To investigate the frequency of Alzheimer's disease and related dementias (ADRD) or Parkinson’s disease (PD) associated with EPG5 missense mutation.

EPG5 functions as a mediator of the autophagosome-lysosome fusion pathway. The disruption of this pathway may lead to accumulation of dysfunctional cellular components which may contribute to the development of neurodegenerative diseases.

Participants in the All of Us Research Program over the age of 40 with medical records and short-read whole genome sequencing data (n=64,739) were analyzed. The five most common EPG5 missense variants (rs3744998, rs1893523, rs59422275, rs3744999, and rs34064739) were analyzed in conjunction with the presence of diagnosis for one of two neurodegenerative diseases: ADRD and PD. ADRD and PD diagnoses were determined using available Electronic Health Records (EHR) data and EPG5 missense mutation was determined using short-read whole genome sequencing. Odds ratios (OR) were calculated to assess relationship association. Bonferroni-adjusted analyses were performed with p<0.002 considered significant after correction.

rs3744998 was associated with significantly higher odds of having a PD diagnosis (OR = 1.35, p<10E-6), while rs1893523 and rs34064739 were found to have lower odds of both AD and PD diagnoses (AD OR = 0.75, PD OR = 0.58; AD OR = 0.51, PD OR = 0.31, p<0.001). In men, rs3744998 was associated with significantly higher odds of PD diagnosis (OR = 1.38, p<0.001) and rs1893523 was associated with significantly decreased odds of AD diagnosis (OR = 0.62, p<0.001) compared to in women. rs1893523 was associated with significantly decreased odds of PD diagnosis regardless of sex (OR= 0.59 in men, 0.67 in women, p<0.001).

These data suggest several genetic variants in EPG5 may influence the development of neurodegenerative diseases.