Aβ-related Cerebrospinal Fluid Proteins in Alzheimer’s Disease Reflect Gene Expression Levels Found in The Healthy Cortex

A growing body of evidence indicates that CSF proteomic signatures shift with increasing brain amyloidosis in Alzheimer’s disease (AD). However, it remains unknown whether protein profiles within cortical regions that are vulnerable to early amyloid-beta (Aβ) deposition contribute to, or predict, CSF Aβ-related protein measures. To address this question, we examined 220 cognitively unimpaired (CU) and cognitively impaired (CI) older participants from the TRIAD cohort who had Aβ- and tau-PET scans, MRI, and CSF NULISA™seq CNS panel data. Aβ-related hierarchical clustering identified 12 clusters corresponding to biologically interpretable gene ontology processes, supported by bootstrap resampling, silhouette analysis, and dynamic tree cutting. Clusters’ composite scores for tau-markers, neuronal-injury, and APOE4 correlated strongly with global neocortical Aβ-PET SUVR (p < 0.001) and showed elevated odds ratios (OR) of Aβ positivity (ORs: 10.4, 2.4, and 4.0, respectively). The Aβ42 cluster, as expected, was inversely associated with brain Aβ burden and predicted reduced Aβ positivity (OR = 0.13). Voxel-wise analyses revealed distinct spatial signatures for each cluster, such as associations in cortical regions (tau-markers, neuronal-injury, and APOE4 clusters), white matter (axonal metabolic injury cluster), and periventricular areas (synaptic signaling and cellular response clusters). The magnitude of Aβ-related cortical associations and CSF protein clusters correlated with the magnitude of regional mRNA expression derived from the Allen Brain Atlas. Our findings support the notion that CSF protein expression reflects underlying regional mRNA expression in cortical regions vulnerable to AD pathophysiology.