Integrating Plasma pTau-217 and Digital Cognitive Assessments for Early Detection in Alzheimer's Disease

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.

Keywords: Alzheimer’s disease; Digital cognitive assessments; early detection; low-burden measures; memory; pTau217.

Figure 1:

Integrating plasma pTau-217 and the C3 enhances prediction of future decline on the PACC. Comparison of models using demographics alone (green), demographics plus pTau-217 (blue), C3 composite (red), or both pTau-217 and C3 (purple) for predicting low performers and future cognitive decline. (Top) ROC curves illustrating the predictive value of each model. (Middle) Violin plots depicting model sensitivity at a false positive rate of 20%. (Bottom) Odds ratios for future decline based on low memory (red), high pTau-217 (blue), or both (purple). (A) At baseline, the C3 composite was the strongest predictor of high and low performers, showing the highest sensitivity and odds ratios. Over two (B) and five (C) years, the combined model (pTau-217 + C3) was the most predictive of future decline, achieving the highest AUCs and sensitivity. Critically, individuals with both high baseline pTau-217 and low baseline C3 performance had significantly higher odds of cognitive decline compared to those with only one of these risk factors.

Figure 2:

Predictive capacity of the combined model (demographics, plasma pTau-217 and C3) differs by APOE4 carrier status but not sex (Top) ROC curves illustrating the predictive value of the combined model in males (blue) and females (red). (Bottom) ROC curves illustrating the predictive value of the combined model in APOE4 noncarriers (blue) and APOE4 carriers (red). (A) At baseline, the model performed similarly in males and females, with a slight advantage in females (top). Additionally, no significant difference was observed between APOE4 carriers and noncarriers in baseline performance. (B–C) When predicting future cognitive decline, the models performed equally well in males and females at both two (B) and five (C) years. However, the predictive capacity was stronger in APOE4 noncarriers compared to carriers at both time points.

Figure 3:

Integrating plasma pTau-217 and C3 enhances prediction of individuals who progress to clinical impairment (< 25) on the MMSE. Comparison of models using demographics alone (green), demographics plus pTau-217 (blue), C3 composite (red), or both pTau-217 and C3 (purple) for predicting low performers and future cognitive decline. (Top) ROC curves illustrating the predictive value of each model. (Bottom) Odds ratios for future impairment on the MMSE based on low memory (red), high pTau-217 (blue), or both (purple). The combined model incorporating both measures was the strongest predictor of individuals who would progress to clinical impairment on the MMSE over the next A) three, B) four, or C) five years, achieving the highest AUCs (top) and demonstrating that individuals with both high pTau-217 and low C3 performance at baseline had the highest odds ratio for progressing to an impaired MMSE (bottom).

Figure 4:

Longitudinal Trajectories Over 240 Weeks on the PACC and MMSE. (A) Individuals in the pTau217*Mem* group exhibited the most rapid decline on the PACC compared to the other three groups. pTau217*Mem_o showed the second fastest decline, followed by pTau217_oMem* which declined more rapidly than pTau217_oMem_o. (B) On the MMSE, pTau217*Mem* individuals again exhibited the steepest decline. pTau217*Mem_o and pTau217_oMem* declined at similar rates, with both declining faster than pTau217_oMem_o.