Data_Sheet_1_Absolute Winding Number Differentiates Mouse Spatial Navigation Strategies With Genetic Risk for Alzheimer’s Disease.docx

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer’s disease, and even in cognitively normal individuals at risk for Alzheimer’s disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer’s disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer’s disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer’s disease.

空间导航与定位已成为评估早期阿尔茨海默病认知改变的有力标志，甚至在认知正常的阿尔茨海默病风险人群中亦然。不同的APOE基因等位基因赋予不同程度的患病风险。APOE2等位基因被认为具有保护作用，APOE3被视为对照组，而携带APOE4等位基因则是已知的阿尔茨海默病主要遗传风险因素。本研究采用了携带三种人类化APOE等位基因的鼠模型，并在Morris水迷宫中对其空间记忆能力进行了测试。我们引入了一个新的指标，即绝对回转数，用以描述通过游泳路径的形状来表征空间搜索策略。研究表明，这一指标对噪声具有鲁棒性，适用于小样本群体。此外，绝对回转数在区分APOE3携带者方面表现更佳，其游泳路径相对于APOE2和APOE4基因型更为直接。最终，这一新颖的指标揭示了APOE4雌性个体更高的易感性。我们推测，空间记忆和导航策略的差异与大脑网络的差异有关，并发现不同基因型对海马体和尾状核皮层回路的不同依赖性，这指向了白质连接在其中的作用。此外，这些差异在雌性中尤为显著。这种从以海马体为中心转向大脑网络的方法，或许能为识别与阿尔茨海默病高风险相关的区域开辟新的途径，从而在疾病明显表现之前识别出来。进一步探索基于空间导航策略的新生物标志物，可能扩大干预的机会窗口。所提出的框架对于剖析与早期阿尔茨海默病认知变化相关的易感回路具有重要意义。