A study links a blood protein to memory and brain changes in Down syndrome

By Pooja Toshniwal PahariaReviewed by Susha Cheriyedath, M.Sc.Oct 11 2026

A study combining blood samples, memory assessments, and brain scans examines whether a protein found at nerve cell connections could help researchers track Alzheimer’s-related changes in adults with Down syndrome.

Study: Changes in serum β-synuclein precede blood biomarkers of Alzheimer pathology in Down syndrome. Image Credit: Orawan Pattarawimonchai / Shutterstock

A recent study published in the journal Alzheimer’s & Dementia suggests that changes in β-synuclein, a presynaptic protein, may precede blood-based markers of Alzheimer’s disease (AD) pathology among people with Down syndrome (DS). Cross-sectional age modeling suggested that serum β-synuclein levels diverged from controls by about two decades before expected AD symptom onset. Higher β-synuclein was associated with hypometabolism and cortical atrophy and correlated with poorer episodic memory performance. The earliest increase could reflect trisomy 21-related neurobiology, early AD-related synaptic dysfunction, or both. Based on the findings, β-synuclein testing may be a valuable addition to research assessing AD-associated synaptic dysfunction in individuals with DS.

Individuals with DS can develop changes in brain synapses linked to AD. Objective biomarkers are required to detect such synaptic changes early in the disease process. Recent studies have demonstrated higher β-synuclein levels in blood samples collected from individuals with DS. But how these changes relate to alterations in pathophysiological blood markers spanning the AD continuum remains unclear.

About the study

In this single-center, cross-sectional study, researchers used immunoprecipitation–mass spectrometry (IP-MS) to quantify β-synuclein levels among Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) participants across groups without AD symptoms (aDS), with prodromal AD (pDS), and with AD dementia (dDS).

The study evaluated β-synuclein alterations in 88 adult individuals living with DS, including 35 without AD symptoms, 18 with prodromal AD, and 35 with AD dementia. For comparison, the study also included 43 cognitively unimpaired individuals without DS from the Sant Pau Initiative in Neurodegeneration (SPIN) cohort. The team also evaluated associations between β-synuclein alterations and established neuroimaging measures and blood biomarkers: tau phosphorylated at threonine 217 (p-tau217) for AD pathology, glial fibrillary acidic protein (GFAP) for astroglial changes, and neurofilament light chain (NfL) for nerve fiber damage. β-synuclein was measured in serum; the other three biomarkers were measured in plasma.

Participants completed several neurological and neuropsychological assessments. In addition to blood samples, consenting participants underwent lumbar puncture to assess cerebrospinal fluid (CSF) biomarkers. Controls were required to have normal core CSF AD biomarker concentrations. The team also analyzed magnetic resonance imaging (MRI) scans from 60 participants with DS and fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) scans from 42 participants. Using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, they categorized intellectual disability (ID) severity based on caregivers’ reports of participants’ best-ever functioning.

The Cambridge Examination for Mental Disorders of Older People with DS and others with intellectual disabilities (CAMDEX-DS) assessed dementia symptoms, whereas the Cambridge Cognition Examination for Older Adults with Down syndrome (CAMCOG-DS) was used to evaluate cognitive performance. The researchers assessed declarative verbal memory using the modified Cued Recall Test's immediate and delayed recall phases. Using linear regression models adjusted for ID severity, the team evaluated associations between β-synuclein and cognitive scores in participants with mild or moderate ID, while locally estimated scatterplot smoothing (LOESS) regressions estimated the age at which biomarker levels diverged between participants with DS and controls.

Results

Serum β-synuclein levels were already higher in participants in their 20s and increased with age through their 30s, 40s, and 50s. Age modeling placed the divergence approximately 21 years before expected prodromal AD onset and more than seven years before changes in other blood-based biomarkers, including p-tau217, NfL, and GFAP.

The age-related curve showed a pronounced increase in β-synuclein at 40 years of age, about 10 years before expected symptom onset. Compared with controls, β-synuclein levels were 1.83-fold, 2.82-fold, and 3.67-fold higher among aDS, pDS, and dDS participants, respectively. β-synuclein was linked to CAMCOG-DS scores in aDS and pDS, but not dDS. When analyzed separately by ID severity, associations with CAMCOG-DS and immediate recall remained significant only in mild ID, while delayed recall associations remained significant in both mild and moderate ID.

Imaging analyses linked higher β-synuclein levels to cortical atrophy and hypometabolism in AD-vulnerable brain regions, including the prefrontal cortex and the medial and lateral temporal and parietal regions. Among participants with DS without AD symptoms, gray matter volume was associated only with the fusiform gyrus, with no significant association with glucose metabolism. In participants with symptomatic AD (pooled pDS and dDS), lower gray matter volume was associated with β-synuclein in the left lateral temporal region and thalamus. Metabolic associations involved the posterior cingulate and medial and lateral temporal structures. Serum β-synuclein concentrations did not differ significantly between sexes or between carriers and noncarriers of apolipoprotein E ε4 (APOE ε4) in the DS and control groups.

Conclusion and Future Directions

The findings support β-synuclein as a potential early blood-based marker of AD-associated synaptic dysfunction in DS. The cross-sectional design cannot establish individual biomarker trajectories. The study did not establish whether β-synuclein predicts future cognitive decline. Estimated divergence ages also depend on sample size and assay sensitivity, and the imaging findings were exploratory because the analyses did not correct for multiple comparisons.

If further longitudinal studies in larger populations confirm these findings, researchers could evaluate β-synuclein alongside other biomarkers for research and clinical trial monitoring. Its prognostic and clinical utility requires further validation. The biological origin of the earliest increase also remains uncertain, as β-synuclein was higher in asymptomatic participants with negative CSF amyloid results.