Neuroplasticity and immune system are related to altered gray matter networks: a cohort study in sporadic Alzheimer’s disease

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ID: 320118
2026
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Abstract
Abstract Gray 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 gray 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 to 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 gray 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.
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Authors Diederick M de Leeuw, Flora H. Duits, Ellen Dicks, Eleonora M. Vromen, Charlotte E. Teunissen, Frederik Barkhof, Wiesje M. van der Flier, Pieter Jelle Visser, Betty M. Tijms
Journal Brain communications
Year 2026
DOI
10.1093/braincomms/fcag257
URL
https://doi.org/10.1093/braincomms/fcag257
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