Streamlining Eligibility Assessment for Alzheimer's Disease-Modifying Therapies: Prediction of MMSE Scores Using the Digital Clock and Recall.

Introduction: The eligibility of anti-amyloid disease-modifying therapies (DMTs) and their integration into clinical practice in some institutions requires a specific range of Mini-Mental State Examination (MMSE) scores. Reliance on this pencil-and-paper psychometric instrument imposes operational burdens and risks perpetuating health disparities due to the test's known educational and cultural biases. This study evaluates the efficacy of the Digital Clock and Recall (DCR Methods: We conducted a retrospective analysis using data from the multi-site Bio-Hermes-001 study (NCT04733989, N=945). Participants were clinically classified as cognitively unimpaired, mild cognitive Impairment, or probable Alzheimer's dementia. We trained a Poisson elastic net regression model using age and multimodal digital features derived from the DCR (including drawing kinematics and voice acoustics) to predict MMSE scores. The model was tested for generalizability using an independent external validation cohort from the Apheleia study (NCT05364307, N=238). Results: The machine learning model predicted MMSE scores with a root mean squared error (RMSE) of 2.31 in the training cohort. This error margin falls within the established test-retest reliability range of the manual MMSE itself (2-4 points), suggesting the prediction is statistically non-inferior to human administration. External validation in the Apheleia cohort demonstrated robust generalizability (RMSE = 2.62). Crucially, the model exhibited demographic fairness, maintaining consistent accuracy across Race (White RMSE = 2.34; Non-White RMSE = 2.14) and Ethnicity (Hispanic RMSE = 2.26; Non-Hispanic RMSE = 2.31). Discussion: Machine learning can leverage multimodal features from the DCR to accurately and equitably crosswalk to MMSE scores in support of current guidelines, transforming a time-intensive manual test into a rapid, automated assessment. By deploying this "digital triage" engine, where traditional assessments are still used for DMT eligibility, healthcare systems can streamline the identification of DMT-eligible patients, reduce specialist referral bottlenecks, and ensure that access to life-altering therapies is determined by pathology rather than demography.