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Lorraine N. Clark, PhD; Lykourgos A. Kartsaklis, MD; Rebecca Wolf Gilbert, MD; Beatriz Dorado, PhD; Barbara M. Ross, BSc; Sergey Kisselev, BSc; Miguel Verbitsky, PhD; Helen Mejia-Santana, MSc; Lucien J. Cote, MD; Howard Andrews, PhD; Jean-Paul Vonsattel, MD; Stanley Fahn, MD; Richard Mayeux, MD, MSc; Lawrence S. Honig, MD, PhD; Karen Marder, MD, MPH

Arch Neurol. 2009;66(5):578-583.

Background  Mutations in the glucocerebrosidase (GBA) gene are associated with Lewy body (LB) disorders.

Objective  To determine the relationship of GBA mutations and APOE4 genotype to LB and Alzheimer disease (AD) pathological findings.

Design  Case-control study.

Setting  Academic research.

Participants  The 187 subjects included patients with primary neuropathological diagnoses of LB disorders with or without AD changes (95 cases), randomly selected patients with AD (without significant LB pathological findings; 60 cases), and controls with neither LB nor AD pathological findings (32 cases).

Main Outcome Measures  GBA mutation status, APOE4 genotype, LB pathological findings (assessed according to the third report of the Dementia With Lewy Body Consortium), and Alzheimer plaque and tangle pathological findings (rated by criteria of Braak and Braak, the Consortium to Establish a Registry for Alzheimer Disease, and the National Institute on Aging–Reagan Institute).

Results  GBA mutations were found in 18% (34 of 187) of all subjects, including 28% (27 of 95) of those with primary LB pathological findings compared with 10% (6 of 60) of those with AD pathological findings and 3% (1 of 32) of those without AD or LB pathological findings (P=.001). GBA mutation status was significantly associated with the presence of cortical LBs (odds ratio, 6.48; 95% confidence interval, 2.45-17.16; P<.001), after adjusting for sex, age at death, and presence of APOE4. GBA mutation carriers were significantly less likely to meet AD pathological diagnostic (National Institute on Aging–Reagan Institute intermediate or high likelihood) criteria (odds ratio, 0.35; 95% confidence interval, 0.15-0.79; P=.01) after adjustment for sex, age at death, and APOE4.

Conclusion  GBA mutations may be associated with pathologically "purer" LB disorders, characterized by more extensive (cortical) LB, and less severe AD pathological findings and may be a useful marker for LB disorders.

Author Affiliations: Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Clark, Dorado, Verbitsky, Vonsattel, Mayeux, Honig, and Marder and Ms Ross), Department of Pathology (Drs Clark, Dorado, and Vonsattel, Ms Ross, and Mr Kisselev), Center for Human Genetics (Dr Clark), Gertrude H. Sergievsky Center (Drs Kartsaklis, Cote, Andrews, Mayeux, Honig, and Marder and Ms Mejia-Santana), Department of Neurology (Drs Wolf Gilbert, Cote, Fahn, Mayeux, Honig, and Marder), Mailman School of Public Health (Dr Mayeux), and Department of Psychiatry (Drs Mayeux and Marder), Columbia University, New York, New York.

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