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

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

doi:10.1016/j.trci.2019.08.005

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

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

Authors

Inga Prokopenko^{1

2}, Gentaro Miyakawa^{3

4}, Bang Zheng⁵, Jani Heikkinen^{1

5}, Daniela Petrova Quayle⁵, Chinedu Udeh-Momoh⁵, Annique Claringbould⁶, Juliane Neumann⁷, Hazal Haytural⁷, Marika A Kaakinen^{1

2

8}, Elena Loizidou¹, Esther Meissner⁴, Lars Bertram^{5

9}; BIOS consortium; Djordje O Gveric¹⁰, Steve M Gentleman¹¹, Johannes Attems¹², Robert Perneczky^{5

13

14}, Thomas Arzberger^{13

15}, Pierandrea Muglia¹⁶, Christina M Lill^{3

5}, Laura Parkkinen⁷, Lefkos T Middleton^{5

17}

Affiliations

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 (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.

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.

Abstract

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