Midlife obesity is a well-established risk factor for the development of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. The increasing proportion of obese people in our society thus likely contributes to the expected increase in AD cases over the coming decades with negative implications for our health care systems and ageing society. Consumption of a Western diet is a dominant factor for the development of obesity and a main cause of metaflammation. Our preliminary data show that systemic inflammation induced by Western diet feeding of mice induces microglial activation and promotes innate immune memory in microglial cells, the principal immune system of the brain. Microglial cell activation is known to play a crucial role in the development of cerebral pathology and behavioural deficits in murine models of beta-amyloid and tau pathology. In keeping with this, we demonstrated that inhibition of the microglial NLRP3 inflammasome protects from the development of pathological Alzheimer’s disease hallmarks as well as learning and memory deficits in APP/PS1dE9 and tau22 transgenic mice. Therefore, we propose to test whether Western diet-induced metaflammation is causally linked to AD pathogenesis by accelerating the spread of pathological proteins in the brain through activation of the NLRP3 inflammasome. Two different models of AD-like neurodegeneration will be tested: Western diet-mediated effects on spread of AD-like pathology: (I) Spreading of beta-amyloid pathology (injection of APP/PS1 brain lysate versus controls) in the hippocampus of APP/PS1 mice fed a chow diet, Western diet, or Western diet followed by chow diet. These experiments will test the hypothesis that Western diet-induced innate immune memory aggravates the beta-amyloid induced innate immune reaction and, thereby, (e.g., through ASC speck formation and pyroptosis) foster the aggregation and deposition of beta-amyloid or compromised microglial beta-amyloid clearance. (II) Tau spread in tau22 mice injected with APP/PS1 brain lysate versus controls: This will test the hypothesis that Western diet aggravates the beta-amyloid induced innate immune reaction and through the regulation of tau kinases and phosphatase PP2A the formation of neurofibrillary tangles in tau22 animals. The readout parameters will include the quantification of beta-amyloid and tau pathology, hippocampal learning and memory behaviour, biochemistry and central and peripheral innate immune profiling. On a functional level, we will assess microglial phenotypes by intravital 2PLSM and the microglial clearance capacity by the methoxy-XO4 assay. The charcterisationof the mutual interaction between microglia and neurons under conditions, such as obesity-induced metaflammation, will lead to the identification and development of specific neuroprotective strategies. We also seek to identify the intraneuronal pathomechanisms that are elicited by metaflammation-driven microglia activation. These studies could provide causal relationships between dietary patterns and susceptibility to AD pathology, which, in turn, should spark both future therapeutic interventions and the development of preventive as well as public health measures.