Association of APOE-ε4 and GAP-43-related presynaptic loss with β-amyloid, tau, neurodegeneration, and cognitive decline

Abstract

Apolipoprotein E-ε4 (APOE-ε4) carriers had elevated cerebrospinal fluid (CSF) presynaptic protein growth-associated protein-43 (GAP-43), but the underlying mechanism is not fully understood. We investigated how the APOE-ε4 genotype affects the baseline and longitudinal changes in CSF GAP-43 and their associations with β-amyloid positron emission tomography (Aβ PET), CSF phosphorylated tau 181 (p-Tau₁₈₁), neurodegeneration, and cognitive decline. Compared to APOE-ε4 non-carriers, APOE-ε4 carriers had higher baseline levels and faster rates of increases in Aβ PET, CSF p-Tau₁₈₁, and CSF GAP-43. Both higher baseline levels and faster rates of increase in CSF GAP-43 were associated with greater baseline Aβ PET and CSF p-Tau₁₈₁, which fully mediated the APOE-ε4 effect on CSF GAP-43 elevations. Independent of Aβ PET and CSF p-Tau₁₈₁, APOE-ε4 carriage was associated with exacerbated GAP-43-related longitudinal hippocampal atrophy and cognitive decline, especially in Aβ+ participants (GAP-43 × time × APOE-ε4). These findings suggest that the APOE-ε4 effect on GAP-43-related presynaptic dysfunction is mediated by primary Alzheimer's pathologies and independently correlates to hippocampal atrophy and cognitive decline in the future.

Keywords: Alzheimer’s disease; Apolipoprotein E; Cognition; Growth-associated protein-43; Neurodegeneration; Presynaptic loss.