Multiomics Reveals Biological Mechanisms Linking Macroscale Structural Covariance Network Dysfunction With Neuropsychiatric Symptoms Across the Alzheimer's Disease Continuum

Background: The high heterogeneity of neuropsychiatric symptoms (NPSs) hinders further exploration of their role in neurobiological mechanisms and Alzheimer's disease (AD). We aimed to delineate NPS patterns based on brain macroscale connectomics to understand the biological mechanisms of NPSs on the AD continuum.

Methods: We constructed regional radiomics similarity networks for 550 participants (AD with NPSs [n = 376], AD without NPSs [n = 111], and normal control participants [n = 63]) from the CIBL (Chinese Imaging, Biomarkers, and Lifestyle) study. We identified regional radiomics similarity network connections associated with NPSs and then clustered distinct subtypes of AD with NPSs. An independent dataset (n = 189) and internal validation were performed to assess the robustness of the NPS subtypes. Subsequent multiomics analysis was performed to assess the distinct clinical phenotype and biological mechanisms in each NPS subtype.

Results: AD patients with NPSs were clustered into severe (n = 187), moderate (n = 87), and mild (n = 102) NPS subtypes, each exhibiting distinct brain network dysfunction patterns. A high level of consistency in clustering NPSs was internally and externally validated. Severe and moderate NPS subtypes were associated with significant cognitive impairment, increased plasma p-tau181 (tau phosphorylated at threonine 181) levels, extensive decreased brain volume and cortical thickness, and accelerated cognitive decline. Gene set enrichment analysis revealed enrichment of differentially expressed genes in ion transport and synaptic transmission with variations for each NPS subtype. Genome-wide association study analysis defined the specific gene loci for each subtype of AD with NPSs (e.g., logical memory), consistent with clinical manifestations and progression patterns.

Conclusions: This study identified and validated 3 distinct NPS subtypes, underscoring the role of NPSs in neurobiological mechanisms and progression of the AD continuum.