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Associations of cerebrospinal fluid measures of synaptic function with white matter microstructure and cognition in older adults

Year: 2026

Type: article

Abstract: Introduction Lower levels of several synaptic proteins in cerebrospinal fluid (CSF) have been associated with greater cognitive decline among older adults, but there is limited understanding of their associations with brain structure. This study is among the first to examine the cross-sectional relationship between levels of three synaptic proteins (VGF, NPTX2, and GluA4) with magnetic resonance imaging (MRI) measures of white matter microstructure and volumes, and with cognitive performance. We also examined whether relationships between synaptic protein levels and white matter measures are influenced by CSF Alzheimer’s disease (AD) biomarker levels [ratio of p-tau 181 /(Aβ 42 /Aβ 40 )]. Methods Participants included 151 middle-aged and older adults without dementia (132 cognitively unimpaired, 19 mild cognitive impairment, M age = 69.3 years). White matter volumes and microstructure [fractional anisotropy (FA), mean diffusivity (MD)], derived from MRI scans, were assessed in three regions: global cerebral, medial temporal lobe, and cerebellar peduncles. Results In linear regression analyses, lower levels of NPTX2, VGF, and GluA4 were associated with lower FA and higher MD, even after accounting for CSF AD biomarker levels. Synaptic proteins were not associated with white matter volumes. Additionally, lower FA, higher MD, and lower VGF levels were associated with poorer executive function performance. An exploratory mediation analysis showed that cerebral white matter MD statistically mediated the relationship between VGF and executive performance. Discussion These findings provide preliminary, cross-sectional support that VGF may act on cognition via white matter microstructure. Together the results suggest that white matter microstructure may represent one pathway linking synaptic proteins levels to cognitive performance among older adults. Future research is needed to advance understanding of the specific mechanisms driving these relationships.

Source: Frontiers in Aging Neuroscience

DOI: 10.3389/fnagi.2026.1851829