Association of ABI3 and PLCG2 Missense Variants With Disease Risk and Neuropathology in Lewy Body Disease and Progressive Supranuclear Palsy
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Abstract Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer’s disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (nTotal = 2008, nPSP = 1037, nLBD-NP = 971) and Thal phase amyloid plaque scores (nTotal = 1786, nPSP = 1018, nLBD-NP = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46–4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = − 0.822, 95% CI − 1.439 to − 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = − 0.995, 95% CI − 1.773 to − 0.218, p = 0.012) than LBD-NP patients (ß = − 0.292, 95% CI − 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = − 0.638, 95% CI − 1.139 to − 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.
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The R522 variant of PLCγ2 is in humans associated with longevity and protection of cognitive function in old age and protects against AD, as well as frontotemporal dementia and dementia with Lewy bodies.
“the R522 variant of PLCγ2 is in humans associated with longevity and protection of cognitive function in old age and protects against AD, as well as frontotemporal dementia and dementia with Lewy bodies (Sims et al. 2017; van der Lee et al. 2019; Strickland et al. 2020).”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Strickland et al. 2020
The Introduction and Discussion (pages unavailable) report reduced Alzheimer’s risk and describe protective associations in some studies of dementia with Lewy bodies and frontotemporal dementia. The Discussion also reports an association with cognitive decline in patients with mild cognitive impairment. The paper does not itself report an association with longevity or establish protection of cognitive function specifically in old age; its own Lewy body disease cohort found no statistically significant association with disease risk. (LLM, conf=0.87)
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Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · see citing works
Self-citationProgressive Supranuclear Palsy: Pathology and Genetics
Dickson, D. W., Rademakers, R., & Hutton, M. L. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00054.x · Cited by 314 · see citing works
Self-citationAlzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Magno, L., Lessard, C. B., Martins, M., Lang, V., Cruz, P., Asi, Y., Katan, M., Bilsland, J., Lashley, T., Chakrabarty, P., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0469-0 · Cited by 143 · see citing works
DESGESCO (Dementia Genetics Spanish Consortium), E. (. D. E. D. B., van der Lee, S. J., biobank), E. (. D. E. D., IFGC (International FTD-Genomics Consortium), I. (. I. P. D. G. C., IPDGC (The International Parkinson Disease Genomics Consortium), Dementia), R.-F. (. A. M. F. I. F.-T., (NBB), N. B. B., The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Conway, O. J., Jansen, I., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02026-8 · Cited by 120 · see citing works
Self-citationConway, O. J., Carrasquillo, M. M., Wang, X., Bredenberg, J. M., Reddy, J. S., Strickland, S. L., Younkin, C. S., Burgess, J. D., Allen, M., Lincoln, S. J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0289-x · Cited by 112 · see citing works
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Flagged first, then by citations
Research works printed but not linked: 18
- [1]Allen M Burgess JD Ballard T Serie D Wang X Younkin CS Sun Z Kouri N Baheti S Wang C Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci Acta Neuropathol 2016 132 197 211 10.1007/s00401-016-1576-7 27115769 PMC4947429 · DOI
- [2]Allen M Carrasquillo MM Funk C Heavner BD Zou F Younkin CS Burgess JD Chai HS Crook J Eddy JA Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases Sci Data 2016 3 160089 10.1038/sdata.2016.89 27727239 PMC5058336 · DOI · Paper page
- [3]Allen M Wang X Serie DJ Strickland SL Burgess JD Koga S Younkin CS Nguyen TT Malphrus KG Lincoln SJ Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy Acta Neuropathol 2018 136 709 727 10.1007/s00401-018-1900-5 30136084 PMC6208732 · DOI
- [4]Allen M Kachadoorian M Carrasquillo MM Karhade A Manly L Burgess JD Wang C Serie D Wang X Siuda J Late-onset Alzheimer disease risk variants mark brain regulatory loci Neurol Genet 2015 1 e15 10.1212/NXG.0000000000000012 27066552 PMC4807909 · DOI · Paper page
- [5]Barker WW Luis CA Kashuba A Luis M Harwood DG Loewenstein D Waters C Jimison P Shepherd E Sevush S Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank Alzheimer Dis Assoc Disord 2002 16 203 212 10.1097/00002093-200210000-00001 12468894 · DOI
- [6]Braak H Alafuzoff I Arzberger T Kretzschmar H Del Tredici K Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry Acta Neuropathol 2006 112 389 404 10.1007/s00401-006-0127-z 16906426 PMC3906709 · DOI · Paper page
- [9]Dickson DW Heckman MG Murray ME Soto AI Walton RL Diehl NN van Gerpen JA Uitti RJ Wszolek ZK Ertekin-Taner N APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology Neurology 2018 91 e1182 e1195 10.1212/WNL.0000000000006212 30143564 PMC6161556 · DOI · Paper page
- [11]Guerreiro R Ross OA Kun-Rodrigues C Hernandez DG Orme T Eicher JD Shepherd CE Parkkinen L Darwent L Heckman MG Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study Lancet Neurol 2018 17 64 74 10.1016/s1474-4422(17)30400-3 29263008 PMC5805394 · DOI · Paper page
- [12]Hauw JJ Daniel SE Dickson D Horoupian DS Jellinger K Lantos PL McKee A Tabaton M Litvan I Preliminary NINDS neuropathologic criteria for Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy) Neurology 1994 44 2015 2019 10.1212/wnl.44.11.2015 7969952 · DOI
- [13]Höglinger GU Melhem NM Dickson DW Sleiman PM Wang LS Klei L Rademakers R de Silva R Litvan I Riley DE Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy Nat Genet 2011 43 699 705 10.1038/ng.859 21685912 PMC3125476 · DOI · Paper page
- [14]Josephs KA Dickson DW Diagnostic accuracy of progressive supranuclear palsy in the Society for Progressive Supranuclear Palsy brain bank Mov Disord 2003 18 1018 1026 10.1002/mds.10488 14502669 · DOI
- [15]Kleineidam L Chouraki V Prochnicki T van der Lee SJ Madrid-Marquez L Wagner-Thelen H Karaca I Weinhold L Wolfsgruber S Boland A PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment Acta Neuropathol 2020 10.1007/s00401-020-02138-6 32166339 PMC7244617 · DOI · Paper page
- [17]McKeith IG Boeve BF Dickson DW Halliday G Taylor JP Weintraub D Aarsland D Galvin J Attems J Ballard CG Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium Neurology 2017 89 88 100 10.1212/WNL.0000000000004058 28592453 PMC5496518 · DOI · Paper page
- [18]Neumann M Mackenzie IRA Review: neuropathology of non-tau frontotemporal lobar degeneration Neuropathol Appl Neurobiol 2019 45 19 40 10.1111/nan.12526 30357887 · DOI · Paper page
- [19]Orme T Hernandez D Ross OA Kun-Rodrigues C Darwent L Shepherd CE Parkkinen L Ansorge O Clark L Honig LS Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies Acta Neuropathol Commun 2020 8 5 10.1186/s40478-020-0879-z 31996268 PMC6990558 · DOI
- [20]Purcell S Neale B Todd-Brown K Thomas L Ferreira MA Bender D Maller J Sklar P de Bakker PI Daly MJ PLINK: a tool set for whole-genome association and population-based linkage analyses Am J Hum Genet 2007 81 559 575 10.1086/519795 17701901 PMC1950838 · DOI · Paper page
- [21]Rizzo G Arcuti S Copetti M Alessandria M Savica R Fontana A Liguori R Logroscino G Accuracy of clinical diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis J Neurol Neurosurg Psychiatry 2018 89 358 366 10.1136/jnnp-2017-316844 29030419 · DOI
- [23]Thal DR Rub U Orantes M Braak H Phases of A beta-deposition in the human brain and its relevance for the development of AD Neurology 2002 58 1791 1800 10.1212/WNL.58.12.1791 12084879 · DOI · Paper page
Cited by
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Reddy, J. S., Heath, L., Linden, A. V., Allen, M., Lopes, K. D. P., Seifar, F., Wang, E., Ma, Y., Poehlman, W. L., Quicksall, Z. S., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14208 · Cited by 29 · see citing works
Self-citationBevan, R. J., Maguire, E., Mackinnon, E., Salis, E., Phillips, T., Simonazzi, E., Vassileva, M., Allen, N. D., Williams, J., & Taylor, P. R. (2026) · Glia · doi:10.1002/glia.70192 · Cited by 1 · see citing works
- Authors
- Strickland, S. L., Morel, H., Prusinski, C., Allen, M., Patel, T. A., Carrasquillo, M. M., Conway, O. J., Lincoln, S. J., Reddy, J. S., Nguyen, T., Malphrus, K. G., Soto, A. I., Walton, R. L., Crook, J. E., Murray, M. E., Boeve, B. F., Petersen, R. C., Lucas, J. A., Ferman, T. J., Uitti, R. J., Wszolek, Z. K., Ross, O. A., Graff-Radford, N. R., Dickson, D. W., & Ertekin-Taner, N.
- Affiliations
- Mayo Clinic in Florida (US)
- Mayo Clinic (US)
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2020-10-22
- Volume
- 8
- Issue
- 1
- Pages
- 172-172
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC7579984
- OpenAlex
- W3093741076
- Cited by
- 15
- References
- 6
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (RF AG051504, R01 AG061796, U01 AG046139)
- National Institute of Neurological Disorders and Stroke (R01 NS080820, R01 NS078086)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ABI3, PLCγ2, missense mutations, Lewy body disease, progressive supranuclear palsy, tau pathology, amyloid pathology, genetic risk, neuropathology, genetic association
- MeSH terms
- Aged, Aged, 80 and over, Female, Humans, Male, Supranuclear Palsy, Progressive, Case-Control Studies, Genetic Predisposition to Disease, Mutation, Missense, Lewy Body Disease, Adaptor Proteins, Signal Transducing, Phospholipase C gamma
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