Functional connectivity among brain regions affected in Alzheimer's disease is associated with CSF TNF-α in APOE4 carriers

It is now recognized that understanding how neuroinflammation affects brain function may provide new insights into Alzheimer's pathophysiology. Tumor necrosis factor (TNF)-α, an inflammatory cytokine marker, has been implicated in Alzheimer's disease (AD), as it can impair neuronal function through suppression of long-term potentiation. Our study investigated the relationship between cerebrospinal fluid TNF-α and functional connectivity (FC) in a cohort of 64 older adults (μ age = 69.76 years; 30 cognitively normal, 34 mild AD). Higher cerebrospinal fluid TNF-α levels were associated with lower FC among brain regions important for high-level decision-making, inhibitory control, and memory. This effect was moderated by apolipoprotein E-ε4 (APOE4) status. Graph theory metrics revealed there were significant differences between APOE4 carriers at the node level, and by diagnosis at the network level suggesting global brain network dysfunction in participants with AD. These findings suggest proinflammatory mechanisms may contribute to reduced FC in regions important for high-level cognition. Future studies are needed to understand the role of inflammation on brain function and clinical progression, especially in APOE4 carriers. [Display omitted] •Higher CSF TNFα correlates with lower FC in decision-making and memory regions.•APOE4 moderates the relationship between TNFα and FC between NAcc and middle temporal gyrus.•NAcc has reduced local efficiency and clustering with elevated TNFα in APOE4 carriers.•FC network level metrics are lower in AD.•A proinflammatory environment may contribute to reduced FC.