Returning APOE and pTau-217 Results: the eSMARTER Randomized Noninferiority Clinical Trial
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Importance
Patients are increasingly learning Alzheimer’s disease (AD) genetic and biomarker results through electronic health portals. Evaluation of alternative scalable delivery models for return of AD risk information is needed to best support patient understanding and psychological well-being.
Objective
To determine whether a patient-centered digital platform is comparable to clinician-mediated telehealth sessions for returning APOE and plasma pTau-217 results on outcomes of knowledge and psychological well-being.
Design
The Evaluation of Self-Mediated Alternatives for Risk Testing Education and Return of Results (eSMARTER) study was a noninferiority trial of a patient-centered digital platform compared to clinician-mediated disclosure of APOE genotype and optional pTau-217 disclosure.
Setting
Decentralized, fully remote trial enrolled participants in the contiguous United States (U.S.) between October 2024 and February 2025, with follow-up completed in November 2025.
Participants
Eligible participants were aged 60-80 and had previously undergone APOE genotyping (without disclosure) via the GeneMatch program, passed psychological screening, had internet access, and were English-speaking.
Interventions
Participants were randomized, 2:1, to the eSMARTER digital platform or clinician-mediated disclosure of APOE genotype. Following the 6-month post- APOE assessment, participants were offered optional pTau-217 disclosure via the same randomized modality.
Main Outcomes and Measures
Primary outcomes at 1-7 days following APOE disclosure included changes in anxiety, disease-specific distress, and AD-related knowledge within a priori non-inferiority margins.
Results
674 persons (mean [SD] age 68 [4.7] years; 451 [67%] female; mean [SD] telephone MoCA=19 [2]) were eligible and provided demographic information. 651 participants were randomized to clinician-mediated (n=216) or digital disclosure (n=435) and completed APOE disclosure (66 [10%] APOE4 homozygotes, 377 [58%] heterozygotes, 208 [32%] non-carriers). 604 participants completed the study; 500 completed optional pTau-217 disclosure. Baseline characteristics were balanced across groups. At 1-7 days following APOE disclosure, scores on AD-related knowledge, PROMIS Anxiety, and disease-specific distress measures met non-inferiority.
Conclusions and Relevance
Disclosure of APOE genotype by the eSMARTER digital platform is non-inferior to clinician-mediated telehealth disclosure. No significant between group differences were found following disclosure of pTau-217 results. Together, these results suggest that this digital platform may provide an evidence-based scalable approach for returning AD genetic and biomarker results.
Trial Registration
ClinicalTrials.gov Identifier NCT06459583
