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.
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BibTeX
@article{wang2026associations,
title = {{Associations between neuropsychiatric symptoms and cerebrospinal fluid amyloid pathology, and convergent proteomic signatures in Alzheimer’s disease}},
author = {Ya-Yu Wang and Huai-Yuan Zhu and Wei Miao and Yue-Hua Wang and Xiao-Han Song and Jia-Jia Qin and Zhi-Xin Wang and Zhong-Wu Sun and Xia Zhou and Xian-Feng Yu and Jian-Hua Zhao and Alzheimer’s Disease Neuroimaging Initiative and Xiao-Qun Zhu},
journal = {BMC Medicine},
year = {2026},
month = oct,
doi = {10.1186/s12916-026-05364-z},
url = {https://link.springer.com/article/10.1186/s12916-026-05364-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Associations between neuropsychiatric symptoms and cerebrospinal fluid amyloid pathology, and convergent proteomic signatures in Alzheimer’s disease
AU - Ya-Yu Wang
AU - Huai-Yuan Zhu
AU - Wei Miao
AU - Yue-Hua Wang
AU - Xiao-Han Song
AU - Jia-Jia Qin
AU - Zhi-Xin Wang
AU - Zhong-Wu Sun
AU - Xia Zhou
AU - Xian-Feng Yu
AU - Jian-Hua Zhao
AU - Alzheimer’s Disease Neuroimaging Initiative
AU - Xiao-Qun Zhu
PY - 2026
DA - 2026/10/29
JO - BMC Medicine
DO - 10.1186/s12916-026-05364-z
UR - https://link.springer.com/article/10.1186/s12916-026-05364-z
AB - 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.
SN - 1741-7015
ER -