Exploring modulators of tau spreading in Alzheimer’s disease through multi-modal neuroimaging biomarkers

Steward, Anna (2024): Exploring modulators of tau spreading in Alzheimer’s disease through multi-modal neuroimaging biomarkers. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterised by a cascade of pathological brain changes starting with the emergence of amyloid plaques decades before the eventual spreading of tau pathology which drives the development of dementia symptoms. There is significant heterogeneity within AD, leading to variations in how the condition manifests clinically and the trajectory in which it progresses. This clinical heterogeneity can be related to heterogeneity in the pathophysiological underpinnings of AD, specifically pertaining to tau pathology which has been identified as the main driver of neurodegeneration, giving rise to distinct clinical phenotypes depending on the deposition pattern and accumulation rate of tau pathology. Specifically, neuroimaging studies demonstrate individual variations in the spreading rate and spatial pattern of tau pathology which correspond to clinical manifestation and progression. However, our understanding of the mechanisms responsible for these variations in tau pathology progression in AD remains limited. Given that tau plays a pivotal role in neurodegeneration and cognitive decline, understanding its modulators is paramount for optimising therapeutic interventions against AD progression. The aim of this thesis was to uncover factors impacting tau spreading through multimodal neuroimaging and genetic markers, with the primary objective of advancing our comprehension of AD pathophysiological progression, and ultimately aiding the development of more precise therapeutic strategies against AD. Recent translational research combining resting-state functional magnetic resonance imaging (rs-fMRI) and tau-positron emission tomography (PET) reveals that tau spreading is activity dependent. Originating from focal areas typically within the medial temporal lobe, tau progressively expands out across the cortex, traversing functionally connected brain regions. This observation demonstrates how tau progression takes distinct routes depending on brain network architecture. Building on this evidence, the first investigation of this dissertation tested whether the functional organisation of the brain i.e., the functional connectome, impacted the rate at which tau accumulation progresses through the cortex. Considering that the functional connectome is of a modular structure made up of communicative but distinct networks, longitudinal exploration was conducted to ascertain whether the baseline rs-fMRI defined functional segregation of networks was associated with the rate of annual tau-PET SUVR change. In a sample of 123 subjects either cognitively healthy or spanning the AD spectrum, it was demonstrated that higher network segregation is associated with an attenuated rate of tau spreading. Moreover, we further demonstrated that the functional segregation of subject-specific tau epicentres i.e., the region where tau initially manifests, influences the subsequent trajectory of tau spreading whereby more segregated epicentres lead to lower tau accumulation rates in the most connected regions and slower future tau progression overall. Together, these results indicate that the spread of tau pathology is influenced by the brain’s functional organisation. Specifically, a more diffuse brain network architecture facilitates inter-regional tau spreading, signifying that individual variations in tau-trajectories may be shaped by the brain’s functional architecture. In the light of new anti-amyloid therapies, the second investigation was conducted into modulators of tau progression in relation to amyloid. Given that amyloid initiates AD’s pathological cascade, triggering tau propagation, it is crucial to identify factors that moderate this. This is essential for optimising therapeutic windows for anti-amyloid treatments to intercept tau before it drives clinical disease progression. The Apolipoprotein E 4 (ApoE4) allele is the strongest known genetic risk-factor for sporadic AD, whereby carriers have increased amyloidosis and faster AD progression, however, how ApoE4 influences amyloid-related tau spreading is unclear. Therefore, we explored connectivity mapped individualised tau spreading trajectories corresponding to amyloid levels using PET data from 367 ApoE genotyped subjects spanning two independent samples to determine the influence of ApoE4 carriage on amyloid’s potential to trigger tau spreading. Results demonstrated that ApoE4 carriers had increased tau accumulation mediated by stronger amyloid deposition in early spreading stages and an accelerated tau spreading trajectory starting at lower amyloid levels. These findings indicate an indirect effect of ApoE4 carriage on tau spreading by driving increased amyloidosis, but also a direct effect whereby tau spreading was triggered earlier and faster relative to amyloid levels in ApoE4 carriers. This implies a need to intervene with anti-amyloid therapies in ApoE4 carriers earlier, to intercept tau progression promptly. In summary, this thesis introduces novel evidence concerning modulators of tau progression in vivo, by employing a multi-modal neuroimaging approach to reflect the connectivity mediated spreading of tau pathology throughout the AD spectrum. Utilising longitudinal tau-PET, individualised patterns of tau spreading were tracked and mapped to brain connectivity dynamics derived from rs-fMRI data, revealing that the onset and pace of tau spreading across interconnected brain regions are influenced by the brain’s connectome and a specific genetic risk factor for AD, i.e., ApoE4. Overall, these findings enrich our understanding of tau's progression within the cortex and carries implications for individualised approaches in determining the timing and target of therapeutic interventions.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Neuroscience, Neuroimaging, tau, MRI, PET, Alzheimer's disease, dementia
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie ; 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 19. September 2024
• 1. Bericht­erstatter:in: Franzmeier, Nicolai