Abstract
Plasma pTau-217 has emerged as a sensitive and specific biomarker for early Alzheimer's disease detection. However, the timeline of pathological changes and the onset of cognitive decline remain unclear. On the other hand, digital cognitive assessments have also shown promise in detecting subtle cognitive changes, but the sensitivity and specificity of these assessments is not fully understood. Here, we investigate whether combining these low-burden tools can improve the identification of cognitively unimpaired individuals at high risk for future cognitive decline. We analyzed 954 amyloid-positive cognitively unimpaired individuals who completed a brief digital cognitive assessment and a blood test for pTau-217, evaluating their ability to identify those at high risk for decline on the Preclinical Alzheimer's Cognitive Composite (PACC) and the Mini-Mental State Exam (MMSE). Further, we investigated whether the predictive value of these measures differed by sex or APOE status. We found that combining memory performance with pTau-217 enhanced the ability to identify individuals who declined on the PACC and MMSE over the next five years, even after controlling for age, sex, education, and baseline cognitive performance. Specifically, individuals with both elevated pTau-217 and low memory performance were at a greater risk for future decline than those with either risk factor alone. Notably, the predictive value of these measures did not differ by sex but was significantly stronger in APOE4 noncarriers compared to carriers. Together, this suggests that combining a brief digital cognitive assessment with plasma pTau-217 provides a reliable and sensitive method for identifying individuals at high risk for future cognitive decline in Alzheimer's disease.