Functional hyperconnectivity is associated with higher levels of sPDGFRβ, a marker of blood brain barrier breakdown, in older adults

Abstract Background Apolipoprotein E4 (APOE4) has toxic effects on the cerebrovascular system, neuronal function, and functional connectivity of brain networks (e.g., default‐mode, frontal‐attention, and salience networks). The thalamus, a vital structure that acts as a relay station between many networks, has become of interest in AD research with studies showing atrophy among those with early AD and diminished cortical‐thalamic connections among those with vascular impairment. Additionally, CSF soluble platelet‐derived growth factor receptor‐β (sPDGFRβ), a marker of blood‐brain barrier breakdown, has been associated with AD risk, especially in APOE4 carriers. The present study investigated the relationship between CSF sPDGFRβ and functional connectivity in APOE4 carriers and non‐carriers. Method One hundred sixty‐six older adults from the Los Angeles area were selected from a larger cohort (96 females, mean age±SD = 67.4±10.7, 68 APOE4 carriers) based on availability of rsfMRI data. Image data was processed using CONN‐toolbox v19c. Grey matter was parcellated using Harvard/Oxford brain atlas, excluding cerebellum. ROI‐to‐ROI analyses were conducted selecting the thalamus as seed region averaging mean connectivity between the left and right structure of other parcellated brain regions. Linear regression models evaluated significant associations between blood oxygen level‐dependent (BOLD) and network connectivity among seed‐target regions and CSF sPDGFRβvalues, while covarying for age and sex. Comparison of averaged functional connectivity values between seed and all target regions among APOE4 carriers and non‐carriers was also examined. Result Higher functional connectivity between the thalamus and resting state network hub regions were associated with higher CSF sPDGFRβ (Fig 1A, 1C). Cortical regions within the networks included posterior cingulate gyrus, anterior cingulate gyrus, and frontal eye field. Averaged functional connectivity between these areas was significantly higher in APOE4 carriers compared to non‐carriers (Fig 1B). Conclusion The thalamus is a key subcortical structure for relaying signals across the brain for memory, attention and sleep/wakefulness cycles, and more recently with relevance to AD. These findings suggest a link between early BBB breakdown and elevated functional connectivity in brain regions known to have high synaptic activity and early pathology among non‐demented older adults at risk for AD.