CSF proteome-wide study of neuropsychiatric symptoms of dementia

Introduction: Neuropsychiatric symptoms in dementia (NPS) are common and among the most troubling aspects of living with dementia, yet their underlying mechanisms remain unclear. Here, we aimed to identify cerebrospinal fluid (CSF) proteins associated with NPS. Methods: Proteomes were profiled from CSF collected at baseline from participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) using mass spectrometry. Here, we included participants having positive AD CSF biomarkers (i.e., pTtau181 / Abeta42 ratio >0.025) and mild cognitive impairment or AD dementia (n=419). Eight NPS domains were assessed longitudinally with the Neuropsychiatric Symptom Inventory Questionnaire. Severity of cognitive impairment was evaluated using the CDR-SB. Proteome-wide differential expression analysis for each NPS domain at baseline was performed. Significant protein-NPS associations underwent mediation analysis to test whether they were mediated by cognitive impairment severity. Cox proportional hazard was modeled for baseline CSF proteins and incident NPS. Additionally, we tested whether candidate NPS causal proteins previously identified in brain are associated with NPS in CSF. Results: We identified 8 CSF proteins associated with apathy at baseline (FDR q<0.05) after adjusting for sex, age, and education - NTNG2, S100A1, FZD1, FSTL5, CDH7, CHODL, FBXO2, and CACNA2D2. Mediation analysis revealed these associations were independent of cognitive impairment severity in four proteins and only partially mediated by cognitive impairment severity in the remaining four proteins. Among the 10 NPS candidate causal proteins previously identified in brain and detected in CSF, the abundance of two proteins (CPD, GRN) in CSF was associated with baseline disinhibition and of two other proteins (PIK3IP1, PCMT1) with both baseline apathy and incident apathy after adjusting for sex, age, and education. Discussion: These findings suggest that proteomic alterations in apathy in MCI/AD encompass synaptic connectivity, calcium regulation, Wnt-signaling, and neuronal proteostasis, highlighting potential CSF biological processes and biomarker candidates for apathy.