Accelerated brain aging is evident in CADASIL, and the brain age gap reflects the cumulative microvascular injury burden and may be involved in the pathophysiological pathway linking disease progression to cognitive impairment.
Individuals with NOTCH3 variants exhibited significantly higher brain age gap (BAG) than controls.
Higher BAG was associated with greater disease severity in CADASIL.
Higher BAG was associated with neuroimaging markers of white matter injury, most prominently peak width of skeletonized mean diffusivity (PSMD).
Higher BAG was associated with poorer clinical performance in individuals with NOTCH3 variants.
BAG showed a partial mediation effect in the association between disease stage and cognitive performance.
A brain-age prediction model was constructed from healthy individuals and validated for application to a CADASIL cohort.
This research suggests that people with CADASIL — a rare inherited condition causing small blood vessel disease in the brain — have brains that appear biologically older than their actual age. Scientists measured this 'brain age gap' by training a computer model on MRI scans from nearly 1,500 healthy people, then using it to estimate brain age in 153 people carrying the CADASIL genetic mutation and 30 healthy comparison participants. People with the mutation had a significantly larger gap between their estimated brain age and their real age, meaning their brains looked older than expected. The study also found that a larger brain age gap was linked to more severe disease, worse performance on clinical tests, and greater damage visible on brain imaging — particularly on a measure called peak width of skeletonized mean diffusivity (PSMD), which detects microscopic injury to the brain's white matter connections. Importantly, the brain age gap partially explained the relationship between how advanced a person's disease was and how well they performed on cognitive tests, suggesting it reflects a real step in the chain of events connecting disease progression to mental decline. This research suggests that brain age gap could serve as a useful single number to summarize the overall burden of brain damage in CADASIL, potentially helping doctors track disease progression or evaluate treatments in future studies. It also highlights that the invisible, microscopic damage to white matter pathways may be especially important in driving how CADASIL ages the brain prematurely.
Hsu S, Lee P, Chou K, Kuo C, Lin C, Liao Y, et al.. (2026). Association of imaging-defined brain age with disease severity and adverse outcomes in CADASIL.. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.71535