Institute of Biomedical Engineering, Shenzhen Bay Laboratory, Shenzhen, China.
Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China.
Neurobiol Aging. 2023 Dec;132:209-219. doi: 10.1016/j.neurobiolaging.2023.09.012. Epub 2023 Sep 23.
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-Tau), 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-Tau, 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-Tau, which fully mediated the APOE-ε4 effect on CSF GAP-43 elevations. Independent of Aβ PET and CSF p-Tau, 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.
载脂蛋白 E-ε4 (APOE-ε4) 携带者的脑脊液 (CSF) 突触前蛋白生长相关蛋白-43 (GAP-43) 水平升高，但其潜在机制尚不完全清楚。我们研究了 APOE-ε4 基因型如何影响 CSF GAP-43 的基线和纵向变化，以及它们与β-淀粉样蛋白正电子发射断层扫描 (Aβ PET)、CSF 磷酸化tau181(p-Tau)、神经退行性变和认知能力下降的关系。与 APOE-ε4 非携带者相比，APOE-ε4 携带者的 CSF GAP-43 基线水平更高，Aβ PET、CSF p-Tau 和 CSF GAP-43 的增长率也更快。CSF GAP-43 的基线水平较高和增长率较快均与 Aβ PET 和 CSF p-Tau 的基线水平更高有关，这完全介导了 APOE-ε4 对 CSF GAP-43 升高的影响。与 Aβ PET 和 CSF p-Tau 无关，APOE-ε4 携带与 GAP-43 相关的纵向海马萎缩和认知能力下降加剧有关，尤其是在 Aβ+ 参与者中（GAP-43×时间×APOE-ε4）。这些发现表明，APOE-ε4 对 GAP-43 相关突触前功能障碍的影响是由主要的阿尔茨海默病病理介导的，并且与未来的海马萎缩和认知能力下降独立相关。
