A study from the Institut de Recerca Sant Pau (IR Sant Pau) published in Alzheimer's & Dementia reports on Mar. 19 that certain brain lesions previously thought to be permanent in people with Down syndrome may actually fluctuate and even decrease over time, especially after the onset of Alzheimer's disease symptoms.
This research is significant because it challenges the long-held belief that white matter hyperintensities (WMH)—lesions linked to small vessel disease and cognitive impairment—are always progressive and irreversible. The findings could impact how clinicians interpret brain scans and evaluate new therapies for Alzheimer's disease, particularly in individuals with Down syndrome who are at high risk for this condition.
The study followed 80 adults with Down syndrome and 53 neurotypical adults as controls, each undergoing at least two magnetic resonance imaging scans separated by six months or more. Researchers found that up to about age 40, changes in WMH were minimal. However, after this age—when most people with Down syndrome already show amyloid pathology associated with Alzheimer's—the evolution of these lesions became more variable. Over a period of two to three years, many participants experienced not just increases but also measurable reductions in WMH volume.
"The cross-sectional analysis gives us a snapshot of each stage of the process, but it does not show how these alterations change within each individual over time. With this study, we were able to see the movie and confirm that the trajectory is not always linear," explains Alejandra Morcillo-Nieto, researcher in the Brain Imaging and Aging group at IR Sant Pau and first author of the article.
Researchers observed that reductions in WMH were more pronounced among those who had developed clinical symptoms of Alzheimer's disease compared to those who remained asymptomatic or were part of the control group. "When we saw that a relevant percentage of participants showed a reduction, we realized that we could no longer interpret these lesions as something fixed and irreversible. At certain points, their behavior is more dynamic than we previously thought," notes Morcillo-Nieto.
The team explored possible biological mechanisms behind these changes, including inflammation related to immune system alterations inherent to trisomy 21 or amyloid accumulation affecting blood vessels. They found an association between cerebral microbleeds—a marker for cerebral amyloid angiopathy—and greater reductions in WMH volume over time. "In Down syndrome, amyloid does not only accumulate in brain tissue but also in the vessels... If this inflammatory process improves, that signal may decrease in subsequent scans," explains Morcillo-Nieto.
Despite previous cross-sectional studies linking higher lesion burden with abnormal Alzheimer’s biomarkers such as beta-amyloid and phosphorylated tau proteins, this longitudinal analysis did not find robust associations between annual changes in WMH volume and biomarker levels. "In cross-sectional analyses, we found associations between lesion burden and Alzheimer's biomarkers. But when we evaluate how these lesions change year by year...that relationship does not appear with the same consistency," says Morcillo-Nieto.
Dr. Alexandre Bejanin, head of the Brain Imaging and Aging group at IR Sant Pau and senior author of the study said: "These results force us to rethink how we interpret white matter hyperintensities in the context of Alzheimer's disease...only by following the same individuals over time can we truly understand what is happening." He added: "At a time when anti-amyloid therapies are being developed and evaluated, it is essential to understand the natural history of these lesions in Down syndrome...If we can separate the true effect of treatment from the biological progression of the disease, we will be able to properly evaluate drugs and identify our ideal intervention window—that is, when is the best time to initiate these therapies safely and effectively."
