CSF synaptic proteins are associated with risk of MCI symptom onset and long-term brain atrophy

Q: Which CSF biomarkers were measured in the study?

The study quantified eight synaptic signaling peptides from CSF (CNTFR, GFRA3, VGF, ACHE, NCAM1, DPP6, GPC1, and CARTPT) and also measured Aβ42/Aβ40 and p-tau181 as traditional AD biomarkers.

Q: How were MCI symptom onset and brain atrophy assessed?

Time to MCI symptom onset was analyzed using Cox regression. Long-term neurodegeneration was assessed by quantifying MRI atrophy with volumetric scans using SPARE-AD and SPARE-BA region composites in mixed-effect models.

Q: What were the main findings about VGF and DPP6?

After accounting for covariates and baseline AD biomarker levels, higher baseline VGF and DPP6 were linked to lower risk of MCI symptom onset and less atrophy over time in AD-signature regions; VGF also showed less age-related atrophy.

Sep 30, 2026

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Background: Abnormal cerebrospinal fluid (CSF) amyloid and tau levels among cognitively unimpaired individuals predict higher risk of mild cognitive impairment (MCI) or Alzheimer’s disease (AD) dementia, but accuracy of these markers alone is limited. Methods: CSF from 268 BIOCARD participants was analyzed for eight synaptic signaling peptides by quantitative mass spectrometry, with AD biomarkers measured by Lumipulse and MRI atrophy quantified using SPARE-AD and SPARE-BA composites. Results and Conclusion: Higher VGF and DPP6 related to lower MCI symptom onset risk and reduced long-term atrophy independent of baseline AD biomarker levels.

LanguageEnglish

CategoryHealthcare

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Background

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Conclusion

DOI: 10. 1002/alz70856_105326 BIOMARKERS POSTER PRESENTATION BIOMARKERS (NON-NEUROIMAGING) CSF synaptic proteins are associated with risk of MCI symptom onset and long-term brain atrophy Anja Soldan1 Chan-Hyun Na2 Yuxin Zhu3 Corinne Pettigrew2 Abhay Moghekar2 Guray Erus4, 5 Christos Davatzikos4, 5 Marilyn S. S. Albert2 Paul F Worley2 the BIOCARD Study Team 1 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2Johns Hopkins University School of Medicine, Baltimore, MD, USA 3Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 4 Centre for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA 5 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Correspondence Anja Soldan, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Email: [asoldan1@jhmi.edu](asoldan1@jhmi.edu) Abstract Background: More abnormal cerebrospinal fluid (CSF) levels of amyloid and tau among cognitively unimpaired individuals are associated with higher risk of mild cognitive impairment(MCI)or dementia due to Alzheimer’s disease(AD). However, the predictive accuracy of these markers alone is limited. This study examined whether novel synaptic markers and neural signaling proteins are associated with time to onset of MCI symptoms and with long-term neurodegeneration, based on MRI, after accounting for traditional CSFAD biomarker levels. Method: CSF was collected from 268 cognitively unimpaired BIOCARD Study participants (mean baseline age = 57. 7 years; mean follow-up = 16. 3 years; n = 77 progressed to MCI/dementia; see Table 1). Levels of eight peptides involved in neuronal signaling were measured, using quantitative parallel reaction monitoring mass spectrometry: CNTFR, GFRA3, VGF, ACHE, NCAM1, DPP6, GPC1, and CARTPT. Levels of Aβ42/Aβ40 and p-tau181 were measured from the same CSF specimens using Lumipulse assays. Atrophy on volumetric MRI scans was quantified from 213 participants as two composites: (1) AD signature regions (SPARE-AD) and (2) regions indexing brain aging(SPARE-BA). All analyses covaried age, sex, years of education, and APOE-e4 status. Results: In Cox regression models, after accounting for covariates and baseline AD biomarker levels, higher baseline levels of both neurosecretory protein VGF and dipeptidyl peptidase-like protein 6 (DPP6) were associated with a lower risk of MCI symptom onset (both p <0.04, see Table 2. In mixed effect models, higher levels of VGF and DPP6 were also associated with less atrophy over time in AD-signature regions (see Table 3), and higher VGF was associated with less age-related atrophy. Interestingly, when AD biomarker levels were not accounted for, none of the signaling proteins were associated with MCI symptom onset or MRI atrophy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Alzheimer’s Association. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. Alzheimer’s Dement. 2025;21(Suppl. 2):e105326. [https://doi.org/10.1002/alz70856_105326](https://doi.org/10.1002/alz70856_105326) wi[leyonlinelibrary.com/journal/alz](leyonlinelibrary.com/journal/alz) 1of4 BIOMARKERS Conclusion: These findings suggest that among cognitively unimpaired individuals, higher levels of the synaptic proteins VGF and DPP6 may slow the onset of the symptomatic phase of AD as well as longitudinal atrophy in AD-vulnerable regions, independently of AD pathology levels. These findings support the view that VGF and DPP6 may be resilience factors against neurodegeneration and cognitive decline and represent fruitful targets for novel therapeutics. BIOMARKERS BIOMARKERS

FAQs

Which CSF biomarkers were measured in the study?

The study quantified eight synaptic signaling peptides from CSF (CNTFR, GFRA3, VGF, ACHE, NCAM1, DPP6, GPC1, and CARTPT) and also measured Aβ42/Aβ40 and p-tau181 as traditional AD biomarkers.

How were MCI symptom onset and brain atrophy assessed?

Time to MCI symptom onset was analyzed using Cox regression. Long-term neurodegeneration was assessed by quantifying MRI atrophy with volumetric scans using SPARE-AD and SPARE-BA region composites in mixed-effect models.

What were the main findings about VGF and DPP6?

After accounting for covariates and baseline AD biomarker levels, higher baseline VGF and DPP6 were linked to lower risk of MCI symptom onset and less atrophy over time in AD-signature regions; VGF also showed less age-related atrophy.

Sep 30, 2026

Uploaded by Pentious