Allele-specific GNB3 modulation of APOE ε4 memory effects

Abstract Modern environmental improvements have extended average lifespan, leading to increased prevalence of neurodegenerative diseases such as dementia. While memory decline is a natural physiological process of aging, numerous studies have demonstrated that certain genotypes increase the risk of cognitive decline and dementia. The apolipoprotein E ( APOE ) ε4 allele is a well-established risk factor for Alzheimer’s disease (AD), the primary cause of dementia. APOE ε4 carriers not only have significantly elevated AD risk but also exhibit poorer cognitive performance and episodic memory decline. However, APOE ε4 alone inadequately predicts AD; its predictive power is limited by incomplete penetrance and polygenic interactions. Genome-wide association studies identify guanine nucleotide-binding protein beta polypeptide 3 ( GNB3 ), a G-protein β subunit hub in APOE ε4-specific co-expression networks, but evidence linking GNB3 C825T to cognition or its interaction with APOE ε4 remains absent. In this study, we genotyped APOE and GNB3 C825T (rs5443) in 369 cognitively healthy adults at a healthy aging exhibition in Taiwan and assessed short-term memory performance. APOE ε4 carriers showed poorer short-term memory performance compared with non-carriers. While GNB3 genotype alone was not associated with memory performance, subgroup analyses suggested a trend toward poorer performance among APOE ε4 carriers with the GNB3 T allele (OR = 2.08, p = 0.08). However, formal interaction analysis did not demonstrate a statistically significant interaction effect. These findings suggest a potential association between APOE ε4 and short-term memory performance and indicate that GNB3 genotype may influence this relationship.