Apolipoprotein E (APOE) epsilon 4 allele and sigma-1 receptor (SIGMAR1) c.5C (Q2P) polymorphisms have been acknowledged as risk factors for developing Alzheimer's disease (AD). However, whether these polymorphisms influence the disease process is unclear. Therefore, two cohorts with a clinical diagnosis of AD were recruited, a postmortem confirmed Australian cohort (82 cases) from the Australian Brain Bank Network, and a Chinese cohort with detailed clinical assessments recruited through an epidemiology study in Shanghai and through the neurology department outpatients clinic of Shanghai Ruijin Hospital (330 cases). SIGMAR1 Q2P and APOE genotyping was performed on all cases. Dementia severity in the Chinese cohort was assessed using MMSE scores, and the stages of senile plaques and neurofibrillary tangles (NFT) assessed in the Australian cohort. Associations between SIGMAR1 Q2P and APOE genotypes and disease severity were assessed using SPSS. Results confirmed that APOE epsilon 4 allele associated with increased NFT stages and cognitive decline, with carriers with one APOE epsilon 2 or epsilon 3 allele often having better clinical outcomes compared to carriers with none or two epsilon 2 or epsilon 3 alleles respectively. SIGMAR1 c.5C polymorphism alone did not associate with MMSE score variability in Chinese or with pathological stages in Caucasians. However, the association studies revealed a significant genetic interaction between the APOE epsilon 4 allele and SIGMAR1 2P carriers in both populations, i.e., in APOE non epsilon 4 allele carriers, SIGMAR1 2P variant had increased cognitive dysfunction and more advanced stages of NFT. Our data demonstrate that SIGMAR1 and APOE interact to influence AD severity across ethnic populations.