Open AccessAlzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants
Author(s) -
Prokopenko Inga,
Miyakawa Gentaro,
Zheng Bang,
Heikkinen Jani,
Petrova Quayle Daniela,
UdehMomoh Chinedu,
Claringbould Annique,
Neumann Juliane,
Haytural Hazal,
Kaakinen Marika A.,
Loizidou Elena,
Meissner Esther,
Bertram Lars,
Gveric Djordje O.,
Gentleman Steve M.,
Attems Johannes,
Perneczky Robert,
Arzberger Thomas,
Muglia Pierandrea,
Lill Christina M.,
Parkkinen Laura,
Middleton Lefkos T.
Publication year - 2019
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1016/j.trci.2019.08.005
Subject(s) - dementia with lewy bodies , apolipoprotein e , allele , dementia , alzheimer's disease , disease , pathology , concomitant , medicine , gastroenterology , biology , genetics , gene
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 TOMM 40 ‐L/ APOE ‐ε4 alleles were associated with DLB (OR TOMM40 ‐ L = 3.61; P value = 3.23 × 10 −9 ; OR APOE ‐ε4 = 3.75; P value = 4.90 × 10 −10 ) and earlier age at onset of DLB (HR TOMM40 ‐L = 1.33, P value = .031; HR APOE ‐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 (OR TOMM40 ‐L = 4.40, P value = 1.15 × 10 −6 ; OR APOE ‐ 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 (OR DLB = 2.93, P value = 3.78 × 10 −99 ; OR DLB+AD = 5.36, P value = 1.56 × 10 −47 ). Discussion APOE ‐ε4/ TOMM 40 ‐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.