Cognitive decline is a consequence of various factors throughout life, including ageing, neurodegenerative diseases, and metabolic syndrome. However, it is unclear how these factors contribute to cognitive function due to their complex interplay at different levels of observation. Recent studies suggest that metabolic syndrome can cause synaptic insulin resistance and cognitive deficits, which, when combined with high amyloid load, increases the risk of Alzheimer’s disease (AD). Additionally, neuroinflammation may play a role, but the underlying mechanisms are still unknown (Ferreira et al., 2014). Recent evidence also indicates that synaptic insulin resistance is a central risk factor for accelerated cognitive decline and AD. However, social and lifestyle interventions such as physical exercise can help prevent this risk (De Felice et al., 2022). In the mechanistic view, basal forebrain cholinergic neurons in the medial septum are crucial modulators of learning and memory. They are high energy-demanding neurons, and it has been shown that they develop insulin resistance in mouse models of AD several months before it is detectable in the hippocampus (Sposato et al., 2019). Through collaboration within squad C, we aim to conduct translational research to bridge the gap between synaptic pathology and cognitive decline in ageing and AD.

Our project involves two study cohorts. The first one is the DELCODE study, which is a longitudinal multi-centre study that includes cognitively asymptomatic older individuals, subjective memory complainers, patients with mild cognitive impairment and early Alzheimer’s dementia. Our research within this cohort has revealed that impaired hippocampal novelty processing is linked to tau pathology but only in the presence of amyloid pathology (Düzel et al., 2022). We used CSF biomarkers and functional MRI in a large sample to elucidate this relationship. We also investigated glucose-PET in a subset of the cohort to assess metabolic dysfunction and synaptic insulin resistance (Jessen et al., 2022). Moreover, volumetric MR data on putatively cholinergic basal forebrain regions‘ atrophy are available (Teipel et al., 2022). We also established a method to disentangle the effects of amyloid and hypertension on cognition through white matter hyperintensities, revealing distinct associations with posterior and anterior white matter hyperintensities. The second cohort is the EnergI Trial, which is a prospective physical exercise intervention study involving 20 older adults with metabolic risk factors undergoing amyloid-PET imaging. Participants engage in a four-month physical intervention or serve as controls, with assessments measuring cognitive tasks tapping into hippocampal function, glucose metabolism via FDG-PET, and neurovascular plasticity in hippocampal regions using structural MRI, arterial spin labelling, and fMRI.

Project C3: Y. Suksangkharn, G. Ziegler

The motivation of the project is to disentangle the complexity of the cognitive decline caused by physiological ageing, neurodegenerative disease, and synaptic insulin resistance. This study intends to exploit the well-established study cohorts and imaging facilities to investigate the pathophysiology of cognitive decline mediated by synaptic insulin resistance on multiple facets, such as structural MRI, functional MRI, FDG-PET, vascular imaging, lifestyle factors, and exercise intervention. The proposed methodology involves the implementation of neuroimaging analysis, multivariate analysis, modelling, and machine learning to identify the factors associated with cognitive decline.

Find out more about the working group by clicking here.