University of Southern California, Leonard Davis School of Gerontology, Los Angeles, CA, USA.
Department of Psychological Science, University of California, Irvine, Irvine, CA, USA.
Alzheimers Res Ther. 2024 Jun 8;16(1):124. doi: 10.1186/s13195-024-01486-9.
Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults.
Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aβ, Aβ), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed.
All autonomic networks were positively associated with Aβ ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected.
The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aβ, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.
自主功能的高级调节由特定皮质和皮质下脑区的协调活动维持，这些脑区统称为中枢自主神经网络（CAN）。在阿尔茨海默病（AD）和痴呆症中经常观察到自主变化，但迄今为止尚无研究调查血浆 AD 生物标志物是否与高危老年人的 CAN 功能连接变化相关。
从社区招募无重大神经或精神疾病的独立生活老年人（N=122）。参与者接受静息状态脑 fMRI 检查，并使用 CONN 功能工具包应用基于体素的荟萃分析获得的 CAN 网络，用于整体、交感和副交感 CAN 连接。研究感觉运动网络连接作为负对照。使用数字免疫测定法评估血浆中淀粉样蛋白（Aβ，Aβ）、神经丝轻链（NfL）和神经胶质纤维酸性蛋白（GFAP）的水平。使用多元线性回归，根据人口统计学协变量和载脂蛋白 E（APOE）基因型调整血浆 AD 生物标志物与网络内功能连接的关系。还评估了与 APOE4 携带者状态的交互作用。
所有自主网络均与 Aβ 比值呈正相关，并且在调整年龄、性别和 APOE4 携带者状态后仍然如此。整体和副交感网络与 GFAP 呈负相关。副交感 CAN 与 GFAP 之间的关系受 APOE4 携带者状态调节，其中副交感 CAN 连接性低的 APOE4 携带者显示出最高的血浆 GFAP 浓度（B=910.00，P=0.004）。如预期的那样，感觉运动连接性与任何血浆 AD 生物标志物均无关。
本研究结果表明，CAN 功能与血浆 AD 生物标志物水平相关。具体来说，CAN 功能连接性降低与血浆 Aβ 降低有关，提示存在脑淀粉样变，并且 APOE4 携带者的血浆 GFAP 升高，这些携带者处于 AD 的高危状态。这些发现可能表明在 AD 的早期阶段存在更高阶的自主和副交感神经功能障碍，这可能具有临床意义。
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