The consumption of ultra-processed foods (UPFs) has been associated with over 30 adverse health outcomes, including cardiovascular diseases, type 2 diabetes, obesity, mental disorders, and mortality (1). More recently, concerns have emerged about the potential impact of UPFs on brain health, with indications that UPF is associated with a higher risk of dementia (1). However, the current literature is limited in providing details regarding the potential mediating effect of APOE ε4 status, the most significant genetic risk factor for dementia (2). This study aimed to investigate the association between UPF intake and cognitive performance in a cohort of community-dwelling Australians aged 40 to 70 years. Furthermore, the study investigated whether these associations differed by APOE ε4 carrier status. Data from the Healthy Brain Project was used. A total of 2,192 dementia-free participants (mean = 56.6 years; 75% female) were included in this cross-sectional analysis. Diet was assessed using a validated 130-item food frequency questionnaire from the European Prospective Investigation into Cancer United Kingdom Norfolk cohort (EPIC-Norfolk), and all food and beverage items were classified according to the Nova system (3). UPF consumption was expressed as a percentage of total grams intake. Cognitive assessment was performed using the Cogstate Brief Battery, generating composite scores for attention and memory. APOE ε4 carrier status was determined via genotyping in a subgroup (n = 1,858), with carriers defined as individuals possessing one or two ε4 alleles. UPFs contributed to 21% of total dietary grams intake. In a model adjusted for age, sex, ethnicity, education, Index of Relative Socio-Economic Disadvantage, physical activity, smoking status, chronic diseases and Mediterranean diet score, each 10% increase in UPF intake was associated with a 0.05-point reduction in attention score (95%CI = -0.09, -0.01; p = 0.011). No significant association was observed in relation to the memory composite (β = 0.01; 95%CI = -0.02, 0.04; p = 0.497). Stratified analysis revealed that the inverse association between UPF intake and attention composite score was statistically significant only among APOE ε4 carriers (β = -0.10, 95%CI = -0.18, -0.02; p = 0.009). These findings build on existing evidence of the harmful effects of UPFs on cognitive health, revealing that higher consumption is linked to poorer attention performance, particularly among individuals with genetic susceptibility, thus highlighting a potential gene–diet interaction. Given the global demographic shift towards an ageing population, these findings underscore the importance of reducing UPF consumption as part of public health strategies aimed at preserving cognitive function and promoting healthy ageing.