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) 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.