A Three-Item Functional Screen for Multimodal Prognostic Triage in Mild Cognitive Impairment: Benchmarking Against Entorhinal Tau PET and Plasma p-tau217.

Importance: Broadening access to biomarker-informed risk stratification in mild cognitive impairment (MCI) has become even more critical to early assessment in Alzheimer disease given recent developments in regulatory approvals of disease-modifying therapies and advancements of blood-based biomarkers. This requires accessible approaches that can be deployed at scale to better differentiate the disease biology from the clinical progression risk prediction. While entorhinal tau positron emission tomography (PET) can refine near-term prognostic assessment, the cost and logistic burden of imaging limit broad clinical use. Objective: Evaluate whether a brief informant-reported screen derived from the Functional Activities Questionnaire (FAQ) could better stratify scalable biologically anchored prognostic information for 3-year progression from MCI to Alzheimer disease dementia. The primary study was designed around FAQ-derived screens performance relative to entorhinal tau PET standardized uptake value ratio (SUVR), plasma phosphorylated tau 217 (p-tau217) and Mini-Mental State Examination (MMSE) score. Secondary analyses evaluated the stable FAQ-derived screen selected for clinical risk separation, tau and amyloid PET biological context, additional plasma biomarkers, resource-use scenarios and sensitivity analyses around subgroups, calibration, decision-curve, survival, timing, early-progressor exclusions and endpoint-ascertainment IPW. Design Setting and Participants: This retrospective secondary progression risk prediction study analyzed 350 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with a baseline clinical diagnosis of MCI at the tau PET anchor visit. All studies were conducted in cohorts with 3-year progression status known. The first primary benchmarking included 157 participants (including 32 progressors) for FAQ with entorhinal tau PET SUVR comparisons and 153 participants (including 31 progressors) for FAQ, entorhinal tau PET SUVR and MMSE comparisons. The second primary benchmarking was derived from a smaller UPENN plasma p-tau217 subset of 66 participants (including 13 progressors). Exposures: The FAQ-derived candidate screens were evaluated by leakage-controlled repeated nested cross-validation. The stable 3-item FAQ-derived screen selected was defined as any informant-reported difficulty in at least one of the three activities comprising finances/checkbook, shopping and games/hobbies ("Locked FAQ Trio"). The Locked FAQ Trio was compared against both biological and cognitive comparators: entorhinal tau PET SUVR, plasma p-tau217 and MMSE score. Amyloid PET status and Centiloid burden as well as plasma biomarkers paired per same-file plasma such as Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and a directionally adjusted 4- marker plasma composite were used for biology or exploratory context and not for defining the clinical endpoint. Main Outcomes and Measures: The primary binary endpoint was progression from baseline MCI at the tau PET anchor visit to Alzheimer disease dementia within 3 years. Model performance used the cross-validated area under the receiver operating characteristic curve (AUC), the difference in AUC (ΔAUC) was bootstrap 95% confidence intervals (CI) at the participant level with P values adjusted using the Benjamini-Hochberg (BH) procedure. Other measures included Brier scores, calibration summaries, survival discrimination and operating characteristics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and screen-positivity prevalence, while decision-curve analyses and resource-use scenarios remained exploratory. Results: A leakage-controlled nested cross-validation selection repeatedly identified a 3-item screen defined as any difficulty in at least one of the three following activities comprising finances/checkbook, shopping and games/hobbies (Locked FAQ Trio). In an independent 3-year progression benchmark analysis of base-covariate models, the Locked FAQ Trio showed higher numerical, directional but not statistically significant, discrimination than entorhinal tau PET among 157 participants including 32 progressors (AUC, 0.787 vs 0.780; ΔAUC, +0.007; 95% CI, -0.099 to 0.113; BH-adjusted P = 0.926) and was statistically significantly higher than MMSE score (AUC, 0.796 vs 0.637; ΔAUC, +0.159; 95% CI, 0.045 to 0.276; BH-adjusted P = 0.029). The Locked FAQ Trio was positive in 37.6% of participants and captured 27 of 32 progressors, showing sensitivity of 84.4%, specificity of 74.4%, PPV of 45.8%, and NPV of 94.9%. Progression within 3 years occurred in 45.8% of screen-positive participants versus 5.1% of screen-negative participants and the corresponding adjusted hazard ratio over full follow-up was 7.46. The screen was also associated with higher entorhinal tau burden and remained consistent across survival, timing-sensitive, amyloid and missingness analyses. A different 3-item FAQ-derived companion screen ("Companion FAQ Trio") was evaluated for sensitivity, it was defined as any impairment in at least one of the three activities comprising forms/papers, shopping and remembering appointments/medications/holidays. The Companion FAQ Trio was positive in 54.1% participants and captured 96.9% of progressors, with 36.5% of screen-positive progressing to dementia versus 1.4% of screen-negative.In a second primary benchmark analysis of a smaller matched plasma subset of 66 participants including 13 progressors, plasma p-tau217 showed the highest discrimination (AUC, 0.890) across all single predictors in a base-covariates model, compared with the Locked FAQ Trio (AUC, 0.749) and entorhinal tau PET SUVR (AUC, 0.798). A stratification study of the Locked FAQ Trio combined with p-tau217 showed separation of observed risk, differentiating lower and higher risk of progression per strata. Notably, none (0 of 31) of the participants in the lower risk cohort progressed and 64.3% (9 of 14) of participants in the higher risk cohort progressed. Nevertheless, 37.5% (3 of 8) of participants in the Locked FAQ Trio-negative/p-tau 217-high cohort progressed. This emphasizes that patients should not be excluded from further biomarker testing when clinical concern remains. Conclusion: A brief 3-item stable FAQ-derived screen was identified as a compelling front-end additional layer to prognostic triage in MCI patients. This Locked FAQ Trio screen demonstrated a higher numerical discrimination than entorhinal tau PET SUVR in 3-year base-covariates prediction risk models. Plasma p-tau217 remained the strongest scalable predictor of progression to dementia in a smaller plasma subset. These findings reinforce that adding a brief functional screen to the staged prognosis assessment triage pathway can help prioritize and contextualize biomarker escalation, offering a scalable, deployable, and low burden solution to expand screening to a broader patient population.