Abstract Background Predicting Alzheimer's disease (AD) and frontotemporal dementia (FTD) using polygenic risk scores (PRS) for late‐onset forms holds promise, but its accuracy might be influenced by social determinants of health (SDOH). This study explores how considering SDOH alongside genes can improve prediction, focusing on potential differences for each disease. Methods Employing logistic regression in 677 individuals (287 AD, 102 FTD, and 288 controls) aged 40‐80 from the ReDLat study across six Latin American countries, we investigated the potential for SDOH to modify the association between PRS and susceptibility to AD and FTD. Analyses were adjusted for a probabilistic score derived from models comparing disease groups to controls with SDOH data (education, occupation, economic stability, healthcare access and quality, and social context) and APOE ε4 carrier status to account for confounding effects. Results Although univariate association tests revealed robust links between PRS and both diseases, adjusted models presented a nuanced picture. In AD, the SDOH score and APOE ε4 carrier status significantly attenuated the PRS effect (p=0.14), suggesting these factors modify genetic risk. In FTD, however, SDOH did not influence the PRS contribution. These findings highlight the potentially distinct roles of social factors in different neurodegenerative pathways. Conclusion The significant modification of PRS effects in AD by SDOH and APOE ε4 underscores the need for comprehensive approaches in future research and interventions in Latin America. Conversely, the unaltered PRS contribution in FTD emphasizes distinct intricacies in gene‐environment interactions. These findings necessitate considering both realms in future efforts, paving the way for targeted strategies in AD and FTD prevention and treatment.