["Journal of Intellectual Disability Research, EarlyView. ", "\nABSTRACT\n\nBackground\nThe validation of noninvasive markers for the early detection of Alzheimer's disease (AD) in Down syndrome (DS) is a crucial goal within this population. DS patients are characterised by their overall vulnerability and, particularly, by their high risk of developing AD due to genetic conditions. Considering this background, in this study, we analysed the benefits that a combination of markers might yield in such detection.\n\n\nMethods\nSixty‐two participants (35 females, 27 males) with DS (age > 45 years) distributed in three groups (asymptomatic [ADS], prodromal [PDS] and dementia [DDS]) underwent clinical and neuropsychological evaluation, together with the assessment of brain volumetry, plasma (neurofilament light and p‐tau217), genetic (APOE4) and EEG markers.\n\n\nResults\nRegression analyses demonstrated the key role of p‐tau217 among the studied biomarkers. However, the inclusion of p‐tau217 failed to produce any significant improvement in the diagnostic model based on verbal memory tasks. This model correctly classified 88.0% of the ADS patients, 75.0% of the PDS patients and 93.8% of the DDS patients. In addition, a strong correlation was observed between p‐tau217, delta power, volumetric scores and memory performance.\n\n\nConclusions\nOur findings suggested that, even when controlling the effect of elevated p‐tau217 levels, the role of memory markers is essential to assist in AD diagnosis within the DS population. The combination of cognitive and plasma markers for the detection of prodromal AD cases in DS appeared to be highly effective. This is especially relevant after the recent FDA's approval of plasma markers such as ptau‐217 for the diagnosis of AD.\n\n"]