Trelle Alexandra N, Sheng Jintao, Wilson Edward N, Romero America, Park Jennifer, Deutsch Gayle K, Sha Sharon J, Greicius Michael D, Andreasson Katrin I, Kerchner Geoffrey A, Mormino Elizabeth C, Wagner Anthony D
bioRxiv. 2025 Jun 25:2025.06.20.660774. doi: 10.1101/2025.06.20.660774.
Amyloid-β (Aβ) and tau pathology begin accumulating decades before clinical symptoms and are influenced by ε4, a key genetic risk factor for Alzheimer's disease (AD). Although the presence of Aβ, tau, and ε4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9±5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. Aβ was measured using CSF Aβ /Aβ or Florbetaben-PET imaging and tau was measured using CSF pTau . Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that ε4 was independently associated with greater Aβ and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by ε4. Among ε4 non-carriers, Aβ burden was linked to a pattern of hippocampal hyperactivity. Among ε4 carriers, CSF pTau was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of ε4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD.
Hippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimer's disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by ε4 in cognitively unimpaired older adults. Amyloid-β-related hyperactivity was observed in the hippocampus among ε4 non-carriers, while CSF pTau was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among ε4 carriers. Our findings highlight synergistic effects of and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.
淀粉样蛋白-β（Aβ）和tau病理变化在临床症状出现前数十年就开始累积，并受ε4影响，ε4是阿尔茨海默病（AD）的关键遗传风险因素。尽管Aβ、tau和ε4的存在被认为会影响脑功能，但它们对临床前AD情景记忆提取的神经关联的影响仍不清楚。我们在斯坦福衰老与记忆研究中对159名认知未受损的老年人（平均年龄68.9±5.8岁；57%为女性）进行了此项研究。参与者在功能磁共振成像（fMRI）的同时完成一项联想记忆任务。使用脑脊液Aβ42/Aβ40或氟比他班正电子发射断层扫描（PET）成像测量Aβ，使用脑脊液磷酸化tau181（pTau181）测量tau。在成功的记忆提取过程中，测量海马单变量活动和皮质恢复，即恢复记忆编码期间出现的新皮质活动模式。分析显示，ε4与更高的Aβ和tau负荷独立相关，并且AD生物标志物与脑功能和记忆的关联受ε4调节。在ε4非携带者中，Aβ负荷与海马过度活跃模式相关。在ε4携带者中，脑脊液pTau181与记忆提取期间较弱的皮质恢复以及较低的记忆表现相关。因此，异常的AD生物标志物和遗传风险协同影响临床前AD中记忆的神经和行为表现。这些发现突出了ε4在调节AD病理对脑功能影响中的关键作用，并确定了可能导致临床前AD记忆障碍风险增加的潜在机制。
依赖海马的皮质恢复是支持情景记忆的关键机制，它导致老年人记忆表现的个体差异。然而，早期阿尔茨海默病（AD）病理对该机制变异性的贡献尚不清楚。我们证明，在认知未受损的老年人中，AD生物标志物与海马活动和皮质恢复的关联受ε4调节。在ε4非携带者中，海马中观察到与Aβ相关的过度活跃，而在ε4携带者中，脑脊液pTau181与记忆提取期间较弱的皮质恢复以及较低的记忆表现相关。我们的发现突出了ε4和AD病理对脑功能的协同作用，并确定了可能是临床前AD记忆障碍风险增加基础的潜在机制。
