阿尔茨海默病(AD)由于其多因素性质,提出了复杂的挑战,病因知之甚少,晚检测。遗传的机制,影响AD易感性的固定和可改变的风险因素正在紧张的调查中,然而,独特的风险因素对大脑网络的影响很难理解,它们之间的相互作用尚不清楚。对包括APOE基因型在内的多个危险因素进行建模,年龄,性别,饮食,我们利用表达人类APOE和NOS2基因的小鼠,与小鼠Nos2相比,免疫反应降低。对加速扩散加权MRI得出的脑连接体进行图形分析,我们评估了无AD病理情况下危险因素的全球和局部影响.衰老和高脂肪饮食影响了包括AD脆弱地区的广泛网络,包括颞叶联合皮层,杏仁核,和水管周围的灰色,参与应激反应。受性别影响的网络,包括性二态区域(丘脑,脑岛,下丘脑)和关键记忆处理区域(菌毛,隔膜)。APOE基因型调节记忆中的连通性,感官,和运动区域,而饮食和免疫力都影响了脑岛和下丘脑。值得注意的是,这些风险因素集中在一个电路上,该电路包括54,946个总连接中的63个(占连接体的0.11%),强调对感觉统合至关重要的区域中多个AD风险因素之间的共同脆弱性,情绪调节,决策,电机协调,记忆,稳态,和内部感受。这些基于网络的生物标志物对区分临床前AD阶段的高风险和低风险参与者具有转化价值。建议电路作为潜在的治疗靶点,并提高我们对与AD风险相关的网络指纹的理解。
■目前对阿尔茨海默病(AD)的干预措施无法治愈,并在神经病变发病数年后分娩。解决风险因素对大脑网络的影响有望早期发现,预防,并在临床前阶段揭示推定的治疗目标。我们利用六个小鼠模型来研究因素的影响,包括APOE基因型,年龄,性别,豁免权,和饮食,在大脑网络上。大型结构连接体来源于高分辨率压缩感知扩散MRI。高度并行化的图分类识别出与独特风险因素相关的子网络,揭示了他们的网络指纹,和一个由63个连接组成的公共网络,对所有风险因素都有共同的脆弱性。APOE基因型特异性免疫特征支持针对风险概况定制的干预措施的设计。
Alzheimer\'s disease (AD) presents complex challenges due to its multifactorial nature, poorly understood etiology, and late detection. The mechanisms through which genetic, fixed and modifiable risk factors influence susceptibility to AD are under intense investigation, yet the impact of unique risk factors on brain networks is difficult to disentangle, and their interactions remain unclear. To model multiple risk factors including APOE genotype, age, sex, diet, and immunity we leveraged mice expressing the human APOE and NOS2 genes, conferring a reduced immune response compared to mouse Nos2. Employing graph analyses of brain connectomes derived from accelerated diffusion-weighted MRI, we assessed the global and local impact of risk factors in the absence of AD pathology. Aging and a high-fat diet impacted extensive networks comprising AD-vulnerable regions, including the temporal association cortex, amygdala, and the periaqueductal gray, involved in stress responses. Sex impacted networks including sexually dimorphic regions (thalamus, insula, hypothalamus) and key memory-processing areas (fimbria, septum). APOE genotypes modulated connectivity in memory, sensory, and motor regions, while diet and immunity both impacted the insula and hypothalamus. Notably, these risk factors converged on a circuit comprising 63 of 54,946 total connections (0.11% of the connectome), highlighting shared vulnerability amongst multiple AD risk factors in regions essential for sensory integration, emotional regulation, decision making, motor coordination, memory, homeostasis, and interoception. These network-based biomarkers hold translational value for distinguishing high-risk versus low-risk participants at preclinical AD stages, suggest circuits as potential therapeutic targets, and advance our understanding of network fingerprints associated with AD risk.
UNASSIGNED: Current interventions for Alzheimer\'s disease (AD) do not provide a cure, and are delivered years after neuropathological onset. Addressing the impact of risk factors on brain networks holds promises for early detection, prevention, and revealing putative therapeutic targets at preclinical stages. We utilized six mouse models to investigate the impact of factors, including APOE genotype, age, sex, immunity, and diet, on brain networks. Large structural connectomes were derived from high resolution compressed sensing diffusion MRI. A highly parallelized graph classification identified subnetworks associated with unique risk factors, revealing their network fingerprints, and a common network composed of 63 connections with shared vulnerability to all risk factors. APOE genotype specific immune signatures support the design of interventions tailored to risk profiles.