| Abstrakt: |
Background: Von Willebrand Factor (VWF), a multimeric glycoprotein involved in hemostasis, and ADAMTS13, a metalloproteinase that cleaves VWF, are associated with dementia risk. In in vitro studies endothelial cells expressing apolipoprotein E (APOE)‐ε4 overexpress VWF but no clinical studies have investigated interactions between VWF or ADAMTS13 with APOE‐ε4 status in predicting brain health. We assessed whether VWF and ADAMTS13 levels predict longitudinal cognitive decline and atrophy, especially in APOE‐ε4 carriers. Methods: Vanderbilt Memory and Aging Project participants (n = 333, 73±7 years, 41% female) underwent blood draw, neuropsychological assessment, and brain magnetic resonance imaging (MRI) serially over a 7‐year period. Plasma abundance measures of VWF and ADAMTS13 at baseline were quantified using mass spectrometry. Linear mixed‐effects regressions related protein levels to longitudinal neuropsychological and brain MRI outcomes (including grey matter volume and an Alzheimer's disease (AD) neuroimaging signature), adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, cognitive status, intracranial volume, APOE‐ε4 status, and follow‐up time. Models were repeated with an APOE‐ε4 interaction. Results: Lower baseline ADAMTS13 levels related to greater longitudinal decline in language, episodic memory, information processing speed, executive function, and visuospatial skills (p‐values<0.02) as well as temporal lobe, occipital lobe, and hippocampal atrophy (p‐values<0.02). APOE‐ε4 interacted with ADAMTS13, such that among APOE‐ε4 carriers, lower baseline ADAMTS13 related to greater decline in naming (p‐values< = 0.002), information processing speed (p = 0.006), executive function (p = 0.001), and visuospatial skills performances (p = 0.001) as well as greater occipital lobe atrophy (p = 0.002) and AD imaging signature thinning (p = 0.02). All results survive false discovery rate correction. By contrast, VWF did not relate to any outcomes (p‐values>0.08). Conclusion: Lower ADAMTS13 levels related to greater cognitive decline and neurodegeneration over a 7‐year follow‐up period, with effects driven by APOE‐ε4 carriers. VWF was unrelated to outcomes, potentially suggesting that ADAMTS13 relates to brain health independent of its role cleaving in VWF. While VWF is the only known substrate of ADAMTS13, ADAMTS13 may be involved in diverse biologic processes (e.g., inflammation, angiogenesis). Replication is needed to fully elucidate the role of VWF. Additional research is also needed to characterize mechanisms underlying interactions between ADAMTS13 and APOE‐ε4 in predicting brain health. [ABSTRACT FROM AUTHOR] |
