Blood Biomarker Detects Alzheimer’s Changes Decades Before Symptoms in Down Syndrome

People with Down syndrome face a particularly high age-related risk, with symptomatic Alzheimer’s disease affecting 90% to 100% by the seventh decade of life. In this population, blood biomarkers could provide a less invasive way to detect early biological changes associated with the disease.

Sant Pau Research Institute (IR Sant Pau; Barcelona, Spain) evaluated serum β-synuclein as a blood biomarker of early synaptic changes associated with Alzheimer’s disease. β-synuclein is located mainly at presynaptic terminals, the structures involved in neuronal communication. Its concentration may provide information about synaptic dysfunction and degeneration, which are considered early events in Alzheimer’s disease.

The study analyzed participants from the Down Alzheimer Barcelona Neuroimaging Initiative and the Sant Pau Initiative on Neurodegeneration. Researchers studied 131 people, including 88 adults with Down syndrome and 43 cognitively healthy individuals without Down syndrome. Among participants with Down syndrome, 35 were asymptomatic, 18 had prodromal Alzheimer’s disease, and 35 had Alzheimer’s dementia.

β-synuclein levels were 1.83 times higher in asymptomatic people with Down syndrome than in controls. Levels were 2.82 times higher in the prodromal stage and 3.67 times higher in people with dementia. Estimates based on participant ages indicated that β-synuclein levels began to differ from controls about 21 years before the average age at diagnosis of prodromal Alzheimer’s disease in the cohort.

The study also compared β-synuclein with phosphorylated tau 217, neurofilament light chain, and glial fibrillary acidic protein. β-synuclein concentrations began to diverge from the third decade of life, while the other biomarkers did not clearly diverge until the late fourth decade or early fifth decade. Higher β-synuclein levels were associated with poorer cognitive performance, poorer episodic memory, lower gray matter volume, and reduced brain metabolism in Alzheimer’s-vulnerable regions. 

The results were published in Alzheimer’s & Dementia on September 21, 2026, with collaboration among Sant Pau Hospital in Barcelona, Martin Luther University, and the German Center for Neurodegenerative Diseases.

The authors stated that the cross-sectional design means the timeline was estimated by comparing participants of different ages rather than following the same individuals over decades. They identified longitudinal studies as the next step to confirm the sequence and determine whether β-synuclein can help predict cognitive decline and disease progression.

 “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,” said Dr. Olivia Belbin, head of the Molecular Neurodegeneration group at IR Sant Pau and corresponding author of the study. 

“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,” said Alba Cervantes, first author of the study and a researcher at IR Sant Pau.

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