A study published in Alzheimer's & Dementia reports that levels of β-synuclein, a protein tied to synaptic function, begin to rise in people with Down syndrome from their third decade of life, long before symptoms appear and earlier than other blood biomarkers of Alzheimer's disease. The work was led by researchers at Sant Pau Research Institute in Barcelona, with collaborators at Martin Luther University in Germany and the German Center for Neurodegenerative Diseases. Based on participants' ages, the researchers estimate that β-synuclein levels begin to differ from those in people without Down syndrome about 21 years before the average age at diagnosis of prodromal Alzheimer's disease in the group studied.
People with Down syndrome have an unusually high risk of Alzheimer's, with prodromal disease typically diagnosed around age 50 and dementia around 54. That close link is what makes the group useful for research. Because the timeline of disease is relatively predictable, scientists can examine the biological changes that occur in the decades before symptoms. β-synuclein is found mainly at presynaptic terminals, the points where neurons communicate, so its levels may reflect synaptic dysfunction and degeneration, which are considered early events in Alzheimer's. The authors note that few blood tests currently detect these early synaptic changes.
The team analyzed 131 people: 88 adults with Down syndrome at different stages of the disease continuum and 43 cognitively healthy controls without Down syndrome. Levels were already 1.83 times higher in asymptomatic people with Down syndrome than in controls, rising to 2.82 times higher in the prodromal stage and 3.67 times higher in those with dementia. The researchers also compared β-synuclein with pTau217, NfL and GFAP. The β-synuclein curve separated from controls more than seven years before changes in those other markers became detectable, although all of them rose more steeply around age 40.
The study adds some evidence that the protein's signal is more than a blood-test difference. Higher β-synuclein was associated with poorer cognition and episodic memory in participants with Down syndrome, and with lower gray matter volume and reduced brain metabolism in regions vulnerable to Alzheimer's. Even among asymptomatic participants, higher levels corresponded to lower volume in the fusiform gyrus. The authors describe the imaging analyses as exploratory and in need of confirmation in larger cohorts. They also caution that they cannot yet separate Alzheimer's-related processes from characteristics linked to trisomy 21.
A blood marker that tracks synaptic change would be easier to collect and repeat than a lumbar puncture or some imaging tests, which matters for following large groups over long periods. The researchers suggest it could help characterize early disease, select trial participants and study treatment responses. The study is cross-sectional, so the timeline was estimated by comparing people of different ages rather than following the same individuals over decades. Longitudinal studies are the next step, to confirm the sequence and test whether β-synuclein can predict cognitive decline in individual patients.