Decades before the first symptoms of Alzheimer’s disease appear, some changes associated with the disease may begin to leave a trace in the blood . A study by the Sant Pau Research Institute (IR Sant Pau) has found that, in people with Down syndrome, levels of β-synuclein, a protein related to synaptic function, begin to rise from the third decade of life , long before symptoms appear and earlier than other blood biomarkers of Alzheimer’s disease.
The results, published in Alzheimer’s & Dementia , are the result of a collaboration between Sant Pau Hospital in Barcelona, Martin Luther University in Germany, and the German Center for Neurodegenerative Diseases. They position β-synuclein as a promising marker of the earliest synaptic changes associated with the disease. According to estimates based on participants’ ages, β-synuclein levels begin to differ from those observed in people without Down syndrome approximately 21 years before the average age at diagnosis of prodromal Alzheimer’s disease in the cohort studied.
“One of the major challenges in Alzheimer’s research is understanding what is happening in the brain many years before the first symptoms appear. Gaining a more in-depth understanding of these earliest changes is essential to identifying when synapses begin to fail and to opening the door to studying interventions at increasingly early stages of the disease,” explains Dr. Olivia Belbin, head of the Molecular Neurodegeneration group at IR Sant Pau and corresponding author of the study.
People with Down syndrome have an exceptionally high risk of developing Alzheimer’s disease as they age. The median age at diagnosis of prodromal Alzheimer’s disease, the early period when the first signs or general symptoms appear before the disease is fully developed, is around 50 years , while the median age at diagnosis of dementia is approximately 54 years . Meanwhile, the prevalence of symptomatic Alzheimer’s disease reaches between 90% and 100% by the seventh decade of life . This close relationship makes it possible to study with particular precision the sequence of biological changes that occur during the decades before symptoms appear.
β-synuclein is a protein located mainly at presynaptic terminals, the structures from which neurons communicate with one another. Its levels may therefore provide information about synaptic dysfunction and degeneration , processes considered among the early events in Alzheimer’s disease. Unlike other disease processes, such as amyloid and tau pathology, neurodegeneration, or glial activation, there are still few blood biomarkers capable of detecting these early synaptic changes .
“Previous studies had already shown that β-synuclein increases early in Alzheimer’s disease and also in people with Down syndrome, but we still needed to understand how it behaves compared with other blood biomarkers and across the different stages of the disease. That is what we set out to examine in this study,” explains Alba Cervantes , first author of the study and a researcher at IR Sant Pau.
To do so, the researchers analyzed participants from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) and the Sant Pau Initiative on Neurodegeneration (SPIN). In total, they studied 131 people , including 88 adults with Down syndrome and 43 cognitively healthy individuals without Down syndrome . Participants with Down syndrome were at different stages along the Alzheimer’s disease continuum: 35 were still asymptomatic, 18 had prodromal Alzheimer’s disease, and 35 had Alzheimer’s dementia.
The results indicated that β-synuclein levels were already 1.83 times higher in asymptomatic people with Down syndrome than in controls. The difference increased as the disease progressed, reaching levels 2.82 times higher in the prodromal stage and 3.67 times higher in people with dementia .
One of the study’s main contributions is the direct comparison of β-synuclein with other blood biomarkers that reflect different processes related to Alzheimer’s disease. The researchers also analyzed pTau217 , associated with tau pathology; NfL , an indicator of axonal damage; and GFAP , associated with astrocyte response. While β-synuclein concentrations began to differ between people with and without Down syndrome from the third decade of life, the curves for pTau217, NfL, and GFAP did not clearly diverge until the late fourth decade or early fifth decade.
According to the study’s estimates, changes in β-synuclein appear more than seven years before detectable changes in these other blood biomarkers . All of them, however, show a steeper increase around age 40, approximately a decade before the average age at symptom onset in the cohort.
“What is particularly interesting is that these biomarkers are not telling us the same thing. pTau217, NfL, and GFAP reflect different disease processes, whereas β-synuclein provides information about the synapses. Being able to place these changes along a timeline helps us better understand how the different alterations associated with Alzheimer’s disease unfold and interact,” explains Alba Cervantes.
In addition, in a specific analysis of participants with Down syndrome who were still asymptomatic and had no detectable abnormalities in the cerebrospinal fluid beta-amyloid ratio, β-synuclein was already significantly elevated compared with controls. Along with NfL, it was the only blood biomarker analyzed that showed changes at this very early stage.
The authors caution, however, that the study cannot yet determine the extent to which this very early elevation specifically reflects Alzheimer’s-related processes or may also reflect neurobiological characteristics associated with trisomy 21. Nevertheless, the associations observed with other biomarkers, cognition, and neuroimaging support the hypothesis that Alzheimer’s-related synaptic dysfunction contributes to these early changes.
The study also provides evidence that increased β-synuclein is not simply a difference detected in a blood test but is associated with other disease-related changes.
Higher levels of this protein were associated with poorer cognitive performance and episodic memory , assessed using tests specifically adapted for people with Down syndrome. The association was observed both in a global measure of cognition and in immediate and delayed recall tests.
“The fact that β-synuclein is also associated with memory and with changes that we can observe directly in the brain reinforces the idea that this is not simply a difference in a blood test, but rather a signal linked to relevant disease processes,” says Dr. Belbin.
The study also incorporated neuroimaging techniques. Sixty participants with Down syndrome had undergone brain magnetic resonance imaging, and 42 had been studied using FDG-PET , a technique used to assess glucose metabolism in the brain.
The analyses showed that higher β-synuclein levels were associated with lower gray matter volume and reduced brain metabolism in regions particularly vulnerable to Alzheimer’s disease, including temporal, parietal, and prefrontal areas. In people who were already symptomatic, the association with brain metabolism was observed, among other areas, in the posterior cingulate and in medial and lateral temporal structures.
Even among participants who were still asymptomatic, higher β-synuclein concentrations were associated with lower volume in the fusiform gyrus, a region located in the temporal lobe. The authors note that these neuroimaging analyses are exploratory and will need to be confirmed in larger cohorts.
The possibility of studying these processes using a blood biomarker is particularly relevant for clinical research. A blood draw is simpler, less invasive, and easier to repeat than a lumbar puncture or certain neuroimaging tests, making it easier to follow large groups of participants over long periods of time.
In the future, β-synuclein could complement other biomarkers to better characterize and monitor the earliest stages of the disease, select participants for clinical trials, and study responses to treatment , particularly in research aimed at intervening before significant cognitive impairment develops.
“If we want to intervene increasingly early in Alzheimer’s disease, we need to understand the sequence of changes that occurs long before dementia. β-synuclein may offer us a window into what is happening at the synapses during a period of the disease that until now has been difficult to study through blood,” says Alba Cervantes.
The study is cross-sectional , meaning that the timeline of changes was estimated by comparing participants of different ages rather than following the same individuals over decades. The next step will be to conduct longitudinal studies to confirm this sequence and determine whether β-synuclein levels can help predict the course of cognitive decline and disease progression in individual patients.
Alzheimer’s & Dementia
Observational study
People
Changes in serum β-synuclein precede blood biomarkers of Alzheimer pathology in Down syndrome
21-Sep-2026