Impact of vascular burden on preclinical Alzheimer’s disease pathology and identification of potential interventional targets

阿尔茨海默病是一个日益严重的全球性挑战，由于人口老龄化和有限的治疗成功而导致患病率增加。目前，有效的非药理学方法的搜索，因为递质替代疗法提供了没有有效的修改的疾病过程。阿尔茨海默病的病理生理过程在临床症状出现之前二十多年就开始了。这一临床前阶段被认为是有效的疾病修饰疗法或预防策略的最合适的时间窗口，因为不可逆的大脑和认知变化仍然是可以预防的。血管因素，如高血压，血脂异常，糖尿病，肥胖和吸烟，是确定的风险因素的发展阿尔茨海默氏病在临床水平;然而，血管风险因素和基础疾病病理之间的关系仍有待充分阐明。为了更好地了解血管危险因素增加阿尔茨海默病风险的机制，我们提出了一项多模式横断面研究，招募基于家族史和部分主观认知问题的阿尔茨海默病风险较高的无症状老年人。我们将利用加拿大蒙特利尔道格拉斯医院研究中心StoP-AD中心的预防AD队列，该队列由300多名认知正常的阿尔茨海默病痴呆高危个体组成。首先，将使用正电子发射断层扫描在体内同时研究可改变的血管危险因素对阿尔茨海默病病理标志淀粉样蛋白和tau蛋白的影响。识别反映血管危险因素对疾病病理的影响的特征拓扑模式旨在更好地理解阿尔茨海默病临床前阶段的疾病表达。在第二步中，我们将研究血管危险因素和淀粉样蛋白-β/ tau之间的相互作用是否调节大脑结构和认知能力下降，这可能是阿尔茨海默病风险较高的基础。因此，将使用标准神经心理学成套测试评估个体认知能力，并使用3特斯拉磁共振成像，通过脑容量测定、皮质厚度测量和弥散张量分析评价脑完整性。最后，它将被探索，如果一个潜在的有益影响，更高的终身体力活动可以缓冲血管危险因素对早期阿尔茨海默病病理的负面影响。该研究项目的总体目标是确定可能延迟甚至预防疾病发作的新策略。

Alzheimer’s disease poses a growing global challenge with an increasing prevalence caused by the aging population and the limited treatment success. Currently, effective non-pharmacological approaches are searched, since transmitter replacement therapies provide no efficient modification of the disease course. The pathophysiological process of Alzheimer’s disease begins more than two decades prior to the manifestation of clinical symptoms. This preclinical phase is considered as the most appropriate time window for effective disease-modifying therapies or prevention strategies, as irreversible brain and cognitive changes might still be preventable. Vascular factors, such as hypertension, dyslipidemia, diabetes, obesity and smoking, are established risk factors for the development of Alzheimer’s disease at the clinical level; however, the relationship between vascular risk factors and the underlying disease pathology remains to be fully elucidated. To better understand the mechanisms by which vascular risk factors increase the risk of Alzheimer’s disease, we propose a multimodal cross-sectional study enrolling asymptomatic older adults with a higher risk for Alzheimer’s disease based on family history and in part subjective cognitive concerns. We will make use of the PREVENT-AD cohort, consisting of more than 300 cognitively normal individuals at high risk of Alzheimer’s disease dementia, of the StoP-AD Center at the Douglas Hospital Research Center in Montréal, Canada. First, the impact of modifiable vascular risk factors on both Alzheimer’s disease pathological hallmarks amyloid-ß and tau will be studied simultaneously in vivo, using positron emission tomography. The identification of characteristic topological patterns that mirror the influence of vascular risk factors on disease pathologies is aimed to provide a better understanding of disease expression in the preclinical stage of Alzheimer’s disease. In a second step, we will investigate whether an interaction between vascular risk factors and amyloid-ß/ tau modulate brain structural and cognitive decline that could underlie the higher risk of Alzheimer’s disease. Therefore, individual cognitive performance will be assessed with a standard neuropsychological test battery and brain integrity will be evaluated via brain volumetry, cortical thickness measurements and diffusion-tensor analyses, using 3-Tesla magnetic resonance imaging. Finally, it will be explored, if a potential beneficial effect of higher lifetime physical activity can buffer the negative effect of vascular risk factors on early Alzheimer’s disease pathology. The overall goal of this research project is to identify novel strategies that may delay or even prevent the onset of the disease.