GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology

Debby Tsuang, James B. Leverenz, Oscar L. Lopez, Ronald L. Hamilton, David A. Bennett, Julie A. Schneider, Aron S. Buchman, Eric B. Larson, Paul K. Crane, Jeffrey A. Kaye, Patricia Kramer, Randy Woltjer, Walter Kukull, Peter T. Nelson, Gregory A. Jicha, Janna H. Neltner, Doug Galasko, Eliezer Masliah, John Q. Trojanowski, Gerard D. SchellenbergDora Yearout, Haley Huston, Allison Fritts-Penniman, Ignacio F. Mata, Jia Y. Wan, Karen L. Edwards, Thomas J. Montine, Cyrus P. Zabetian

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


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.

Original languageEnglish
Pages (from-to)1944-1950
Number of pages7
Issue number19
StatePublished - Nov 6 2012

Bibliographical note

Funding Information:
Study funding: Supported by grants from the Department of Veterans Affairs (1I01BX000531) and the National Institutes of Health (P30 AG008017, P30 AG028383, P30 AG010124, P30 AG010161, P50 AG005131, P50 NS062684, P50 AG005136, P50 AG005133, R01 AG007584, R01 AG010845, R01 AG015819, R01 AG017917, R01 NS048595, R01 NS065070, U01 AG006781, and U01 AG016976) .

ASJC Scopus subject areas

  • Clinical Neurology


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