@article{c8688cb3cb3b4038b1f58233a931786b,
title = "GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology",
abstract = "Objectives: Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both. Methods: We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD). Results: Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8-31.9; p = 0.006; LBD-AD: OR - 4.6; CI = 1.2-17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2-6.6; p = 0.92). There was a highly significant trend test across groups (x2(1) = 19.3; p = 1.1 × 10-5), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB. Conclusions: GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.",
author = "Debby Tsuang and Leverenz, {James B.} and Lopez, {Oscar L.} and Hamilton, {Ronald L.} and Bennett, {David A.} and Schneider, {Julie A.} and Buchman, {Aron S.} and Larson, {Eric B.} and Crane, {Paul K.} and Kaye, {Jeffrey A.} and Patricia Kramer and Randy Woltjer and Walter Kukull and Nelson, {Peter T.} and Jicha, {Gregory A.} and Neltner, {Janna H.} and Doug Galasko and Eliezer Masliah and Trojanowski, {John Q.} and Schellenberg, {Gerard D.} and Dora Yearout and Haley Huston and Allison Fritts-Penniman and Mata, {Ignacio F.} and Wan, {Jia Y.} and Edwards, {Karen L.} and Montine, {Thomas J.} and Zabetian, {Cyrus P.}",
note = "Funding Information: D. Tsuang is funded by grants from Department of Veterans Affairs, NARSAD, and NIH. J. Leverenz has served as a consultant for Bayer and Teva Pharmaceuticals and is funded by grants from the American Parkinson Disease Association, Michael J. Fox Foundation, NIH, and Northwest Collaborative Care. O. Lopez is funded by the NIH. R. Hamilton performs diagnostic neuropathology (40% effort) and bills for these procedures. He is partly supported by grants from the NIH. D. Bennett serves on the editorial board of Neurology {\textregistered}; serves on the scientific advisory board for Vigorous Minds; serves/has served as a consultant to Danone Research B.V., Willmar Schwabe GmbH, Eli Lilly, and Gerson Lehrman Group; and receives research support from Danone Research B.V., the NIH, the Illinois Department of Public Health, and the Robert C. Borwell Endowment Fund. J. Schneider served on a scientific advisory board for GE Healthcare; serves as a consultant for Avid Radiopharmaceuticals, Inc.; and receives research support from Avid Radiopharmaceuticals, Inc. and the NIH. A. Buchman is funded by the NIH. E. Larson receives research support from the NIH. P. Crane is funded by grants from the Alzheimer's Association and NIH. J. Kaye receives research support from the Department of Veterans Affairs and the NIH. Individuals who work in the research centers he directs receive research support from Johnson & Johnson, Roche, and Bristol Myers Squibb. Dr. Kaye is compensated for serving on a data monitoring committee for Eli Lilly; he serves as a paid advisor for Janssen Pharmaceutical. Dr. Kaye receives reimbursement through Medicare or commercial insurance plans for providing clinical assessment and care for patients; is salaried to see patients at the Portland VA Medical Center; and serves as an unpaid Vice-Chair for the International Professional Interest Area Work Group of the International Society to Advance Alzheimer's Research and Treatments (ISTAART) and as an unpaid Commissioner for the Center for Aging Services and Technologies. P. Kramer reports no disclosures. R. Woltjer is funded by the NIH. W. Kukull is funded by grants from the Alzheimer's Association and NIH. P. Nelson is funded by grants from the NIH. G. Jicha serves as a consultant for Pfizer and Eli Lilly, and receives research support from Pfizer, Elan Corporation, Janssen, Medivation, Inc., Danone, and the NIH/NIA. J. Neltner reports no disclosures. D. Galasko serves on safety monitoring committees for clinical trials for Janssen Pharmaceuticals, Elan Pharmaceuticals, and Balance Pharmaceuticals, and has served as a paid advisor to Elan Pharmaceuticals, Phloronol, Inc., and United BioSource. He has received research funding from the National Institute on Aging. E. Masliah is funded by grants from the NIH. J. Trojanowski has received funding for travel and honoraria from Takeda Pharmaceutical Company, Ltd.; has received speaker honoraria from Pfizer; may accrue revenue on patents regarding modified avidin-biotin technique, method of stabilizing microtubules to treat Alzheimer disease, method of detecting abnormally phosphorylated tau, method of screening for Alzheimer disease or disease associated with the accumulation of paired helical filaments, compositions and methods for producing and using homogeneous neuronal cell transplants, rat comprising straight filaments in its brain, compositions and methods for producing and using homogeneous neuronal cell transplants to treat neurodegenerative disorders and brain and spinal cord injuries, diagnostic methods for Alzheimer disease by detection of multiple MRNAs, methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases, compositions and methods for producing and using homogeneous neuronal cell transplants, method of identifying, diagnosing and treating α-synuclein positive neurodegenerative disorders, mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and parkinsonism linked to chromosome-17: genotype predicts phenotype, microtubule stabilizing therapies for neurodegenerative disorders, and treatment of Alzheimer and related diseases with an antibody; and receives research support from the NIH (NIA, NINDS) and from the Marian S. Ware Alzheimer Program. G. Schellenberg serves on a scientific advisory board and receives honoraria from the American Health Assistance Foundation; has served as a consultant for and received funding for travel from Integra-Gen; holds/has filed patents regarding chromosome 14 and familial Alzheimer disease genetic markers and assays, chromosome 1 gene and gene products related to Alzheimer disease, and genetic basis of Alzheimer disease and diagnosis and treatment thereof; and receives/has received research support from the NIH (NIA, NIMH), the Autism Genome Project, Autism Speaks, CurePSP, the Rainwater Foundation, and Peebler PSP Research Foundation. He is an uncompensated member (other than travel funds to meetings of these boards) of the Alzheimer's Association Medical and Scientific Advisory Council, CSP #546 Executive Committee, Veterans Affairs Dementia Prevention Study of Vitamin E and Memantine, the Board of the Peebler PSP Research Foundation, and the Medical Advisory Board, Society of Progressive Supranuclear Palsy. D. Yearout and H. Huston receive salary support from the Department of Veterans Affairs and NIH. A. Fritts-Penniman received salary support from the Department of Veterans Affairs and NIH. I. Mata is funded by grants from the Department of Veterans Affairs, NIH, and Parkinson's Disease Foundation. J. Wan receives salary support from the Department of Veterans Affairs and NIH. K. Edwards and T. Montine are funded by grants from the NIH. C. Zabetian is funded by grants from the American Parkinson Disease Association, Department of Veterans Affairs, NIH, Northwest Collaborative Care, and Parkinson's Disease Foundation. Go to Neurology.org for full disclosures. ",
year = "2012",
month = nov,
day = "6",
doi = "10.1212/WNL.0b013e3182735e9a",
language = "English (US)",
volume = "79",
pages = "1944--1950",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "19",
}