Researchers from the Neurobiology of Dementia group at the Sant Pau Research Institute (IR Sant Pau) have published two pioneering studies in the journals Alzheimer’s & Dementia and Neurology, revealing key advances in understanding Alzheimer’s disease in individuals with Down syndrome (DS). They have demonstrated the relationship between white matter hyperintensities and cerebral microhemorrhages with the development of this disease in this population.
Studies in individuals with DS are crucial because this population has a highly determined genetic risk for developing Alzheimer’s due to the triplication of chromosome 21. This genetic condition leads to the overproduction of beta-amyloid, one of the primary biological characteristics of the disease. As a result, almost all individuals with DS show biological signs of this condition from the age of forty, although clinical symptoms may appear later.
This phenomenon makes DS a unique model for studying the early mechanisms of Alzheimer’s disease and its interactions with cerebrovascular factors, providing data that may also be applicable to the general population. “The life expectancy of individuals with DS has significantly increased in recent decades, but this success has highlighted the need to address the growing impact of Alzheimer’s in this population,” says Dr. Alexander Bejanin, researcher in the Neurobiology of Dementia group at IR Sant Pau, who coordinated the two studies now published. “Our studies allow us to identify key factors that could improve early detection and prognosis of the disease, not only in individuals with DS but also in the general population.”
White matter hyperintensities (WMHs) are detected through magnetic resonance imaging (MRI) as bright areas in the brain. In individuals with DS, these lesions appear earlier and with greater severity than in the general population. They are key indicators of cerebrovascular issues and are strongly linked to the progression of Alzheimer’s disease.
According to Alejandra Morcillo-Nieto, the lead author of the study published in Alzheimer’s & Dementia, “WMHs are crucial for understanding how cerebrovascular disease and Alzheimer’s disease are related in individuals with DS. These lesions are particularly prevalent in periventricular, frontal, parietal, and occipital regions, and this is the first study to identify the areas where they are most common in this population.”
The study, which analysed 261 adults with DS and 131 adults without this condition, shows that “WMHs increase with age and are correlated with biomarkers such as beta-amyloid and phosphorylated tau, suggesting a direct connection with the pathophysiology of Alzheimer’s disease, independent of vascular risks,” says Morcillo-Nieto. Moreover, these anomalies are related to clinical status, suggesting that they may be directly influencing functional deterioration.
Cerebral microhemorrhages are small deposits of blood in the brain that may indicate vascular damage and are associated with Alzheimer’s disease. In individuals with DS, these lesions are more frequent and primarily concentrate in the posterior regions of the brain, such as the cerebellum and occipital areas. This is one of the findings of the study published in Neurology, and although they are not exactly the same areas as those for WMHs, they are strongly related.
According to Sàra Zsadanyi, the lead author of the study, “microhemorrhages are a key piece of understanding the risk of complications in anti-amyloid therapies. Their increasing prevalence with age allows us to better identify key moments for intervention.” The study identified microhemorrhages in 20% of individuals with DS, compared to only 8.9% in healthy controls.
These lesions increase not only with age but also with clinical severity, rising from 12% in early stages to 35% in advanced stages of dementia. The results also show a correlation with Alzheimer’s disease biomarkers, highlighting their relevance for monitoring and treating this vulnerable population.
According to Dr. Alexander Bejanin, “with our studies, we want to highlight the crucial role of characterising these two vascular lesions in the development of new therapies for Alzheimer’s disease.” Dr. Bejanin also emphasises that the findings “are not only relevant for Down syndrome but have broader implications for understanding Alzheimer’s disease in general.”
These discoveries have a direct impact on the management and treatment of the disease. “With the arrival of new anti-amyloid therapies, these lesions are a crucial factor to consider, as they may increase the risk of adverse effects,” warns Dr. Bejanin. This underscores the importance of using MRI to monitor disease progression and personalise treatments.
The research also opens the door to exploring new preventive and therapeutic strategies. According to Dr. Bejanin, “studies in DS allow us to better understand the relationship between vascular lesions and Alzheimer’s pathology, offering a unique opportunity to apply this knowledge to the general population.” The researchers highlight that these findings could improve understanding of the role of vascular lesions in Alzheimer’s, both as a cause and a consequence of the disease.
Sant Pau Hospital is an international reference centre for neurodegenerative diseases associated with DS. Its Alzheimer-Down Unit, the only one in Spain, continues to lead research redefining the future of diagnosis and treatment for these conditions. This unit works in a multidisciplinary way, combining clinical and translational research with a personalised approach to meet the specific needs of individuals with DS.
