Background: Targeting multiple risk factors through preventive interventions can halt the onset or progression of dementia. The clinical efficacy of this approach was shown in the multimodal FINGER trial, yet knowledge of the underlying biological mechanisms is limited. In the current study, we applied for the first time a multimodal lifestyle intervention in mice to study effects on cognition and associated molecular pathways. Methods: We have established a novel experimental model, the lifestyle intervention PAW (Prevention of Alzheimer's by a Multimodal Lifestyle Protocol - Working-mechanisms for Memory Gains) in mice. In this model, we combined different modalities of intervention aiming to achieve synergistic effects. The animals were given access to running wheels (voluntary exercise), Fortasyn Connect (a medical food that slows disease progression in early Alzheimer's disease), and they were subjected to cognitive training in an IntelliCage environment (PAW group). To separately investigate the effects of pharmacological vascular management as a preventive measure, another group of mice was given Atorvastatin and Enalapril (cholesterol and blood pressure lowering pharmaceuticals, respectively) dosed in the diet (Pharma group). Control mice were housed in normal conditions. We included 12 wild type C57BL/6J female mice 6.5 months of age per group. The full intervention lasted for 8 weeks. Blood pressure was measured at baseline and the end of the intervention. All mice underwent a battery of behavioural testing after the eight weeks of intervention. Hippocampi were dissected for proteomics analysis. Results: During the intervention, the PAW group actively participated in the intervention by learning the different cognitive training programs and by using the running wheels. At the end of the intervention, the PAW group showed a lowering of blood pressure to a similar extent as in the Pharma group (systolic 158 mmHg to 139 mmHg, p = 0.003, and 163 mmHg to 136 mmHg, p = 0.042, respectively). Furthermore, the PAW group displayed a better short-term spatial working memory compared to the control group as assessed by the spontaneous alternation in the Y maze test (66.5% and 56.7%, respectively, p = 0.036). Proteomic analysis of the hippocampi and downstream bioinformatic analysis revealed that several pathways were upregulated in the PAW mice including synaptogenesis (Z = 4.27, p = 1.26E-18) and glutamate binding, activation of AMPA receptors and synaptic plasticity (Z = 3.74, p = 3.16E-19). Conclusions: Our findings suggest that the PAW model effectively mimics the clinical effects of multimodal lifestyle dementia prevention, and further demonstrates the activation of hippocampal-specific molecular drivers of memory gains.
