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

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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.