Age-associated proteins explain the role of medial temporal lobe networks in Alzheimer's disease.

The structural connectivity (SC) of the medial temporal lobe and its associated cortical anterior temporal and posterior medial networks (MTL-AT-PM) is linked to pathologies and memory decline in Alzheimer's disease (AD). However, neuroimaging analyses cannot tell us how SC changes occur in AD at the molecular level and do not provide a means of intervening to slow/prevent pathology-related changes in MTL-AT-PM SC. The current study aimed to understand how and where AD-related changes occur within MTL-AT-PM using proteomics. We used a 4-step approach in 101 older adults from a local sample, aiming to understand how proteins and SC in combination at the multivariate level predict AD pathology, and to identify specific proteins related to SC and AD pathology. Separately, we validated the discovered proteins in relation to SC and AD pathology using ADNI sample. We identified 12 latent factors linking proteins and SC; five showed significant relationships with AD pathology and/or episodic memory. Insulin-like growth factor binding proteins and tumor necrosis factor receptors, and hippocampal/parahippocampal edges contributed most to AD-related latent factors. Fast causal inference found protein-protein, protein-SC, and protein-pathology pathways, with seven proteins showing directional links to SC and AD-related neurodegeneration. We validated these results by identifying significant relationships between six available proteins with SC and amyloid-beta and phosphorylated tau in ADNI. We identified multivariate relationships between proteins and MTL-AT-PM networks that add to our understanding of AD pathology and suggest specific non-pathological proteins that warrant further study in relation to brain networks and AD pathology as possible therapeutic targets.