Development of Alzheimer's Disease Risk Score for Future Primary Care: A White-Box Approach.

Importance: Interpretable scoring system can contribute to bridge the gap between the timeliness and complexity of diagnosing Alzheimer's disease (AD) and promote early intervention at non-specialist settings. Objective: To develop a risk score to predict the likelihood of AD with interpretable machine learning using variables that are obtainable at integrated primary care settings. Design: A secondary data analysis including cohort studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the National Alzheimer's Coordinating Center (NACC) extracted in August 2023 and March 2024. Setting: The ADNI and NACC are multi-site cohort studies in North America. Participants: Participants with normal cognition or mild cognitive impairment at baseline visit were identified. Participants with the same diagnosis overtime were assigned to the stable group, and those converted to AD were placed in the progressive group. Main Outcomes and Measures: Cognitive tests and daily functioning measured with Functional Assessment Questionnaire (FAQ) at baseline visit. Results: A total of 676 participants from ADNI and 4592 participants from NACC were identified. After removing incomplete data, 665 ADNI (mean age [SD]: 73.44 [6.90]; 293 [44.1%] female; 374 stable and 291 progressive) and 3657 NACC participants (mean age [SD]: 70.96 [10.03]; 2405 [65.8%] female; 2445 stable and 1212 progressive) remained. Combinations of 4 measures were selected to generate 10 scorecards using FasterRisk algorithm, showing strong performance (area under the curve [AUC] = 0.868-0.892) in ADNI and remaining robust when validated in NACC (AUC = 0.795). The features were Category Animal ≤ 20 (2 points), Trail Making Test B ≤ 143 (-3 points), Logical Memory Delayed ≤ 3 (4 points), Logical Memory Delayed ≤ 8 (3 points), and FAQ ≤ 2 (-5 points). The probable AD risk corresponded to total points: 7.4% (-8), 25.3% (-4), 50% (-1), 74.7% (2), and > 90% (≥ 6). We refer to this model as the (F)unctioning, (LA)nguage, (M)emory, and (E)xecutive functioning or FLAME scorecard. Conclusions and Relevance: Our findings highlight the potential to predict AD development using obtainable information, allowing for applicability at integrated primary care. While our scope centers on AD, this foundation paves the way for other dementia types.