The Cognitive, Age, Functioning, and Apolipoprotein E4 (CAFE) Scorecard to Predict the Development of Alzheimer's Disease: A White-Box Approach

ImportanceInterpretable scoring system can contribute to bridge the gap between the timeliness and complexity of diagnosing Alzheimers disease (AD) and promote early intervention at non-specialist settings. ObjectiveTo develop a risk score to predict the likelihood of AD with interpretable machine learning using variables that are obtainable at integrated primary care settings. DesignA secondary data analysis including cohort studies from the Alzheimers Disease Neuroimaging Initiative (ADNI) and the National Alzheimers Coordinating Center (NACC) extracted in August 2023 and March 2024. SettingThe ADNI and NACC are multi-site cohort studies in North America. ParticipantsParticipants 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 Outcome(s) and Measure(s)Cognitive tests and daily functioning measured with Functional Assessment Questionnaire (FAQ) at baseline visit. ResultsA 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 RelevanceOur 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 Key PointsO_ST_ABSQuestionC_ST_ABSCan accessible information, such as demographics, cognitive tests, and functioning questionnaire, yield in reliable results for predicting Alzheimers disease development using interpretable machine learning? FindingsThe results of 665 participants from the Alzheimers Disease Neuroimaging Initiative demonstrated robust performance of determining Alzheimers disease development using four separate measures of (F)unctioning, (LA)nguage, (M)emory, and (E)xecutive functioning or the FLAME scorecard. It remains reliable when externally validated with a separate dataset of 3657 participants from the National Alzheimers Coordinating Center. MeaningThe FLAME scorecard shows potential to be implemented in integrated primary care settings to promote early detection and intervention of cognitive decline due to Alzheimers disease.