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Alzheimers Dement (N Y). 2019 Nov 20;5:814-824. doi: 10.1016/j.trci.2019.08.005. eCollection 2019.

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

Author information

1
Section of Genomics of Common Disease, Department of Medicine, Imperial College London, London, UK.
2
Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, School of Biosciences and Medicine, University of Surrey, Guildford, UK.
3
Genetic and Molecular Epidemiology Group, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
4
Max Planck Institute for Molecular Genetics, Berlin, Germany.
5
Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London, UK.
6
Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands.
7
Nuffield Department of Clinical Neuroscience, Neuropathology and Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
8
Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College London, London, UK.
9
Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany.
10
Multiple Sclerosis and Parkinson's Tissue Bank, Imperial College London, London, UK.
11
Neuropathology Unit, Department of Medicine, Imperial College London, London, UK.
12
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
13
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany.
14
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
15
Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
16
Neuroscience Discovery Medicine, UCB Pharma, Brussels Area, Belgium.
17
Neurology, Public Health Directorate, Imperial College NHS Healthcare Trust Hospitals, London, UK.

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:

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 (ORDLB = 2.93, P value = 3.78 × 10-99; ORDLB+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.

KEYWORDS:

APOE; Alzheimer's disease; Apolipoprotein E; Association analysis; Brain banks; Dementia with Lewy bodies; Lewy body dementias; Neuropathology; Parkinson's disease; Parkinson's disease dementia; TOMM40

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