Association of glucocerebrosidase mutations with dementia with lewy bodies.
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.


METHODS
Case-control study.


METHODS
Academic research.


METHODS
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).


METHODS
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.


CONCLUSIONS
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.
Clark
Lorraine N
LN
Taub Institute for Research onAlzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
Kartsaklis
Lykourgos A
LA
Wolf Gilbert
Rebecca
R
Dorado
Beatriz
B
Ross
Barbara M
BM
Kisselev
Sergey
S
Verbitsky
Miguel
M
Mejia-Santana
Helen
H
Cote
Lucien J
LJ
Andrews
Howard
H
Vonsattel
Jean-Paul
JP
Fahn
Stanley
S
Mayeux
Richard
R
Honig
Lawrence S
LS
Marder
Karen
K
D000368:Aged; D000369:Aged, 80 and over; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D016631:Lewy Bodies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020961:Lewy Body Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D058225:Plaque, Amyloid / Q000201:enzymology / Q000235:genetics / Q000473:pathology
D053327:Apolipoprotein E4; D005819:Genetic Markers; D005962:Glucosylceramidase