Are myelin alterations associated with primary pathologies and functional brain changes in Alzheimer’s disease? A multimodal MRI and PET study.

• Applicant: Professor Dr. Michael Ewers
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570971002

Alzheimer’s disease (AD) is defined by the deposition of amyloid plaques and fibrillar tau pathology. Recent evidence from multiple lines of research suggests that in addition to these grey matter changes, myelin in the white matter is substantially reduced in AD dementia. Although recent studies in transgenic mouse models suggest a direct link between primary AD pathologies with myelin damage, the association between myelin alterations on the one hand and amyloid plaques and fibrillar tau on the other hand in patients with AD remains poorly understood. In addition, small vessel disease, which is common in AD, may contribute to myelin damage. Given that myelin plays a fundamental role in neuronal signal transduction and thus brain function, it is pivotal to understand myelin changes within the AD brain and downstream effects on functional network changes underlying cognitive decline in AD. The three major aims of the prospective cross-sectional study in participants with biomarker evidence of AD are to test whether 1) myelin alterations are associated with core AD pathologies including amyloid plaques and fibrillar tau. 2) SVD related white matter lesions contribute independently from core AD pathology to myelin damage.3) a decrease in myelin of fiber tracts is associated with disrupted functional connectivity in major networks and thus cognitive decline.We will include 70 participants who are amyloid-positive and show mild cognitive impairment (MCI) and 35 amyloid-negative cognitively normal controls.As our primary measures of myelin, we will employ diffusion-informed multicompartment relaxometry (MCR) based on multi-echo gradient echo (GE) sequence. In addition, a recently developed gradient echo (GE) based chi-separation approach to distinguish myelin from iron will be applied. For our first aim, we will assess the association between MRI-assessed myelin alterations and PET markers of amyloid plaques (18F-flutemetamol) and fibrillar tau (18F-PI-2620). For our second aim, we will test a composite score of MRI-assessed SVD-related white matter lesions (WMH, lacunes, microbleeds, perivascular spaces) as a predictor of myelin alterations. For the third aim, we will test whether myelin levels in the fiber tracts are associated with reduced functional connectivity (assessed by 30-min. resting-state fMRI) and episodic memory impairment. The proposed study will thus decipher the associations of SVD and core AD pathology with myelin alterations and determine the contribution of myelin damage to functional impairment in AD. Our study will provide pivotal insight into regional myelin alterations in association with core brain pathology and its contribution to cognitive decline in the predementia phase of AD. A better understanding of the correlates of myelin alterations is especially pertinent given that several drugs targeting myelin have been already approved for other diseases, and could be potentially repurposed for the treatment of AD.

• DFG Programme: Research Grants