Association of APOE-4 and GAP-43-related presynaptic loss with -amyloid, tau, neurodegeneration, and cognitive decline

Apolipoprotein E-epsilon 4 (APOE-e4) 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-e4 genotype affects the baseline and longitudinal changes in CSF GAP-43 and their associations with beta-amyloid positron emission tomography (A beta PET), CSF phosphorylated tau 181 (p-Tau181), neurode-generation, and cognitive decline. Compared to APOE-e4 non-carriers, APOE-e4 carriers had higher baseline levels and faster rates of increases in A beta 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 A beta PET and CSF p-Tau181, which fully mediated the APOE-e4 effect on CSF GAP-43 elevations. Independent of A beta PET and CSF p-Tau181, APOE-e4 carriage was associated with exacerbated GAP-43-related longitudinal hippocampal atrophy and cognitive decline, especially in A beta+ participants (GAP-43 x time x APOE-e4). These findings suggest that the APOE-e4 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.(c) 2023 Elsevier Inc. All rights reserved.