Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

Abstract

Background and objectives: To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally.

Methods: In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time.

Results: This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (n_CU- = 197); CU Aβ-positive (n_CU+ = 55), mild cognitively impaired (MCI) Aβ-negative (n_MCI- = 228), MCI Aβ-positive (n_MCI+ = 193), and AD dementia Aβ-positive (n_AD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (p = 0.01), worse brain atrophy (p = 8.8 × 10^-27), and worse MMSE scores (p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, p = 1.5 × 10^-14]). Despite the significant association with Aβ pathology (η² _{Aβ PET} = 0.09, P _{Aβ PET} < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η² _pTau-181 = 0.53, P _pTau-181 < 0.001; η² _tTau = 0.59, P _tTau < 0.001).

Discussion: High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.