Bidirectional transitions between subjective cognitive decline and normal cognition and risk of mild cognitive impairment: A multistate Markov model study in NACC UDS

Background Subjective cognitive decline (SCD) may be an early indicator of Alzheimer's disease but often reverts to normal cognition (NC), leaving its prognostic significance uncertain. Objective To quantify bidirectional transitions between SCD and NC and to evaluate the long-term risk of progression to mild cognitive impairment after reversion. Methods Using longitudinal data from the National Alzheimer's Coordinating Center Uniform Data Set, we fitted continuous-time multistate Markov models for NC, SCD, mild cognitive impairment (MCI), and dementia. Three cohorts were analyzed: baseline SCD, baseline NC, and post-SCD reversion. Transition intensities and 15-year state-occupancy probabilities were estimated, and covariate effects were assessed using nested multivariable models. Death was evaluated as a competing absorbing state in a sensitivity analysis. Results The primary analysis included 4283 participants with baseline SCD, 11,709 with baseline NC, and 2099 in the post-SCD reversion cohort. In the baseline-SCD cohort, reversion to NC was substantially more frequent than progression to MCI (transition intensity ratio, 3.27; 95% CI, 3.05–3.50). However, the post-SCD reversion cohort showed a long-term cognitive risk profile similar to the baseline-SCD cohort and less favorable than the baseline-NC cohort. Older age, APOE ε4 carriage, informant-reported decline, and greater neuropsychiatric or functional impairment were associated with higher progression risk, whereas older age and depression were associated with lower reversion intensity. Conclusions SCD is a dynamic cognitive state with substantial potential for reversion, but reversion to NC does not necessarily restore the long-term risk profile observed in individuals cognitively normal at baseline.