Abstract Background The identification of cognitive tests sensitive to subtle changes in the preclinical stage of Alzheimer’s disease (AD) is of upmost importance to early detection of the disease, and to optimizing AD clinical trial recruitment. We used a delayed matching‐to‐sample (DMS) paradigm to study working memory for semantic relatedness in young adult carriers and non‐carriers of an autosomal dominant AD (ADAD) mutation from the Colombian kindred. Methods 35 cognitively‐unimpaired Presenilin1 ( PSEN1 ) E280A mutation carriers and 26 non‐carrier family members took the “Memory for Semantically‐Related Objects” test (MESERO), a computerized DMS working memory test for semantically‐related (and unrelated objects) developed by our group. The MESERO shows an equal number of either 4 or 6 objects that are semantically‐related or unrelated and records accuracy out of 80 points total (40 semantically‐related trials; 40 unrelated trials), as well as reaction time in milliseconds. Participants also completed the Mini‐Mental State Exam (MMSE). MESERO behavioral responses between groups were evaluated with the Mann‐Whitney test; age, MMSE scores, and education were compared with independent samples t ‐tests. Results Non‐carriers were significantly older (M = 36.7 years, SD = 6.5) and had slightly, but significantly higher MMSE scores (M = 28.8, SD = 6.5) than the carriers (age: M = 30.5, SD = 5.3; t = 3.92, p <.001; MMSE: M = 28.1, SD = 1.2; p< .001). The groups did not differ on education (∼mean of 11 years for both; t = 0.29, p = .39). On the MESERO total score, mutation carriers had significantly lower performance (mean = 70.8, SD = 6.5) relative to non‐carriers (mean = 73.5, SD = 5.7; U = 312, p = .04). The PSEN1 E280A carriers, in particular, performed worse on the semantically‐related trials (mean = 33.9, SD = 4.2) relative to non‐carriers (mean = 35.8, SD = 2.9; U = 312.5, p = .04), but not on unrelated trials ( U = 357, p = .19). The carriers performed worse than non‐carriers on trials with 4‐items (mean = 35.5, SD = 4.2 vs. mean = 37.3, SD = 3.2) ( U = 300.5, p = .02), but not with 6‐items in the study phase ( U = 366.5, p = .19). Conclusion A brief computerized working memory task for semantically‐related objects was able to distinguish cognitively unimpaired mutation carriers from non‐carriers from a Colombian kindred with autosomal dominant Alzheimer’s disease, approximately 14 years before the median age of mild cognitive impairment onset in this cohort. Working memory for semantic relatedness warrants further study as a potential marker of preclinical AD.