Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies
Open accessAbstract
Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
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The other mechanisms of APOE4 dysfunction probably explain the association with neurodegenerative diseases in general, such as Parkinson's disease, Lewy body dementia, TDP-43 proteinopathy, and vascular dementia.
“The other mechanisms of APOE4 dysfunction probably explain the association with neurodegenerative diseases in general, such as Parkinson’s disease (odds ratio ~1.6–4.19) and Lewy body dementia (odds ratio ~2.4–6.1) (Bras et al, 2014; Guerreiro et al, 2018; Huang et al, 2006; Irwin et al, 2012; Tropea et al, 2018; Tsuang et al, 2013); TDP-43 proteinopathy (odds ratio ~2) (Josephs et al, 2014; Wenn”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Bras et al, 2014
The Results and Discussion report an association between APOE ε4 and dementia with Lewy bodies. But the Discussion says this association is likely driven by the variant’s amyloid-β-promoting effect and only notes that other mechanisms cannot be excluded. The cited passages do not establish that other APOE4 mechanisms explain an association with Parkinson’s disease or substantiate the quoted odds-ratio ranges. (LLM, conf=0.88)
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Cites
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- Authors
- Bras, J., Guerreiro, R., Darwent, L., Parkkinen, L., Ansorge, O., Escott-Price, V., Hernandez, D. G., Nalls, M. A., Clark, L. N., Honig, L. S., Marder, K., Van Der Flier, W. M., Lemstra, A., Scheltens, P., Rogaeva, E., St George-Hyslop, P., Londos, E., Zetterberg, H., Ortega-Cubero, S., Pastor, P., Ferman, T. J., Graff-Radford, N. R., Ross, O. A., Barber, I., Braae, A., Brown, K., Morgan, K., Maetzler, W., Berg, D., Troakes, C., Al-Sarraj, S., Lashley, T., Compta, Y., Revesz, T., Lees, A., Cairns, N., Halliday, G. M., Mann, D., Pickering-Brown, S., Dickson, D. W., Singleton, A., & Hardy, J.
- Affiliations
- University of Oxford (GB)
- National Institutes of Health (US)
- Columbia University Irving Medical Center (US)
- Amsterdam Neuroscience (NL)
- University of Toronto (CA)
- Lund University (SE)
- University of Gothenburg (SE)
- Mayo Clinic in Florida (US)
- University of Nottingham (GB)
- German Center for Neurodegenerative Diseases (DE)
- King's College London (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Washington University in St. Louis (US)
- UNSW Sydney (AU)
- University of Manchester (GB)
- UCL Queen Square Institute of Neurology (GB)
- ORCID
- Guerreiro, Rita
- Darwent, Lee
- Parkkinen, Laura
- Ansorge, Olaf
- Hernandez, Dena G.
- Clark, Lorraine N.
- Honig, Lawrence S.
- Marder, Karen
- Lemstra, Afina
- Scheltens, Philip
- Rogaeva, Ekaterina
- Londos, Elisabet
- Zetterberg, Henrik
- Ferman, Tanis J.
- Ross, Owen A.
- Braae, Anne
- Morgan, Kevin
- Maetzler, Walter
- Berg, Daniela
- Troakes, Claire
- Lashley, Tammaryn
- Compta, Yaroslau
- Lees, Andrew
- Cairns, Nigel
- Halliday, Glenda M.
- Mann, David
- Pickering-Brown, Stuart
- Dickson, Dennis W.
- Singleton, Andrew
- Hardy, John
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-06-27
- Volume
- 23
- Issue
- 23
- Pages
- 6139-6146
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4222357
- OpenAlex
- W2152098155
- Cited by
- 230
- References
- 4
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 20 · 2023: 9 · 2022: 15 · 2021: 21 · 2020: 18 · 2019: 24 · 2018: 20 · 2017: 23 · 2016: 28 · 2015: 21 · 2014: 4
- FWCI
- 15.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by
- Locations
- Human Molecular Genetics (publishedVersion)
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- Funders
- U.S. Department of Health and Human Services
- Michael J. Fox Foundation for Parkinson's Research (R01 NS078086, NS078086)
- Mayo Clinic
- Parkinson's Disease Foundation (NS078086, P50NS038370, NINDS R01)
- University of Dundee
- Wellcome Trust (WT089698, 100140, 089701, 089703, 081864, 089698)
- Neuroscience Research Australia
- Vanderbilt University Medical Center
- Alzheimer's Society
- National Institute for Health and Care Research
- Parkinson's UK (G-0907, K-1204)
- University of Sheffield
- University of New South Wales
- Ministerio de Ciencia e Innovación (SAF2006-10126, SAF2010‐22329‐C02‐01)
- University College London Hospitals NHS Foundation Trust
- Stichting Dioraphte
- National Institutes of Health (UL1TR000040, NS072187)
- Canadian Institutes of Health Research
- Medical Research Council (MR/L022656/1, MC_G1000735, MR/L016397/1, MR/L010305/1, WT089698)
- National Health and Medical Research Council
- National Institute on Aging (Z01AG000951, P50AG008702, AG000951-12)
- National Institute of Neurological Disorders and Stroke (NS078086, R01NS078086, P50NS038370, R01NS060113, NS072187, P50NS072187, NS060113)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- dementia with Lewy bodies, apolipoprotein E, SNCA, SCARB2, lysosomal dysfunction, genetic risk factors, Parkinson's disease, Alzheimer's disease, genetic association
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Female, Humans, Lysosomes, Male, Parkinson Disease, Risk Factors, Cohort Studies, Case-Control Studies, Lewy Body Disease, Receptors, Scavenger, alpha-Synuclein, Lysosomal Membrane Proteins, Genetic Loci, Genetic Association Studies
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