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Plasma von Willebrand Factor and ADAMTS13 Interact With APOE-ε4 in Predicting Longitudinal Brain Atrophy and Cognitive Decline Over a 9-Year Follow-Up

Adegboye, Hailey A.; Sun, Yunyi.; Zhang, Panpan.; Liu, Dandan.; Khan, Omair A.; Tanriverdi, Kahraman.; Risitano, Antonina.; Libby, Julia.; Patterson, Khiry L.; Arul, Albert B.; Oliver, Nekesa C.; Whitaker, Marsalas D.; Janve, Vaibhav A.; Dumitrescu, Logan C.; Pechman, Kimberly R.; Shashikumar, Niranjana.; Bolton, Corey J.; Davis, L. Taylor.; Landman, Bennett A.; Freedman, Jane E.; Robinson, Renã A. S.; Hohman, Timothy J.; Jefferson, Angela L. (2026)..Journal of the American Heart Association, 15(9), e043186.

Researchers wanted to know whether two blood proteins, von Willebrand factor (VWF) and ADAMTS13, could help predict brain aging, memory decline, and changes in brain structure. VWF helps blood clot, and ADAMTS13 is a protein that helps control VWF activity. The study followed 332 older adults in the 91 Memory and Aging Project for about 6 years on average, with repeated blood tests, memory and thinking tests, and brain MRI scans. The main finding was that lower starting levels of ADAMTS13 were linked to faster decline in several thinking skills, including language, processing speed, executive function, memory, and visuospatial ability, as well as faster growth of white matter hyperintensities, which are bright spots on MRI that often reflect damage to the brain’s small blood vessels. These links were strongest in people who carried APOE-ε4, a gene variant known to increase Alzheimer’s disease risk. VWF by itself was not clearly linked to most outcomes, but it did interact with APOE-ε4: among people without the APOE-ε4 variant, higher VWF was associated with faster shrinkage of gray matter, the brain tissue made up mostly of neuron cell bodies. Overall, the study suggests that ADAMTS13 may be a promising blood marker of brain aging, while the role of VWF may depend on a person’s genetic background.

Figure 2. Baseline VWF×APOE‐ε4 status and longitudinal brain health outcomes.

Each datapoint represents a participant included in analytical models, illustrating each participant’s baseline plasma protein abundance (x axis) and their unadjusted annual change in brain health outcomes of interest (yaxis). Datapoints are colored according to APOE‐ε4 carrier status, with black datapoints representing noncarriers and red datapoints representing carriers. The solid line reflects the line of best‐fit from univariate linear regression of unadjusted annual change in brain health measures on baseline plasma protein abundance Z scores. Shading reflects 95% CI. For all outcomes illustrated, negative annual change indicates cognitive decline or gray matter atrophy over longitudinal follow‐up.A, Boston Naming Test.B, Hooper Visual Organization Test.C, Episodic memory composite.D, Total gray matter volume.E, Frontal lobe gray matter volume.F, Parietal lobe gray matter volume.G, Temporal lobe gray matter volume.H, Occipital lobe gray matter volume.I, Hippocampal gray matter volume.APOE‐ε4 indicates apolipoprotein E‐ε4; NPX, Normalized Protein eXpression; and VWF, von Willebrand factor.

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