E326K GBA polymorphism is associated with clinical and pathological features of synucleinopathy in the absence of overt Parkinson's disease or Lewy body dementia

Heterozygote carriers of Gaucher's disease mutations and other polymorphisms in the glucocerebrosidase (GBA) gene show an increased incidence of Parkinson's disease. We hypothesized that common GBA polymorphisms would be associated with subtle parkinsonian features, mild cognitive impairment, and “silent” Lewy body (LB) pathology in aging individuals without a clinical diagnosis of parkinsonism. The most prevalent GBA variants, T369M and E326K, appear in the general population at rates of approximately 0.6% and 1%, respectively. We evaluated 845 participants from the Oregon Alzheimer's Disease Research Center (OADRC) with SNP data generated by the National Centralized Repository of Alzheimer's Disease (NCRAD). Twenty-one subjects were E326K carriers and eighteen were T369M carriers. Clinical measures and postmortem neuropathology were compared between each SNP group and non-carriers. Although there were no statistically significant clinical differences related to synucleinopathy across groups, neuropathological analyses revealed a significantly higher prevalence of LB pathology in E326K carriers compared to T369M carriers. When stratifying each genetic group by LB status (LB+ or LB−), LB+ E326K carriers demonstrated a significant reduction in Mini-Mental State Examination (MMSE) scores compared with LB− non-carriers and a modest decrease compared with T369M carriers. These preliminary findings from a small, uni-center cohort suggest that the E326K GBA polymorphism may predict LB pathology and subtle cognitive decline in aging individuals who lack overt parkinsonian symptoms. Further validation in a larger cohort is warranted. Identifying at-risk individuals through targeted genetic screening may ultimately support earlier intervention and preventative care strategies.