Work

Differential associations of NFL and GFAP with neuropsychiatric symptoms by amyloid status across the Alzheimer’s disease continuum

Year: 2026

Type: article

Abstract: Background Neuropsychiatric symptoms (NPS) are key clinical manifestations across the Alzheimer’s disease (AD) continuum and predict worse clinical outcomes, yet their biological correlates remain incompletely understood. It remains unclear whether biomarkers of neuroaxonal injury and astrocytic activation, namely neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP), are associated with NPS independently of amyloid- β (Aβ) pathology or through downstream structural brain changes. Methods We conducted a cross-sectional study of 478 individuals from the First Affiliated Hospital of the University of Science and Technology of China, spanning the cognitive spectrum from cognitively unimpaired (CU) to mild cognitive impairment (MCI), AD dementia, and non-AD dementia. NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPIQ). We measured core AD biomarkers (Aβ42/40, pTau181, and pTau217) and serum NFL and GFAP using single-molecule array (Simoa) assays. Aβ status was determined by amyloid PET or CSF Aβ42/Aβ40 ratio, and cortical thickness was derived from 3D T1-weighted MRI. Results NPS burden was substantially higher in both AD dementia and non-AD dementia than in CU or MCI, highlighting the transdiagnostic nature of NPS in dementia syndromes. Associations between serum biomarkers and NPS differed by Aβ status. In Aβ − individuals, serum NFL was associated with global NPIQ burden and multiple symptom domains, whereas in Aβ + individuals, serum GFAP was associated with global NPIQ burden and several symptom domains. Formal interaction analyses confirmed significant effect modification by Aβ status for serum NFL, but not for serum GFAP. Sensitivity analyses excluding extreme NFL values yielded unchanged results. Conclusion These findings support an Aβ-dependent dissociation in biomarker correlates of NPS, with stronger NFL-related associations in Aβ − individuals and stronger GFAP-related associations in Aβ + individuals. Our results suggest that biologically distinct pathways may underlie neuropsychiatric manifestations across the cognitive continuum and support biomarker-informed subtyping of NPS in aging and dementia.

Source: Frontiers in Neurology

DOI: 10.3389/fneur.2026.1782816