Brain Imaging Behav. 2026 Jul 23;20(4):112. doi: 10.1007/s11682-026-01181-3.
ABSTRACT
Growth-associated protein 43 (GAP-43), a synaptic protein involved in neuronal plasticity, has emerged as a potential biomarker for Alzheimer’s disease (AD) and mild cognitive impairment (MCI), with elevated levels linked to synaptic dysfunction. This dysfunction, in turn, has been associated with reduced cerebral glucose metabolism, which further exacerbates cognitive decline and accelerates disease progression. However, the link between CSF GAP-43 and cerebral glucose metabolism, measured by FDG-PET, remains less understood. This study aimed to investigate the relationship between CSF GAP-43 levels, cerebral glucose metabolism, and cognitive performance across different stages of cognitive impairment, specifically in individuals with AD (n = 83), MCI (n = 370), and cognitively normal (CN; n = 215). Cognitive function was assessed using the ADAS-Cog 13 scale, CSF GAP-43 levels were measured via ELISA, and cerebral glucose metabolism was analyzed with FDG-PET. The results showed that CSF GAP-43 levels were significantly elevated in the AD group compared to the CN and MCI groups (p < 0.001). In the MCI group, there was a modest but statistically significant negative association between CSF GAP-43 levels and cerebral glucose metabolism (β = -0.126, FDR p = 0.003), whereas this association was not significant in the CN (β = -0.031, FDR p = 0.612) or AD groups (β = 0.157, FDR p = 0.584). Mediation analysis, adjusted for age, sex, education, and APOE ε4 carrier status, showed that FDG-PET cerebral glucose metabolism partly and statistically mediated the association between CSF GAP-43 and cognitive performance only in the MCI group (β = 0.047, FDR-adjusted p = 0.009). These findings indicate that higher CSF GAP-43 was associated with lower cerebral glucose metabolism, which in turn was associated with worse cognitive performance in MCI. However, because of limitations, cross-sectional design, and modest magnitude of the effects, these results should be interpreted as statistical associations rather than evidence that CSF GAP-43 impairs glucose metabolism or cognition.
PMID:42489996 | DOI:10.1007/s11682-026-01181-3
