We have shown that carriers of GBA mutations are significantly more likely than noncarriers to have cortical LB pathological findings. This is true when adjusting for sex, age at death, the presence of AD pathological findings, APOE4, and clinical diagnosis of dementia. The presence of a GBA mutation is not associated with AD pathological findings, whereas APOE4 is independently associated with AD diagnostic pathological findings in the same model, suggesting that GBA mutation status may be a useful clinical marker in the accurate diagnosis of LB disorders.
GBA mutations are not exclusively present in cases with LBs, even in this autopsy series of elderly persons. One case with no significant AD or LB pathological findings and 10 cases with autopsy-proved primary AD (4 of which lacked any LB pathological findings) nonetheless had GBA mutations. A previous report analyzing GBA status in a clinic-based series of 74 Ashkenazi patients with AD geno-typed for only 6 mutations (N370S, L444P, 84GG, IVS+1, V394L, and R496H) found that 4% (3 of 74) carried a GBA mutation. This is not dissimilar from our observed mutation frequency of 10% (6 of 60) in cases with primary pathological diagnoses of AD; 2 of these cases had rare LBs, but 4 had complete absence of any discernible LBs. The mutations in these 6 cases were all of the mild or unknown function type.
Two previously published studies have examined GBA
genotype in neuropathologically confirmed DLB cases from autopsy series.17,18
Mata et al18
examined 57 cases with DLB (54 had autopsies) and found a mutation frequency of only 3.5%, but they sequenced for only 2 GBA
mutations (N370S and L444P). Goker-Alpan et al17
did perform full genotyping of GBA
in 63 cases with LB pathological findings including 35 with cortical LBs (DLB or LBV-AD) and 28 with pure PD. They found an overall GBA
mutation frequency of 14% (9 of 63) among the LB cases but 29% (8 of 28) among the cases with cortical LB.17
Thus, the frequency of GBA
mutations of 28% that we found in a set of LB cases (of which few had pure PD pathological findings) is similar to that observed in the previous studies. Our study, which examined not only individuals with LB pathological findings but also those with AD and some with neither AD nor LB pathological findings and included genotyping for APOE
, shows that GBA
is a marker for cortical LB pathological findings, independent of AD pathological features, and is unrelated to APOE
We, like Goker-Alpan et al,17
observed a higher frequency of GBA
mutation carriers among those with cortical LBs than among those with only brainstem LBs (pure PD), although we had proportionately few cases with pure PD. If this finding should be further confirmed, there are several possible explanations, including that GBA
relates specifically to cortical LB degeneration, as differentiated from pure PD, or that GBA
relates to some combination of age at onset, rapidity of disease progression, and mortality. We are currently expanding our studies to distinguish between these possibilities.
It is unclear whether specific mutations in the GBA
gene are more likely to be associated with specific phenotypic responses. In the study of Goker-Alpan et al, 9 of 63 subjects with LBs (14%) carried a GBA
mutation including N370S (n = 5), R120W (n = 1), A359X (n = 1), T267I (n=1), and I161N (n=1).17
We also found that N370S was the most frequent mutation in subjects with LBs; this mutation was found in 29% (10 of 34) of our GBA
mutation carriers. We also observed additional mutations that have been previously reported in PD cases and that are reported to be pathogenic in cases of Gaucher disease.25
Five mutations identified in our study are novel. Three of these are missense mutations, 1 is a silent mutation (synonymous substitution), and 1 nucleotide substitution is located in the noncoding promoter region of exon 1. Currently, the pathogenicity of these mutations is unknown, and functional studies will be needed to determine their effects on the GBA
protein. The mechanism by which GBA
mutations might increase the likelihood of LB disease, such as DLB, is unclear. The mutations are nearly exclusively heterozygous and many are deemed “mild” for Gaucher disease even if homozygous, so it is unlikely but possible that gene product insufficiency might be the predisposing factor. More likely, alterations in GBA
might affect lysosomal protein degradational processes, increasing the likelihood of aberrant α-synuclein processing, and LB neurodegeneration.