Amyloid accumulation in Alzheimer’s disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD (App^NL-G-F/hMapt), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923/ALX001) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.

阿尔茨海默病 （AD） 中的淀粉样蛋白积累与突触损伤和脑网络连接改变有关。虽然小鼠模型中淀粉样蛋白积累和生化变化的测量可用于某些疗法的转化研究，但对于旨在改善神经网络的药物，使用临床相关的 fMRI 测量对改变的大脑连接进行临床前分析尚未得到很好的开发。在这里，我们在 AD 的双敲入小鼠模型 （App^NL-G-F/hMapt） 中进行了纵向研究，通过静息态 fMRI 监测大脑连接。虽然 4 个月大的 AD 小鼠与野生型对照 （WT） 无法区分，但相对于 WT 小鼠，默认模式网络中连接性降低对 AD 小鼠在 6 个月大时是显着的，并且在 9 个月大时很明显。在第二组 20 个月大的小鼠中，相对于 WT 具有持续的 AD 功能连接缺陷，我们评估了使用已知可挽救突触密度的 mGluR5 （BMS-984923/ALX001） 的无声变构调节剂口服治疗两个月的影响。老年 AD 小鼠的功能连接缺陷通过 mGluR5 定向治疗逆转。fMRI 的纵向应用使我们能够定义 AD 相关功能连接变化的临床前时间轨迹，并展示了用于监测疾病出现、进展和对突触挽救治疗的反应的可转化指标。