# Longitudinal changes of blood β-synuclein in cognitively unimpaired, mild cognitive impairment and sporadic Alzheimer´s disease

## TL;DR

This study tracks blood levels of β-synuclein over time in people with Alzheimer's disease, mild cognitive impairment, and no cognitive issues, showing it could help predict future cognitive decline.

## Contribution

The study provides the first longitudinal analysis of serum β-synuclein levels across the Alzheimer's disease continuum.

## Key findings

- β-synuclein levels were higher in MCI and AD dementia compared to cognitively unimpaired individuals.
- Longitudinal β-synuclein levels predicted MCI-to-dementia conversion and future cognitive decline better than CSF neurogranin.
- β-synuclein levels showed dynamic changes across all stages of Alzheimer's disease with individual variability.

## Abstract

β-Synuclein is an emerging synaptic blood biomarker for Alzheimer´s disease (AD) and correlates with cognitive impairment, brain atrophy and amyloid/tau pathology. Longitudinal data from individual patients are missing so far but are important to evaluate how changes of β-synuclein might be used in early diagnosis, prediction, disease progression and treatment monitoring.

In this observational study, we investigated serum β-synuclein by immunoprecipitation-mass spectrometry (IP-MS) in 463 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including clinically diagnosed cognitively unimpaired, mild cognitive impairment (MCI) and AD dementia subjects with ≥ 1 follow-up samples for 235 individuals and clinical follow-up for up to 19 years. CSF AD biomarker levels were available for 194 participants.

Participants (40.0% female, n = 185) had a mean (± SD) age of 76.2 ± 6.7 years. The cross-sectional group comparison yielded higher β-synuclein levels in MCI and AD dementia compared with CU and in AD dementia vs MCI patients. Mean follow-up time of longitudinal serum samples was 2.3 ± 1.2 years. The longitudinal data indicate that β-synuclein levels are dynamic during all stages of the AD continuum (CU, MCI, dementia) with substantial inter-individual variation. β-Synuclein predicted MCI-to-dementia conversion and future cognitive decline and it performed better in discrimination of AD dementia patients than CSF neurogranin.

Our longitudinal data support the use of serum β-synuclein levels for prediction of future cognitive decline and MCI-to-dementia conversion but needing confirmation. Further studies with biologically and clinically defined participants must verify the trajectories of β-synuclein during the AD continuum.

The online version contains supplementary material available at 10.1186/s13195-026-01973-1.