ABSTRACT Background Neuropsychiatric symptoms (NPS) may serve as early predictors of Alzheimer's disease (AD). However, NPS evolve over time, and most existing studies have relied on single or sparse assessments that do not capture clinically meaningful longitudinal patterns. Aims To examine whether distinct trajectories of NPS are associated with the risk of incident AD, neurodegeneration and cognitive decline. Methods NPS were assessed using the neuropsychiatric inventory questionnaire. We first characterised and compared the retrospective trajectories of NPS between 290 incident AD dementia cases and 74 healthy controls who remained free of dementia during 8 years of follow‐up. Latent class growth modelling was then applied to identify NPS trajectories over the first 3 years among 982 people without dementia at baseline. Cox regression and linear mixed‐effects models were used to investigate the associations between NPS trajectories and incident AD risk, cognitive decline, brain atrophy and changes in brain metabolism during early (baseline to year 3) and later (years 3–8) follow‐up periods. Interaction between NPS trajectories and APOE ε4 was examined. Causal mediation analyses were conducted to assess whether neurodegeneration mediated the associations between NPS trajectories and cognitive function. Results Compared to individuals who remained free of dementia, people who developed AD showed progressively increasing NPS levels prior to AD diagnosis ( p < 0.005). Three NPS trajectories were identified: consistently no symptoms (71.8%, as reference), increasing trajectory (18.6%) and remitting trajectory (9.6%). The increasing trajectory was significantly associated with a higher risk of AD during both the early (hazard ratio HR = 1.720, p < 0.001) and late (HR = 2.130, p = 0.026) follow‐up periods. The remitting trajectory was associated with an elevated risk of AD only in the early follow‐up (HR = 1.980, p < 0.001). The increasing trajectory was also linked to faster brain atrophy ( β = −139.662, p < 0.001 for the hippocampus, β = −108.642, p = 0.007 for the entorhinal cortex and β = −305.059, p = 0.003 for the middle temporal regions), greater declines in brain metabolism ( β = −0.013, p = 0.007) and accelerated cognitive deterioration ( β = −0.162 for the memory, β = −0.154 for the executive function, all p < 0.001) during the late follow‐up period. These associations were stronger among APOE ε4 carriers. Brain volume loss and metabolism decline partially mediated the relationships of increasing NPS and cognitive impairment. Conclusions NPS trajectories can predict AD risk, neurodegeneration and cognitive decline, especially among APOE ε4 carriers. Progressive neurodegenerative changes may underlie these associations.
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