this study possible by donating brain tissue to the collaborating Brain banks of our study. Tissue material and associated clinical and neuropathological data were obtained from the following brain banks: the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK and the NIHR Oxford Biomedical Research Centre; the Parkinson's UK Tissue Bank, funded by Parkinson's UK, a charity registered in England and Wales (258197) and Scotland (SCO37554); the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia research, a joint venture between Alzheimer's Society and Alzheimer's Research UK. Part of this work was performed using the Imperial College High Performance Computing Service, URL: http://www.imperial.ac.uk/admin-services/ict/self-service/research-support/hpc/. The study was supported by grants from Parkinson's UK (G0909), the Michael J Fox Foundation and UCB Pharmaceuticals to LTM. I.P. was funded by the European Union's Horizon 2020 research, and innovation programme (LONGITOOLS, H2020- SC1-2019-874739; DYNAhealth, H2020-PHC-2014-633595); and the Wellcome Trust (WT205915). M.A.K. was funded by the European Commission under the Marie Curie Intra-European Fellowship, project MARVEL (PIEF-GA-2013-626461). E.L. was supported by MRC CASE studentship. Further support came from the ERC (as part of the EMIF-AD project to LB, the Possehl foundation, the Renate Maa? foundation, the German Research Foundation (FOR2488/1, GZ LI 2654/2-1) and the University of L?beck (medical section, grant number: J21-2016) to C.M.L. L.P. is supported by a grant from Monument Trust Discovery Award (J-1403) from Parkinson's UK.
Publisher Copyright:
© 2019 The Authors
PY - 2019
Y1 - 2019
N2 - 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 - ε 4 = 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.
AB - 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 - ε 4 = 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.
UR - http://www.scopus.com/inward/record.url?scp=85075163647&partnerID=8YFLogxK
U2 - 10.1016/j.trci.2019.08.005
DO - 10.1016/j.trci.2019.08.005
M3 - Journal articles
AN - SCOPUS:85075163647
SN - 2352-8737
VL - 5
SP - 814
EP - 824
JO - Alzheimer's and Dementia: Translational Research and Clinical Interventions
JF - Alzheimer's and Dementia: Translational Research and Clinical Interventions
ER -