Subtle cognitive impairment as a marker of Alzheimer's pathologies and clinical progression in cognitively normal individuals

INTRODUCTION: Subtle cognitive impairment (SCI) may appear before pathological changes surpass thresholds for abnormality. We aimed to investigate whether SCI could predict Alzheimer's pathologies and advancement. METHODS: A total of 816 cognitively normal individuals were enrolled to assess the longitudinal neuropathological and clinical correlates of baseline SCI, via linear mixed‐effects and Cox proportional‐hazard models. Cross‐lagged panel models were used in specific time waves. RESULTS: SCI individuals had a faster increase in brain amyloid burden and a higher risk of conversion. They also showed greater rates of cerebrospinal fluid (CSF) phosphorylated tau (p‐tau)(181) increase and glucose metabolism decrease. In addition, baseline SCI predicted worse clinical progression, whereas multi‐domain SCI advanced faster compared to the single domain group. DISCUSSION: Baseline SCI could be an imperative prediction indicator of clinical and pathological progression. It enables cognitive measures to be informative at a very early stage and provided objective criteria for high‐risk population screening.