期刊
ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
卷 5, 期 1, 页码 814-824出版社
WILEY
DOI: 10.1016/j.trci.2019.08.005
关键词
Parkinson's disease; Alzheimer's disease; Parkinson's disease dementia; Dementia with Lewy bodies; Apolipoprotein E; APOE; TOMM40; Association analysis; Brain banks; Lewy body dementias; Neuropathology
资金
- Medical Research Council (MRC)
- Brains for Dementia Research (BDR) (Alzheimer Society)
- Brains for Dementia Research (BDR) (Alzheimer Research UK)
- Autistica UK
- NIHR Oxford Biomedical Research Centre
- Parkinson's UK Tissue Bank - Parkinson's UK [258197, SCO37554]
- Newcastle Brain Tissue Resource - UK Medical Research Council [G0400074]
- Brains for Dementia research
- Parkinson's UK [G0909]
- Michael J Fox Foundation
- UCB Pharmaceuticals
- European Union [H2020- SC1-2019-874739, H2020-PHC-2014-633595]
- Wellcome Trust [WT205915]
- European Commission under the Marie Curie Intra-European Fellowship, project MARVEL [PIEF-GA-2013-626461]
- MRC CASE studentship
- ERC
- Possehl foundation
- Renate Maass foundation
- German Research Foundation [FOR2488/1, GZ LI 2654/2-1]
- University of Lubeck [J21-2016]
- Monument Trust Discovery Award from Parkinson's UK [J-1403]
IntroductionThe 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). MethodsWe 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. ResultsTOMM40-L/APOE-epsilon 4 alleles were associated with DLB (ORTOMM40-L=3.61; P value=3.23x10(-9); ORAPOE-epsilon 4=3.75; P value=4.90x10(-10)) and earlier age at onset of DLB (HRTOMM40-L=1.33, P value=.031; HRAPOE-epsilon 4=1.46, P value=.004), but not with PDD. The TOMM40-L/APOE-epsilon 4 effect was most pronounced in DLB individuals with concomitant AD pathology (ORTOMM40-L=4.40, P value=1.15x10(-6); ORAPOE-epsilon 4=5.65, P value=2.97x10(-8)) but was not significant in DLB without AD. Meta-analyses combining all APOE-epsilon 4 data in DLB confirmed our findings (ORDLB=2.93, P value=3.78x10(-99); ORDLB+AD=5.36, P value=1.56x10(-47)). DiscussionAPOE-epsilon 4/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.
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