Thesis defense Maximilian Wiesmann (Donders series 268)

16 March 2017

Promotor: prof. dr. A. Heerschap, Copromotors: dr. A. Kiliaan, dr. J. Claassen

Vascular risk factors and Alzheimer’s disease. Therapeutic approaches in mouse models

The first aim of this thesis was to elucidate the impact of major vascular risk factors like hypertension, apoE4 and stroke during the very early phase of Alzheimer’s disease (AD) using several mice models. Hypertension has proven to be associated with cerebrovascular impairment already at young age in AD model mice leading to reductions in structural and functional connectivity accompanied by an impaired cognition. Notably, aged AD mice developed an increased systolic blood pressure (SBP) concomitant with several AD-like pathological changes, like impairment in cerebral hemodynamics resulting in an impaired cognition, structural and functional connectivity, increased locomotor activity, and anxiety-related behavior without induced hypertension. Notably, also in aged transgenic apoE4 mice an impaired cerebrovascular circulation, reduced cortical post-synaptic density, lowered white and gray matter integrity in white matter tracts, and a lowered functional connectivity (FC) were detected. In conclusion, the (vascular) risk factors being present or induced in our mouse models have proven to be involved in the very early development of neurodegenerative processes in AD. Another aim of this thesis was to reveal the possible capacity of antihypertensives and specific multi-nutrient diets to serve as preventive or treatment against AD-like symptoms and vascular risk factors for AD. Furthermore, we showed that antihypertensives have beneficial effects on pathological processes of AD like counteracting the impaired cerebral blood flow, and the reduced structural and functional connectivity. Therefore, it is important to improve development of more effective tailor-made blood pressure-lowering treatments for AD patients and to increase awareness for hypertension as a risk factor for AD. Furthermore, we demonstrated the value of a multi-modal approach, including advanced MR neuroimaging tools, for detecting changes in brain structure and function with respect to dietary intervention. The investigated multicomponent diet showed several beneficial effects as preventive but also as therapeutic approach on pathological alterations in mouse models for (vascular) risk factors for AD. Future studies should therefore focus on optimization of multicomponent combinations comprising dietary components of the Mediterranean diet to improve clinical outcome after a stroke to lower the incidence of stroke accompanied by a reduction of the incidence of dementia. Therefore, future research should focus on preventive/ therapeutic approaches using personalized multinutrient dietary approaches targeting pathological processes of dementia. Future studies should evaluate a mixed preventive approach containing cognitive and physical exercise, in combination with a personalized multicomponent diet during the very early phases of AD.