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

Yaxin Li^1*Xuanming Xu²Liang Tang²

• ¹Nantong University, Nantong, China
• ²Capital medical university, beijing, China

Background: It 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 A β deposition affected CSF GAP-43 through inflammation. Methods: A 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 2 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. Results: Compared 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. Conclusion: Our 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.