Mapping U.S. POINTER Cognitive-Slope Gains Onto Predicted Clinical Progression: An External-Cohort Translation Analysis With Exploratory Economic Thresholds

Background: U.S. POINTER reported a modest structured-versus-self-guided difference in the annual rate of global cognitive change. However, the clinical and economic implications of this incremental standardized cognitive-slope benefit for delaying progression from cognitively normal status to mild cognitive impairment or dementia remain uncertain. Objectives: To translate the U.S. POINTER cognitive-slope benefit into clinically interpretable progression outcomes in ADNI, A4, and LEARN, and to summarize scenario-based economic implications in ADNI subgroups. Design: External-cohort translation analysis using two complementary analytic frameworks: an early-change landmark Cox model targeting Month 24 with a prespecified fallback window and a joint longitudinal-survival model. Setting: ADNI, A4, and LEARN. Participants: Cognitively normal participants. Landmark analytic samples included 399 ADNI participants with 61 events, 124 A4 participants with 37 events, and 394 LEARN participants with 45 events. Joint-model samples included 486 ADNI participants with 86 events, 1,064 A4 participants with 410 events, and 505 LEARN participants with 87 events. Intervention: No multidomain lifestyle intervention was administered in ADNI, A4, or LEARN. ADNI and LEARN were observational longitudinal cohorts, whereas A4 was a randomized solanezumab trial; the present analysis did not estimate solanezumab treatment effects. We evaluated a counterfactual +0.029 SD/year improvement in cohort-specific mPACC slope, corresponding to the structured-versus-self-guided cognitive-slope difference reported in U.S. POINTER. Measurements: The clinical outcome was sustained progression to mild cognitive impairment or dementia. Main translated measures were hazard ratios (HRs), 5-year risk differences (RDs), number needed to treat (NNT), and restricted mean survival time (RMST) differences. ADNI subgroup economic summaries used incremental 2-year delivery-cost scenarios and prespecified willingness-to-pay thresholds for prevented progression events and MCI-free years. Results: Landmark analyses yielded small translated effects. For the +0.029 SD/year slope shift, HRs were 0.972 (95% CI, 0.949-0.989) in ADNI, 0.998 (0.989-1.005) in A4, and 0.996 (0.990-1.003) in LEARN, with corresponding 5-year RDs of 0.31 percentage points (95% CI, 0.12-0.57), 0.06 (-0.13 to 0.27), and 0.08 (-0.05 to 0.20). Joint models produced larger effects, with HRs of 0.831 (95% CrI, 0.776-0.879), 0.917 (0.907-0.927), and 0.833 (0.746-0.907), and 5-year RDs of 1.26 percentage points (0.90-1.68), 3.04 (2.65-3.43), and 2.25 (1.24-3.45), respectively. Corresponding NNT values were 79.1, 32.9, and 44.5, and RMST gains were 0.297, 1.242, and 0.617 months. In exploratory ADNI subgroup analyses, the small joint-model APOE-{varepsilon}4+ & A{beta}+ subgroup (61 participants, 22 events) showed the largest translated clinical effect, with HR 0.775 (95% CrI, 0.597-0.919), RD 2.65 percentage points (0.93-4.82), NNT 37.7, and RMST gain 0.723 months. In an exploratory threshold exercise, assuming an incremental 2-year delivery cost of $400 per participant for a structured intervention relative to a self-guided/reference intervention and a willingness-to-pay threshold of $100,000 per prevented progression event, the largest threshold-based net monetary benefit was observed in the APOE-{varepsilon}4+ & A{beta}+ joint-model subgroup (+$2,250/person). On an MCI-free-year basis under the same incremental-cost assumption, this subgroup also had the largest threshold-based net monetary benefit (+$5,622/person). These values should be interpreted as scenario-dependent thresholds rather than empirical cost-effectiveness estimates. Conclusions: A U.S. POINTER-referenced structured-versus-self-guided cognitive-slope increment translated into directionally consistent reductions in predicted progression risk across ADNI, A4, and LEARN. The absolute clinical delay was generally modest and varied with cohort risk structure, biomarker/genotype enrichment, and analytic framework. Exploratory economic-threshold results suggested more favorable margins in higher-risk ADNI subgroups under low incremental-cost and high willingness-to-pay assumptions, but these findings should be interpreted as hypothesis-generating translation estimates rather than empirical cost-effectiveness evidence.