Abstract
BACKGROUND: Preclinical Alzheimer's disease (AD) trials enroll cognitively unimpaired, amyloid-positive older adults; however, most remain clinically stable over typical trial durations. Limited near-term decline reduces statistical power and drives large sample sizes and high costs. Scalable enrichment strategies capable of identifying individuals most likely to decline are critically needed. OBJECTIVES: To determine whether a brief digital memory assessment (DMA) and plasma phosphorylated tau 217 (pTau217), individually or combined, identify preclinical AD participants at elevated risk for cognitive and biological progression, and whether such enrichment reduces clinical trial sample-size requirements. DESIGN: Analysis of data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, a multicenter randomized clinical trial with 240 weeks of follow-up. SETTING: Secondary-prevention trial conducted across sites in the United States, Canada, Australia, and Japan. PARTICIPANTS: A total of 1,169 cognitively unimpaired adults aged 65-85 years who were amyloid-positive and completed both a baseline DMA and plasma pTau217 measurement. MEASUREMENTS: Primary outcome was change in the Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks. Secondary outcomes included Clinical Dementia Rating-Sum of Boxes, Mini-Mental State Examination, Cognitive Function Instrument, and annualized change in amyloid PET, plasma pTau217, and tau PET. RESULTS: Participants with both elevated pTau217 and low DMA exhibited the greatest cognitive decline and reached the 240-week PACC decline of the overall cohort 83 weeks earlier. Participants with neither marker showed minimal decline. Dual enrichment reduced sample-size estimates for a clinical trial from 3,252 to 818 participants per arm (75 % reduction). These individuals also demonstrated faster increases in plasma pTau217 and neocortical tau PET. CONCLUSIONS: A brief DMA combined with plasma pTau217 identifies a subset of cognitively unimpaired, amyloid-positive older adults at highest risk for cognitive and biomarker progression. This dual-marker enrichment strategy enables smaller, shorter, and more cost-efficient preclinical AD trials and supports more targeted evaluation of preventive therapies.