Plasma von Willebrand Factor and ADAMTS13 Interact With APOE-ε4 in Predicting Longitudinal Brain Atrophy and Cognitive Decline Over a 9-Year Follow-Up.
BACKGROUND: Von Willebrand factor (VWF) and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) are linked to dementia risk, and limited evidence suggests apolipoprotein E (APOE)-ε4 alters VWF release. This study assessed whether baseline VWF and ADAMTS13 levels predict neurodegeneration and cognitive decline and evaluated effect modification by APOE-ε4 carriership. METHODS: Vanderbilt Memory and Aging Project cohort participants (n=332, 73±7 years, 59% male) completed serial blood draw, neuropsychological assessment, and brain magnetic resonance imaging over 6.4 years (range 1.4-9.7 years). Baseline plasma VWF and ADAMTS13 levels were quantified using mass spectrometry and Olink. Fully adjusted linear mixed-effects models related protein×time and protein×APOE-ε4×time interaction terms to longitudinal brain magnetic resonance imaging and neuropsychological outcomes. RESULTS: Lower baseline ADAMTS13 predicted faster declines in language (β=0.11, P=0.01), information processing speed (β=0.27, P=0.001), executive function (β=0.01, P=0.03), episodic memory (β=0.01, P=0.03), and visuospatial ability (β=0.11, P=0.001) and faster increases in global (β=-0.29, P=0.01) and frontal (β=-0.17, P=0.01) white matter hyperintensity volumes. Associations between ADAMTS13 and faster rates of cognitive decline and white matter injury were driven by APOE-ε4 carriers. Models relating VWF to longitudinal outcomes were null. APOE-ε4 interacted with VWF on longitudinal gray matter volumetric outcomes, such that faster rates of global gray matter atrophy were observed with higher baseline VWF levels among APOE-ε4 noncarriers only (β=-1530.5, P<0.001). CONCLUSIONS: ADAMTS13 shows promise as a potential plasma biomarker for brain aging outcomes, but additional research is warranted to understand the performance of VWF in the presence versus absence of an APOE-ε4 allele.