Proteins involved in synapse organization are associated with longitudinal loss in gray matter network connectivity in prodromal AD

Abstract

AbstractBackgroundLower gray matter connectivity measures are related to faster cognitive decline in prodromal Alzheimer’s Disease (AD). We investigated the biological underpinnings responsible for this loss of brain connections using cerebrospinal fluid (CSF) proteomics.MethodData from ADNI was used to select 82 individuals with MCI and abnormal CSF amyloid (mean age±SD 74±7) and 37 controls with normal amyloid levels (mean age±SD 75±5), for whom repeated MRI‐scans (median of 6 scans over 1.5 follow‐up years) and baseline CSF proteomic data (in total 306 proteins) were available. We used an automated pipeline (Tijms, Series et al. 2012) to construct gray matter networks from 3D‐T1 sequences and calculate connectivity density and gamma – measures previously found to be most strongly related to cognitive decline (Dicks, Vermunt et al. 2020). Linear mixed models were applied to test associations between baseline CSF protein levels and repeated connectivity metrics, controlling for intracranial volume, age and sex. Proteins that demonstrated significant associations (p<0.05) were identified and examined for their biological relevance according to Gene Ontology.ResultConnectivity density declined over time with ‐0.8% per year (pMCI = 0.001; figure 1), which did not differ from controls (pdif = 0.15). Gamma declined faster in MCI than in controls (bMCI = ‐0.016 vs. bCN = ‐0.007, pdif <0.001; figure 1). Higher levels of 99/108 proteins were associated with faster decline in connectivity density (a.o. tau and neuroprentaxins). These proteins were involved in regulation of synapse organization (GO:0050807; pFDR = 7.00E‐07; figure 2). Higher levels of 9/108 proteins associated with less decline and were involved in chemotaxis (GO:0048247; pFDR = 1.40E‐02). Similarly, 25 out 30 proteins (83%) associated with alterations in gamma over time, showed associations of higher levels with less gamma decline and were also involved in chemotaxis (GO:0050926; pFDR = 9.42E‐05; figure 3). There were no protein‐connectivity relationships in controls.ConclusionProteins involved in synapse organization were associated with faster decline in connectivity density over time in patients, while chemotaxis was associated with less decline. This suggests that synaptic degeneration may predict disease progression while immune responses may serve as a resilience mechanism in AD.