Associations between CSF proteins and medial temporal lobe atrophy across the AD continuum

Abstract

AbstractBackgroundCortical atrophy is a typical feature of Alzheimer´s disease (AD). The biological processes that associate with or possibly lead to atrophy remain largely unexplored. We hypothesized that disease stage would modulate the associations between cerebrospinal fluid (CSF) proteins and regional cortical thickness in individuals with abnormal CSF beta‐amyloid.MethodCognitively normal (CN), mild cognitive impairment (MCI) and AD individuals were selected from ADNI, based on abnormal CSF beta‐amyloid (<192 ng/l). All examined individuals had cortical thickness measurements and CSF proteomic data available (measured with MRM and RBM). Correlations between 217 CSF proteins and cortical thickness in 34 cortical regions (averaged over the left and right hemispheres) were analyzed with linear models, adjusted for age and sex. Interactions for diagnosis were evaluated for each protein‐cortical thickness association. Protein enrichment analysis was performed with Cytoscape ClueGO.ResultWe included 197 individuals (32 CN; 104 MCI; 61 AD) with a mean age 74.8 (SD 7.1) years, 41.6 % women.Cortical thickness declined according to disease progression in 28 brain regions, most significantly in the entorhinal cortex (ANOVA p‐value <0.0001), the middle temporal gyrus (p<0.0001) and the inferior temporal cortex (p<0.0001). 9 proteins, including phospho‐tau and BACE activity, showed interactions for diagnosis in the entorhinal cortex, 12 in the middle temporal gyrus and 19 inferior temporal cortex. These proteins were associated with beta‐amyloid metabolic process, dendritic cell differentiation, and oligodendrocyte development in ClueGO enrichment analyses. A consistent finding was that higher levels of the majority of these CSF proteins correlated with lower cortical thickness in CN, and that these correlations were attenuated with disease progression.ConclusionAlterations in the levels of CSF proteins are associated with cortical atrophy in the medial temporal regions, and the biological processes underlying cortical atrophy seem to begin already in the preclinical stage of AD. These results suggest that therapies targeted at preventing cortical atrophy would need to be initiated already in the CN stage.