Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants

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...

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Main Authors: 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
Format: Article
Language:English
Published: Wiley 2019-01-01
Series:Alzheimer’s & Dementia: Translational Research & Clinical Interventions
Subjects:
Parkinson's disease
Alzheimer's disease
Parkinson's disease dementia
Dementia with Lewy bodies
Apolipoprotein E
APOE
Online Access:https://doi.org/10.1016/j.trci.2019.08.005
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Summary: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.
ISSN:2352-8737

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