We investigate those factors that drive the progression of brain pathologies or confer cognitive resilience in Alzheimer’s disease (AD). To this end, we use neuroimaging based functional connectomics, genetics, and biofluid analyses. A major focus is the MRI-based functional network mapping to predict the progression of key AD pathologies. Other major foci include the identification of genetic modulating factors of tau and the role of myelin changes in the development of AD.
Functional connectome & progression of tau pathology
Neurofibrillar tangles are the single most important drivers of neurodegeneration and cognitive decline in AD. The tau-bearing tangle deposits progress in spatiotemporally distinct patterns in the brain, but which factors shape that spatial distribution is unclear. Based on joined resting-state fMRI connectivity and tau PET analysis, we found that fibrillar tau accumulation progresses from initial epicenters of high tau to those brain areas that are most closely connected to the epicenter (Franzmeier et al. 10.1126/sciadv.abd1327; & 10.1038/s41467-022-28896-3). Our approach allows to predict the progression of tau accumulation at the patient-level, thus providing an important step towards precision medicine.
Modulating factors of tau progression
We recently set forth a comprehensive framework for modeling the susceptibility to develop tau pathology (Vogel et al. doi: 10.1038/s41583-023-00731-8). In addition to axonal connections as pathways for tau spreading in the brain, other factors including molecular tissue properties such as gene expression and presence of co-pathology may drive tau pathology (figure). In accordance with that framework, we recently found that combining connectomics with both regional brain expression of MAPT, i.e. the gene that encodes tau, and elevated local levels of amyloid-PET deposition substantially improved the accuracy to predict tau PET levels (Zheng et al. doi: 10.1002/ana.26818). Furthermore, we identified those AD-risk SNPs that are associated with higher fibrillar tau deposition, such as SNPs in BIN1 (Franzmeier et al., doi: 10.1002/alz.12371) and Klotho (Neitzel et al. DOI: 10.1038/s41467-021-23755-z). By employing gene set enrichment analyses and creating polygenic risk scores (Rubinski et al. 10.1002/ana.26588), we aim to understand which biological pathways interact with different types of AD pathologies during the course of the disease.
Fig. 4 | The next generation of connectome-based approaches to model tau: Integrating dynamic brain changes over time and factors of tissue vulnerability. (adopted from Vogel et al. doi: 10.1038/s41583-023-00731-8).
Myelin changes in AD: A role in the etiology of amyloid and tau pathology?
Myelin enwraps the axons in the brain and enables the fast signal transduction between distant brain regions. Recent single cell transcriptomic studies revealed myelin-producing oligodendrocytes as a major cell type that undergoes dramatic changes in AD. However, the causes and effects of myelin changes in the cascade of AD pathologies are poorly understood. We recently found that those regions that are typically lower myelinated in the human brain are more susceptible to develop tau pathology in AD (Rubinski et al. 10.1186/s13195-022-01074-9). Furthermore, a decrease in myelin was predictive of higher rates of tau accumulation in patients with AD (Rubinski et al. 10.1007/s00259-023-06530-8). Together, these findings suggest that reduced myelin is not only a marked brain alteration in AD, but also worsens the progression of AD. Using advanced MRI methods that are highly sensitive and specific to myelin, we are currently investigating how myelin track and interact with amyloid and tau pathology during the course of AD.
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Michael Ewers, Prof. Dr. / PI
Ying Luan, PhD (post-doc)
I obtained my Bachelor degree from Southeast University in China in 2015. Afterwards, I was enrolled in a Master and PhD program in Medical Imaging and Nuclear Medicine at Southeast U, focusing on the hearing loss-related cognitive decline. In September 2019, I joined Michael Ewers’ group as a joint PhD student supported by the Chinese Scholarship Council (CSC)/LMU scholarship. I am currently pursuing post-doctoral work at the Ewers Lab and work as a radiologist. I have a strong interest in the neuroimaging in Alzheimer’s disease, particularly in functional network mapping of tau accumulation and domain-specific cognitive impairment in Alzheimer’s disease. In my spare time, I like travelling and cooking.
Lukai Zheng, PhD student
I grew up in China and studied medicine at West China School of Medicine, Sichuan University (graduated in 2017). After that, I completed my master’s in Neurology at the same university (2020), with a focus on hemorrhagic transformation after ischemic stroke. In October 2020, with a scholarship from the China Scholarship Council, I joined the group of Ewers as a PhD student. My current work focuses on modelling tau pathology progression in Alzheimer’s disease with PET images and brain transcriptome.
Jannis Denecke, PhD student
Following a bachelor’s degree in Psychology, I pursued a master’s degree in Psychology as well as Social and Economic Data Science both at the University of Konstanz. I joined Michael Ewers’ group and the Graduate School of Systemic Neurosciences to follow up with a PhD focusing on brain mechanisms that underlie cognitive resilience in neurodegenerative diseases. Furthermore, I am professionally interested in research methods, network analysis, statistics, and computational modeling. My private interests include photography, cooking, and board games.
Carolina Valentim, PhD student
I am a PhD student from Lisbon, Portugal. I hold a Bachelor's degree in Psychology and a Master's in Clinical and Experimental Neuropsychology from the University of Lisbon, in collaboration with the Universities of Coimbra and Minho.
During my Master's, I completed my thesis and an ERASMUS+ internship at the University Medical Center (UMC) Utrecht, where I worked on small vessel disease and gained valuable experience in neuroimaging. Motivated by my previous research activities, I joined the Ewers Group as a PhD student at the Institute for Stroke and Dementia Research (LMU Klinikum) and the Graduate School for Systemic Neurosciences (GSN).
My PhD work aims to explore the temporal dynamics and genetic influences on Aβ and tau pathologies, with the ultimate goal of improving prediction and intervention strategies in Alzheimer's disease. Outside of the lab, I enjoy traveling, learning new languages, and explore nature and different cities with friends.
Hedwig Pietsch, Team Assistant Research
Originally from Düsseldorf, Germany, I did a Master of Arts degree in Political Science/International Politics at LMU Munich and a Certificate in Event Management. During my long professional career, I worked as Assistant to Executive Board Members, Project Manager Congress/Event and Clinical Research Assistant/paediatric trials. I joined ISD as Team Assistant Research in 2016.
E-Mail: Hedwig.Pietsch@med.uni-muenchen.de
Phone: +49 89 4400 46220
Prof. Michael Ewers
Tel: +49 89 4400 46221
michael.ewers@med.uni-muenchen.de