Associations between neuropsychiatric symptoms and cerebrospinal fluid amyloid pathology, and convergent proteomic signatures in Alzheimer’s disease

Abstract Background Neuropsychiatric symptoms (NPSs) are highly prevalent in Alzheimer’s disease (AD) and may accelerate cognitive decline, but the molecular mechanisms linking NPSs to AD pathology remain unclear. Methods In this cross–sectional study, we analyzed 713 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with available NPSs assessments, cerebrospinal fluid (CSF) amyloid–β42 (Aβ42), SomaScan 7 K proteomics, and cognition data. NPSs were assessed using the Neuropsychiatric Inventory Questionnaire and clustered into four subsyndromes (hyperactivity, psychosis, affective, and apathy). Associations between NPSs, CSF Aβ42, and cognition were examined using regression and mediation analyses. Weighted gene co–expression network analysis (WGCNA), protein–protein interaction (PPI) network, and Mendelian randomization (MR) were applied to identify and validate NPSs–associated protein modules and hub proteins. Results Higher NPSs burden, as well as hyperactivity, affective and apathy, was cross-sectionally associated with lower CSF Aβ42, which partially mediated the NPSs–cognition association. WGCNA identified three NPSs–associated modules. MEyellow, the largest and most phenotypically relevant, was enriched in protein folding, ubiquitination, stress responses, and immune regulation, predominantly in neurons. PPI network analysis revealed a hub cluster centered on the heat shock proteins (HSP) and ubiquitin-conjugating enzymes E2 families, which significantly mediated the NPSs–Aβ42 association. MR supported causal effects of HSPB1 on hyperactivity and HSPA1A on apathy. Conclusions These findings suggest a potential relationship among NPSs, reduced CSF Aβ42, and cognitive impairment, and implicate the HSP family as a candidate therapeutic target for early intervention in AD, pending further validation.