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Role of GBA variants in Lewy body disease neuropathology

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Abstract

Rare and common GBA variants are risk factors for both Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: −0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0–1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease–risk associations of GBA in PD, PD dementia, and DLB.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

LBD:

Lewy body disease

LB:

Lewy body

PD:

Parkinson’s disease

DLB:

Dementia with Lewy bodies

AD:

Alzheimer’s disease

GWAS:

Genome-wide association study

TH-ir:

Tyrosine hydroxylase immunoreactivity

SN:

Substantia nigra

NFT:

Neurofibrillary tangle

pS65-Ub:

Phospho-ubiquitin

TDP-43:

TAR DNA-binding protein-43

VaD:

Vascular disease

H & E:

Hematoxylin and eosin

MF:

Middle frontal

ST:

Superior temporal

IP:

Inferior parietal

CG:

Cingulate

PH:

Parahippocampal

SN:

Substantia nigra

PC:

Principal component

MAF:

Minor allele frequency

OR:

Odds ratio

CI:

Confidence interval

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Acknowledgements

We would like to thank all those who have contributed to our research, particularly the patients and families who donated brain, blood, and DNA samples for this work. We would like to acknowledge the continuous commitment, technical support and teamwork offered by Linda G. Rousseau, Virginia R. Phillips, and Monica Castanedes-Casey. This work was supported by the Mayo Clinic LBD Center WithOut Walls (CWOW; U54-NS110435), Ted Turner and family, the Little Family Foundation, and the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy body dementia program, and in part by the Mayo Clinic Florida Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187), Alzheimer’s disease Research Center (P50 AG016574), an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research and the Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence.

Funding

OAR and DWD are both supported by NINDS Tau Center without Walls Program (U54-NS100693) and NIH (UG3-NS104095). OAR is supported by NIH (P50-NS072187; R01- NS078086; U54-NS100693; U54- NS110435), DOD (W81XWH-17-1-0249), The American Brain Foundation, The Michael J. Fox Foundation, The Little Family Foundation, Ted Turner and family, the Mayo Clinic Foundation, and the Center for Individualized Medicine. DWD receives research support from the NIH (P50-AG016574; P30-AG062677; U54-NS100693; P01-AG003949), CurePSP, the Tau Consortium, and the Robert E. Jacoby Professorship. SK is supported by the State of Florida Ed and Ethel Moore Alzheimer’s Disease Research Program and Mayo Clinic ADRC Research Grant. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206) and Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. WS is supported by NIH [U54 NS110435, R01 NS085070, R01 NS110085, and R56 AG062556], the Department of Defense Congressionally Directed Medical Research Programs (CDMRP) [W81XWH-17-1-0248], the Michael J. Fox Foundation for Parkinson’s Research (MJFF), the Ted Nash Long Life Foundation, Mayo Clinic Foundation, the Center for Biomedical Discovery (CBD), and the Robert and Arlene Kogod Center on Aging. XH is supported by a pilot grant and a developmental project award from the Mayo Clinic Alzheimer Disease Research Center (ADRC, P30 AG062677) and fellowships awarded by the APDA and Alzheimer’s Association [AARF-22–973152]. FCF is the recipient of fellowships from the Younkin Scholar Program and the APDA and is supported in part by the Florida Department of Health—Ed and Ethel Moore Alzheimer’s Disease Research Program [22A07], the MJFF, a Gerstner Family Career Development Award from the Center for Individualized Medicine (CIM) and an auxiliary award from the CBD at Mayo Clinic. VJL serves as consultant for Bayer Schering Pharma, Philips Molecular Imaging, Piramal Imaging, AVID Radiopharmaceuticals, Eisai Inc., Eli Lilly, and GE Healthcare and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIH (NIA, NCI), and the MN Partnership for Biotechnology and Medical Genomics. TJF is supported by NIH (P30-AG062677, U01-NS100620, U19-AG071754) and the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy body dementia program. The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Author notes

  1. Ronald L. Walton, Shunsuke Koga, and Owen A. Ross have contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Ronald L. Walton, Shunsuke Koga, Alexandra I. Beasley, Teresa Griesacker, Melissa E. Murray, Koji Kasanuki, Xu Hou, Fabienne C. Fiesel, Wolfdieter Springer, Nilufer Ertekin-Taner, Dennis W. Dickson & Owen A. Ross

  2. Division of Clinical Trials and Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, USA

    Launia J. White & Michael G. Heckman

  3. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Ryan J. Uitti, Nilufer Ertekin-Taner, Neill R. Graff-Radford & Zbigniew K. Wszolek

  4. Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA

    Julie A. Fields

  5. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Hugo Botha, Vijay K. Ramanan, Rodolfo Savica, Jonathan Graff-Radford, Ronald C. Petersen & Bradley F. Boeve

  6. Department of Neuroradiology, Mayo Clinic, Rochester, MN, USA

    Kejal Kantarci & Clifford R. Jack

  7. Department of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA

    Val J. Lowe

  8. Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Joseph E. Parisi & R. Ross Reichard

  9. Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA

    Tanis J. Ferman

  10. Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA

    Owen A. Ross

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  1. Ronald L. Walton
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Contributions

RLW performed genotyping and quality control assessments on all samples, and assisted in drafting the manuscript. SK, KK, and DWD provided brain tissue samples for all cases and provided manuscript improvements. DWD also performed all neuropathological assessments of LBD cases. AIB, TG, MEM, XH, FCF, WS, RJU, JAF, HB, VKR, KK, VJL, CRJ, NE, RS, JG, RCP, JEP, RRR, NRG, TJF, BFB, and ZKW provided manuscript improvements. LJW performed the statistical analysis. OAR led the study, oversaw all methodological developments, and approved the final manuscript. MGH performed the statistical analysis and drafted the manuscript.

Corresponding author

Correspondence to Michael G. Heckman.

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This study was approved by the Mayo Clinic Institutional Review Board. All subjects or legal next of kin provided written informed consent.

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Walton, R.L., Koga, S., Beasley, A.I. et al. Role of GBA variants in Lewy body disease neuropathology. Acta Neuropathol 147, 54 (2024). https://doi.org/10.1007/s00401-024-02699-w

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