Fischer Larissa, Adams Jenna N, Molloy Eóin N, Vockert Niklas, Tremblay-Mercier Jennifer, Remz Jordana, Pichet Binette Alexa, Villeneuve Sylvia, Maass Anne
German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
Department of Neurobiology and Behavior, University of California, Irvine, USA.
Alzheimers Res Ther. 2025 Apr 25;17(1):91. doi: 10.1186/s13195-025-01742-6.
Both aging and Alzheimer's disease (AD) affect brain networks, with early disruptions occurring in regions involved in episodic memory. Few studies have, however, focused on distinguishing region-specific effects of AD-biomarker negative "normal" aging and early amyloid- and tau pathology on functional connectivity. Further, longitudinal studies combining imaging, biomarkers, and cognition are rare.
We assessed resting-state functional connectivity (rsFC) strength and graph measures in the episodic memory network including the medial temporal lobe (MTL), posteromedial cortex (PMC), and medial prefrontal cortex alongside cognition over two years. For this preregistered study, we included 100 older adults who were amyloid- and tau-negative using CSF and PET measurements to investigate "normal" aging, and 70 older adults who had longitudinal CSF data available to investigate functional changes related to early AD pathology. All participants were cognitively unimpaired older adults from the PREVENT-AD cohort. We used region of interest (ROI)-to-ROI bivariate correlations, graph analysis, and multiple regression models.
In the amyloid- and tau-negative sample, rsFC strength within PMC, between parahippocampal cortex and inferomedial precuneus, and between posterior hippocampus and inferomedial precuneus decreased over time. Additionally, we observed a longitudinal decrease in global efficiency. Further, there was a steeper longitudinal decrease in rsFC and global efficiency with higher baseline age particularly of parahippocampal-gyrus regions. Further, lower rsFC strength within PMC was associated with poorer longitudinal episodic memory performance. In the sample with available CSF data, a steeper increase in rsFC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher MTL-PMC rsFC strength was differentially associated with episodic memory trajectories depending on APOE4 genotype.
Our findings suggest differential effects of aging and AD pathology. Hypoconnectivity within PMC was related to aging and cognitive decline. MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. Future studies should investigate more diverse samples, nonetheless, our approach allowed us to identify longitudinal functional changes related to aging and early AD pathology, enhancing cross-sectional research. Hyperconnectivity has been proposed as a mechanism related to early AD pathology before, we now contribute specific functional connections to focus on in future research.
衰老和阿尔茨海默病（AD）都会影响脑网络，情景记忆相关区域会出现早期破坏。然而，很少有研究关注区分AD生物标志物阴性的“正常”衰老以及早期淀粉样蛋白和tau病理对功能连接的区域特异性影响。此外，结合成像、生物标志物和认知的纵向研究很少见。
我们评估了情景记忆网络（包括内侧颞叶（MTL）、后内侧皮质（PMC）和内侧前额叶皮质）的静息态功能连接（rsFC）强度和图谱指标，并在两年时间内监测了认知情况。在这项预先注册的研究中，我们纳入了100名使用脑脊液和PET测量显示淀粉样蛋白和tau阴性的老年人，以研究“正常”衰老；还纳入了70名有纵向脑脊液数据的老年人，以研究与早期AD病理相关的功能变化。所有参与者均为来自PREVENT-AD队列的认知未受损老年人。我们使用了感兴趣区域（ROI）到ROI的双变量相关性分析、图谱分析和多元回归模型。
在淀粉样蛋白和tau阴性样本中，PMC内、海马旁皮质与楔前叶下内侧之间以及海马后与楔前叶下内侧之间的rsFC强度随时间下降。此外，我们观察到全局效率呈纵向下降。此外，rsFC和全局效率的纵向下降在基线年龄较高时更明显，尤其是海马旁回区域。此外，PMC内较低的rsFC强度与较差的纵向情景记忆表现相关。在有脑脊液数据的样本中，海马前部与楔前叶上部之间rsFC的更陡峭增加与较高的基线AD病理相关。较高的MTL-PMC rsFC强度根据APOE4基因型与情景记忆轨迹存在差异关联。
我们的研究结果表明衰老和AD病理存在不同影响。PMC内的低连接性与衰老和认知衰退有关。MTL-PMC的高连接性与APOE4携带者的早期AD病理和认知衰退有关。未来的研究应该调查更多样化的样本，尽管如此，我们的方法使我们能够识别与衰老和早期AD病理相关的纵向功能变化，加强了横断面研究。高连接性之前已被提出是与早期AD病理相关的一种机制，我们现在为未来研究贡献了具体的功能连接以供关注。
