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Abstract Introduction We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease (AD) in the general population would apply to adults with Down syndrome (DS). Methods Plasma samples were obtained from 398 members of a community‐based cohort of adults with DS. A total of n = 186 participants were determined to be non‐demented and without mild cognitive impairment (MCI) at baseline and throughout follow‐up; n = 50 had prevalent MCI; n = 42 had prevalent AD. Results The proteomic profile yielded an area under the curve (AUC) of 0.92, sensitivity (SN) = 0.80, and specificity (SP) = 0.98 detecting prevalent MCI. For detecting prevalent AD, the proteomic profile yielded an AUC of 0.89, SN = 0.81, and SP = 0.97. The overall profile closely resembled our previously published profile of AD in the general population. Discussion These data provide evidence of the applicability of our blood‐based algorithm for detecting MCI/AD among adults with DS.