Participant and study partner prediction and identification of cognitive impairment in preclinical Alzheimer’s disease: study partner vs. participant accuracy

BACKGROUND: Preclinical Alzheimer’s disease (AD) clinical trials require participants to enroll with a study partner, a person who can attend visits and report changes in the participant’s cognitive ability. Whether study partners, compared to participants themselves, provide added information about participant cognition in preclinical AD trials is an open question. We tested the hypothesis that study partners provide meaningful information related to participant cognition cross-sectionally and longitudinally, and assessed whether amyloid status modified observed effects. METHODS: We assessed participant and study partner Everyday Cognition (ECog) scores and participant Alzheimer’s Disease Assessment Scale 13-item cognitive subscale (ADAS13) data from 335 cognitively normal participant-partner dyads in the AD Neuroimaging Initiative. We used random forest and linear mixed effects (LME) models to predict ADAS13 scores as a function of participant and/or study partner ECog scores over time. LME models were adjusted for potential confounding factors, including APOE4 status, amyloid status, baseline age, years of education, and sex. Random forest models were split into the above factors, as well as race/ethnicity and other available neuropsychological battery test scores. RESULTS: In random forest models predicting ADAS13 12 months from baseline, we observed no difference in the estimated mean variable importance (eMVI) associated with baseline study partner ECog compared to the baseline participant ECog (eMVI = 0.15, 95%CB 0.13, 0.16 for partner; eMVI = 0.15, 95%CB 0.14, 0.16 for participant). In models predicting ADAS13 48 months after baseline, the eMVI associated with baseline study partner ECog was slightly lower than that associated with baseline participant ECog (eMVI = 0.21, 95%CB 0.20, 0.22 for partner; eMVI = 0.24, 95%CB 0.22, 0.25 for participant). In cross-sectional models, study partner eMVI was twice as large as participant eMVI at 12 months (eMVI = 0.20, 95%CB 0.19, 0.21 for partner; eMVI = 0.09, 95%CB 0.09, 0.10 for participant) and three times as large at 48 months (eMVI = 0.38, 95%CB 0.36, 0.39 for partner; eMVI = 0.13, 95%CB 0.12, 0.14 for participant). We did not observe qualitative differences by amyloid status. CONCLUSIONS: While baseline participant reports reasonably predict subsequent cognitive change, informants perform better at cross-sectionally recognizing cognitive status as observation time grows. The study partner requirement may be essential to ensure trial data integrity, especially in longer trials.