To understand whether glucocerebrosidase (GBA) polymorphisms are associated with mild signs of parkinsonism and cognitive impairment, as well as “silent” Lewy body (LB) pathology, in a population of aging subjects who were not clinically diagnosed with parkinsonism.

Recent studies have shown that heterozygote carriers of Gaucher’s disease mutations and other polymorphisms in the GBA gene are associated with worse clinical outcomes in Parkinson’s disease. However, the most common GBA polymorphisms, T369M and E326K, appear in the general population at rates of 0.6% and 1%, respectively.

Our study evaluated a cohort of 845 Oregon Alzheimer’s Disease Center (OADC) subjects who had SNP data generated by the National Centralized Repository of Alzheimer’s Disease (NCRAD), 21 of whom were E326K positive and 18 of whom were T369M positive and compared clinical and postmortem neuropathological analysis features between each SNP group and non-carriers.

Interestingly, although not statistically significant, E326K carriers showed trends toward worse clinical measurements (lower MMSE and higher CDR scores) compared to T369M carriers and non-carriers. Neuropathology analysis revealed a significant increase in LB presence in individuals with the E326K variant compared to the T369M variant with a higher proportion of E326K carriers showing neocortical spread compared to non-carriers with LB pathology. When further stratified by the presence of LBs (LB+ or LB-) within each group, there was a significant decrease in MMSE scores in LB+ E326K carriers compared to LB- non-carriers, as well as a slight decrease compared to T369M carriers.

These preliminary results indicate that the E326K GBA polymorphism may predict cognitive function decline and LB pathology in aging patients without manifest parkinsonism. Ultimately, these results have profound implications for identifying vulnerable populations through genetic screening for preventative management and care.