The role of non-pathogenic GBA polymorphisms in aging

A preliminary study in the Oregon Alzheimer’s Disease Research Center (OADRC) cohort identified variant-specific associations between common GBA1 alleles (E326K and T369M) and neuropathological and cognitive outcomes in aging individuals without clinical Parkinson’s disease (PD). Although GBA1 variants are established risk factors for PD and dementia with Lewy bodies, their effects in older adults without overt synucleinopathy remain poorly understood. As genetic testing becomes more common, there is a critical need to determine whether specific GBA1 variants confer vulnerability, resilience, or neutral effects in late-life brain aging. Based on our preliminary findings, we hypothesize that E326K is associated with increased Lewy body pathology and worse cognitive outcomes even in the absence of clinical PD, whereas T369M may demonstrate neutral or potentially protective effects.

We propose to validate and extend these findings in a larger national cohort using NIAGADS genomic data linked with National Alzheimer’s Coordinating Center (NACC) clinical and neuropathological datasets. We will conduct a retrospective cohort study of >26,000 individuals with genotype and harmonized phenotypic data. Participants will be stratified by GBA1 carrier status (E326K, T369M, non-carriers), focusing on those without clinical PD at last evaluation. NACC measurements will include global and domain-specific cognition, dementia status, motor findings, Lewy body distribution, Braak stage, neuritic plaque burden, and other Alzheimer’s disease–related pathology measures.

The large sample size provides increased power to detect modest genotype effects, ensure stable estimates for low-frequency variants, and support subgroup analyses (e.g., Lewy body–positive vs. negative). Analyses will use primarily non-parametric methods with adjustment for age, sex, and relevant covariates. This study will be conducted at Oregon Health & Science University (OHSU) in collaboration with the Biostatistics and Design Program and is consistent with NIAGADS data use limitations.

This study will examine how two common genetic variants in the GBA1 gene affect brain aging. While GBA1 mutations are known risk factors for Parkinson’s disease, many carriers never develop Parkinson’s, and the meaning of these variants in aging remains unclear. We will combine national genetic data from NIAGADS with clinical and brain pathology data from NACC to compare individuals with and without these variants. We aim to determine whether one variant is linked to harmful brain changes while another may be neutral or protective. These findings may improve interpretation of genetic testing results and advance understanding of early brain changes related to neurodegenerative disease.