Plasma neurofilament light chain and regional brain atrophy mediate the association of neuropsychiatric symptoms with cognition in Alzheimer’s disease: evidence from two population-based studies

Background Neuropsychiatric symptoms (NPSs) are prevalent in Alzheimer’s disease (AD), yet their neurobiological etiology remains elusive. We investigated relationships between NPS subsyndromes, plasma neurofilament light chain (NFL), AD-vulnerable brain atrophy, and cognition. Methods We included 146 participants from a Chinese cohort. NPSs were assessed using the Neuropsychiatric Inventory Questionnaire and clustered into four subsyndromes (hyperactivity, psychosis, affective, apathy), each graded by severity (none, mild, severe). Sequential mediation analyses examined whether NPSs influence cognition through NFL and atrophy. Additionally, 1534 ADNI participants were enrolled to (1) replicate mediation effects; (2) examine longitudinal relationships of NPSs with incident cognitive decline; and (3) evaluate cognitive discrimination of NPSs and NFL and onset hazards of NPS subsyndromes. Results In the discovery cohort, global NPSs burden and three subsyndromes (hyperactivity, affective, apathy) were associated with elevated plasma NFL, poorer global cognition and memory, and reduced brain volumes (all P < 0.05). Sequential mediation revealed that plasma NFL and atrophy mediated the cross-sectional NPSs–cognition relationship, replicated in ADNI. Adding NPSs and NFL improved cognitive discrimination (AUC: 0.6754 to 0.8210, P < 0.001). Additionally, apathy and psychosis showed lower onset hazards than affective and hyperactivity (both P < 0.001). Conclusions Baseline NPSs were cross-sectionally associated with elevated NFL, brain atrophy, and poorer cognition. Sequential mediation models supported a pathway linking NPSs to cognition via NFL and atrophy, though longitudinal evidence did not fully confirm temporal directionality. These hypothesis-generating findings require prospective validation.