Duits, Flora H.

Abstract Grey matter network topology is altered in Alzheimer’s disease and these alterations are related to cognitive decline. Understanding the biological underpinnings of loss of brain connectivity may provide insights into mechanisms related to developing Alzheimer’s dementia (i.e. dementia A+). We investigated which biological processes as measured in CSF proteomics were associated with loss of brain connections across the Alzheimer’s disease continuum. We included 347 individuals with abnormal CSF amyloid [mean age ± standard deviation (SD) 66 ± 8; 98 cognitively unimpaired—A+, 88 mild cognitive impairment—A+, 161 dementia A+] and 146 cognitively unimpaired individuals with normal CSF amyloid (mean age ± SD 62 ± 8) and available T1w MRI-scans and CSF proteomic data (3097 proteins using tandem mass tag spectrometry) from the Amsterdam Dementia Cohort. We used an automated pipeline to construct grey matter networks from 3D-T1 sequences and for each network, calculated the small-worldness coefficient, which we previously found to be robustly related to cognitive decline. Linear models were applied to test associations between CSF protein levels and connectivity measures using an interaction term for clinical stage while controlling for connectivity density, age and sex. We validated our results in data from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Pathway enrichment analysis was performed for proteins associated with loss of brain connectivity (P < 0.05) using the Gene Ontology database. Individuals across the Alzheimer’s disease continuum had lower small-worldness coefficients compared with controls (ANOVA P < 0.001). In amyloid positive individuals, higher levels of 222 proteins and lower levels of 482 proteins were associated with lower small-worldness coefficients and were enriched for innate immune system and neuroplasticity pathways, respectively. Stratified for disease stage, most protein associations with lower small-worldness coefficients were found in mild cognitive impairment A+ (n = 527 proteins) and dementia A+ (n = 799 proteins) with considerable overlap (n = 239 proteins). Proteins in these stages were enriched for complement activation and synaptic integrity. In cognitive unimpairment A+, we found proteins enriched for processes involved in apoptosis. We did not find any enriched biological processes in controls. Repeating analyses in ADNI indicated that similar biological processes were associated with altered grey matter network connectivity. Higher CSF levels of proteins involved in immune responses and lower levels of proteins related to neuroplasticity were associated with lower small-worldness coefficients across the Alzheimer’s disease continuum. This suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to amyloid and tau.

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.