What has long been interpreted as permanent and irreversible vascular damage may not be exclusively so. In people with Down syndrome—one of the most robust populations for studying Alzheimer’s disease due to the near-universal presence of the characteristic proteinopathies of this dementia from the age of 40—some lesions visible on magnetic resonance imaging do not follow a linear course. A longitudinal study from the Institut de Recerca Sant Pau (IR Sant Pau), published in Alzheimer’s & Dementia, shows that these alterations can fluctuate and even decrease over time in the Down syndrome population. This is especially true once the clinical symptoms of Alzheimer’s disease have begun to manifest.
The study analyzed the evolution of white matter hyperintensities (WMH), lesions typically associated with cerebral vascular alterations that appear as brighter areas on magnetic resonance imaging. These alterations are considered a marker of small vessel disease and have been linked to cognitive impairment in different contexts.
Previous studies from IR Sant Pau had shown that, in people with Down syndrome, the burden of these lesions increases with age and is associated with characteristic Alzheimer’s biomarkers, such as beta-amyloid and phosphorylated tau proteins. However, those studies were cross-sectional and provided a snapshot of the disease at different time points, without allowing observation of its evolution within the same individuals.
“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.
The study included 80 adults with Down syndrome and 53 neurotypical adults as a control group, all of whom had at least two magnetic resonance scans separated by a minimum of six months. At baseline, 65 participants with Down syndrome were in the asymptomatic stage of Alzheimer’s disease, and 13 were in the symptomatic stage—prodromal or dementia. During follow-up, ten initially asymptomatic individuals progressed to symptomatic stages, allowing researchers to analyze structural changes across different points of the clinical continuum.
Unlike previous cross-sectional studies, this work made it possible to calculate the annual change in WMH volume in the same individuals over time. The analysis was conducted both globally and by specific brain regions—frontal, parietal, temporal, and occipital lobes; basal ganglia; and periventricular areas—using a longitudinal segmentation methodology designed to detect true changes and minimize potential technical variability between scans.
The results indicated that up to approximately age 40, changes were minimal and relatively stable. From that age onward—when virtually all individuals with Down syndrome already present cerebral amyloid pathology—greater variability in the evolution of these lesions began to emerge. Over an approximate interval of two to three years, the predominant trajectory was not progressive increase but rather a heterogeneous evolution, in which a relevant proportion of individuals who already had WMH experienced measurable reductions.
“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 Alejandra Morcillo-Nieto.
The analysis strongly suggested that the annual decrease in WMH volume was significantly greater in individuals with clinical symptoms of Alzheimer’s disease than in those in the asymptomatic stage and in controls. In other words, the decline was not observed in the early stages but rather when the disease had already become clinically manifest.
While asymptomatic participants showed minimal changes and a relatively stable trajectory during follow-up, the symptomatic group exhibited more pronounced reductions. “In people with Down syndrome, it is estimated that by around age 40, virtually all already have Alzheimer’s pathology, although symptoms appear later. The fact that this greater variability and reduction coincides with that stage is temporally very significant,” explains Alejandra Morcillo-Nieto.
Differences were particularly evident in parietal and occipital regions and in periventricular areas, locations that previous IR Sant Pau studies had already identified as particularly affected in this population. The fact that the greatest instability is concentrated in these regions reinforces the idea that WMH may reflect processes linked to the interaction between amyloid burden, vascular alterations, and clinical progression, rather than a simple linear accumulation of damage.
To understand this phenomenon, the team explored different possible biological mechanisms that could explain why, in a relevant proportion of participants, hyperintensities decreased over time. In some cases, the reduction could be associated with white matter atrophy linked to neurodegeneration. However, this explanation was not sufficient for all observed cases, suggesting the involvement of additional processes.
In this regard, there is increasing evidence that inflammation in the brain plays an important role. In Down syndrome, this inflammation may have several origins: alterations of the immune system inherent to trisomy 21, the accumulation of abnormal proteins such as amyloid (related to Alzheimer’s disease), and changes in cerebral blood vessels.
The analysis indicated that the presence of cerebral microbleeds—a marker of cerebral amyloid angiopathy—was associated with a greater longitudinal reduction in hyperintensities. This finding points to a possible role of vascular changes related to amyloid deposition in the dynamics of these lesions. “In Down syndrome, amyloid does not only accumulate in brain tissue but also in the vessels. This can alter the barrier that protects the brain and allow fluid leakage, generating a signal visible on MRI. If this inflammatory process improves, that signal may decrease in subsequent scans,” explains Alejandra Morcillo-Nieto.
Regardless of the cause, inflammation in the brain may contribute to the appearance of these lesions, but it may also decrease over time, which would explain why in some cases hyperintensities subsequently decline. Overall, the data suggest that these hyperintensities do not always follow a linear course, but rather reflect dynamic processes in which neurodegeneration, inflammation, and vascular changes interact.
The study also analyzed the relationship between the annual change in WMH volume and different Alzheimer’s disease biomarkers in cerebrospinal fluid and plasma, including beta-amyloid and phosphorylated tau proteins. Previous cross-sectional studies from IR Sant Pau had shown that a higher lesion burden was associated with alterations in these biological markers. However, in the longitudinal analysis, no robust significant associations were identified between annual WMH volume variation and changes in these biomarkers.
This result clearly differentiates longitudinal findings from cross-sectional ones. Researchers note that this lack of association may be masked by the inherent complexity and clinical heterogeneity during adulthood in Down syndrome, where biomarker trajectories are not linear and depend on disease stage.
“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 in the same individuals, that relationship does not appear with the same consistency. This may reflect that the evolution of these markers has quite unfamiliar and non-linear phases throughout adulthood,” explains Alejandra Morcillo-Nieto.
Overall, the findings underscore that Alzheimer’s disease—even in a genetic model as well defined as Down syndrome—does not follow simple or linear trajectories. The evolution of WMH does not respond to an exclusively cumulative pattern but rather shows phases of stability, increase, or even reduction, depending on the clinical moment and biological context.
This dynamic behavior reinforces the idea that in the brain multiple processes coexist and may interact over time: amyloid accumulation, vascular changes, inflammatory phenomena, and neurodegeneration do not necessarily progress at the same rate or with the same intensity.
“These results force us to rethink how we interpret white matter hyperintensities in the context of Alzheimer’s disease. We cannot automatically assume that every increase or decrease responds to the same mechanism, because the brain is undergoing different processes at the same time. That is why it is essential to study the disease longitudinally: only by following the same individuals over time can we truly understand what is happening,” says Dr. Alexandre Bejanin, head of the Brain Imaging and Aging group at IR Sant Pau and senior author of the study.
These findings are particularly relevant in the current context of developing therapies targeting the amyloid protein. Some of these interventions may be associated with radiological alterations linked to cerebral amyloid angiopathy, making it essential to understand how these lesions evolve in the absence of treatment.
“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,” says Dr. Alexandre Bejanin. “Knowing that these lesions show natural fluctuations requires us to be highly precise in clinical trials. 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.”
In this sense, the study provides a necessary basis for more accurately interpreting radiological changes in future clinical trials and opens new lines of research into the biological mechanisms underlying this variability.
Morcillo-Nieto AO, Rozalem-Aranha M, Maure-Blesa L, Rodríguez-Baz Í, Arriola-Infante JE, Franquesa-Mullerat M, Zsadanyi SE, Vaqué-Alcázar L, Parra JA, Zhao Z, Arranz J, Videla L, Barroeta I, Del Hoyo Soriano L, Benejam B, Fernández S, Hernandez AS, Pertierra L, Giménez S, Alcolea D, Belbin O, Lleó A, Carmona-Iragui M, Fortea J, Bejanin A. Temporal dynamics of white matter hyperintensities related to Alzheimer’s disease in adults with Down syndrome. Alzheimers Dement 2026;22:e71157. https://doi.org/10.1002/alz.71157
Last update: 19 de March de 2026
