AUTHOR=Li Yaxin , Xu Xuanming , Tang Lian ,  on behalf of the Alzheimer’s Disease Neuroimaging Initiative 

TITLE=GAP-43 is associated with faster amyloid-associated neurodegeneration and cognitive decline in Alzheimer’s disease

JOURNAL=Frontiers in Neurology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1629389

DOI=10.3389/fneur.2025.1629389

ISSN=1664-2295

ABSTRACT=BackgroundIt has been proposed that amyloid-β (Aβ) deposition may trigger neurodegeneration and cognitive decline. The elevated levels of presynaptic growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) were significantly associated with Alzheimer’s disease (AD). To examine whether GAP-43 was associated with faster amyloid-associated neurodegeneration or cognitive decline, it was necessary to further explore whether Aβ deposition affected CSF GAP-43 through inflammation.MethodsA total of 671 participants from Alzheimer’s Disease Neuroimaging Initiative (ADNI) were enrolled with available baseline CSF GAP-43, microglia activation [measured by CSF soluble triggering receptor expressed on myeloid cells (sTREM2) and progranulin (PGRN)], neurodegeneration (measured by CSF t-tau), and Aβ pathology (measured by amyloid-PET). To compare CSF GAP-43 levels across different Aβ and clinical stages, the analysis of variance (ANOVA) and Bonferroni post hoc tests were conducted. Multiple linear regression models were used to explore the association of CSF GAP-43 with sTREM2, PGRN, amyloid-PET, p-tau, t-tau and cognitive measures at baseline. Moreover, mediation models with 10,000 bootstrapped iterations were performed to investigate whether CSF GAP-43 was related to accelerated amyloid-associated neurodegeneration, then further contribute to cognitive decline, and how Aβ deposition affected CSF GAP-43 leading to neurodegeneration.ResultsCompared with the amyloid− (A−) group, CSF GAP-43 was significantly higher at baseline in the amyloid+ (A+) group. When stratified by diagnosis, similar results were observed in A+ cognitively normal (CN) and A+ mild cognitive impairment (MCI), compared with A−CN or A−MCI participants. We found that baseline of CSF GAP-43 was positively related to CSF sTREM2, PGRN, amyloid-PET and t-tau, whereas it was negatively associated with cognition. Besides, CSF GAP-43 mediated the faster progression of amyloid-associated neurodegeneration and cognitive decline. Furthermore, the mediation analysis revealed that CSF sTREM2/PGRN was related to CSF t-tau mediated by CSF GAP-43 in the A+ group.ConclusionOur findings provided evidence that CSF GAP-43 was related to the accelerated amyloid-associated neurodegeneration, and further contributed to cognitive decline. We also demonstrated that Aβ deposition may act as a trigger for synaptic dysfunction by promoting inflammation.