Introduction Souvenaid® containing Fortasyn® Connect is a medical food designed to support synapse synthesis in persons with Alzheimer’s disease (AD). Fortasyn Conne ct includes precursors (uridine monophosphate; choline; phospholipids; eicosopentaenoic acid; docosahexaenoic acid) and cofactors (vitamins E, C, B12, and B6; folic acid; seleni um) for the formation of neuronal membranes. Whether Souvenaid slows cognitive decline in treate d persons with mild-to-moderate AD has not been addressed. Methods In a 24-week, double-masked clinical trial at 48 clinical centers, 527 participants taking AD medications [52% women, mean age 76.7 years (Standard Deviation, SD = 8.2) , and mean Mini-Mental State Examination score 19.5 (SD = 3.1, range 14–24)] were randomized 1:1 to daily, 125-mL (125 kcal), oral intake of the active product (Souvenaid) or an iso-caloric control. The primary outcome of cognition was assessed by the 11-ite m Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog). Compliance w as calculated from daily diary recordings of product intake. Statistical analyses were performed using mixed models for repeated measures. Results Cognitive performance as assessed by ADAS-cog showed decli ne over time in both control and active study groups, with no significant difference between stud y groups (difference =0.37 points, Standard Error, SE = 0.57, p = 0.513). No group differences in adverse event rates were found and no clinically relevant differences in blood safe ty parameters were noted. Overall compliance was high (94.1% [active] and 94.5% [control]), whic h was confirmed by significant changes in blood (nutritional) biomarkers. Conclusions Add-on intake of Souvenaid during 24 weeks did not slow cognitive decline in pe rsons treated for mild-to-moderate AD. Souvenaid was well tolerated in c ombination with standard care AD medications.