Impact of APOE genotype and age on large-scale MTL neurocognitive networks

Research on medial temporal lobe (MTL) function converges on the notion that the hippocampus and perirhinal cortex (PRC) are specialised for different types of representational content: scenes and objects. The evolutionary accretion model advances this further, proposing that these MTL structures constitute key nodes within the extended hippocampal navigation and feature networks, respectively. The former network is considered more vulnerable to the impact of age and age-related neurodegenerative disease, including Alzheimer’s disease (AD). Additionally, young carriers of the apolipoprotein E (APOE) ε4 allele – an AD risk factor – have been shown to exhibit alterations within this network, supporting lifespan accounts of cognitive decline. Recently, however, this network-selective vulnerability has been challenged by reports of object-related impairments in ageing and AD risk. This thesis therefore investigated the impact of APOE genotype – especially APOE ε4 – and age on these two neurocognitive networks and their representations. To achieve this, web-based cognitive testing (Chapter 2), magnetic resonance imaging (MRI)-based structural covariance analysis (Chapter 3), and diffusion MRI-based tractography (Chapter 4) were used. In middle-aged and older adults, APOE ε4 and APOE ε2 – a risk-reducing allele – were associated with divergent age trends in perceptual discrimination independent of condition (Chapter 2). Conversely, in a sample spanning the adult lifespan, age and gender/sex – but not APOE ε4 – were associated with the structural covariance of the hippocampus and PRC (Chapter 3). Finally, in younger adults, APOE ε4 impacted the lateralisation of inferior longitudinal fasciculus (ILF) microstructure – a key tract in the feature network (Chapter 4). The findings of this thesis provide evidence that APOE genotype and age impact aspects of these networks and their representations, but it remains challenging to interpret them collectively. Nonetheless, this research addresses pre-existing limitations, and provides a foundation for studies that could aid our understanding of age- and APOE-related impact(s) on the brain and cognition

Tract-specific differences in white matter microstructure between young adult APOE ε4 carriers and non-carriers:A replication and extension study

The parahippocampal cingulum bundle (PHCB) interconnects regions known to be vulnerable to early Alzheimer's disease (AD) pathology, including posteromedial cortex and medial temporal lobe. While AD-related pathology has been robustly associated with alterations in PHCB microstructure, specifically lower fractional anisotropy (FA) and higher mean diffusivity (MD), emerging evidence indicates that the reverse pattern is evident in younger adults at increased risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) ε4 allele – the strongest common genetic risk factor for AD – showed higher FA and lower MD in the PHCB but not the inferior longitudinal fasciculus (ILF). These results are consistent with proposals claiming that heightened neural activity and intrinsic connectivity play a significant role in increasing posteromedial cortex vulnerability to amyloid-β and tau spread beyond the medial temporal lobe. Given the implications for understanding AD risk, here we sought to replicate Hodgetts et al.‘s finding in a larger sample (N = 128; 40 APOE ε4 carriers, 88 APOE ε4 non-carriers) of young adults (age range = 19–33). Extending this work, we also conducted an exploratory analysis using a more advanced measure of white matter microstructure: hindrance modulated orientational anisotropy (HMOA). Contrary to the original study, we did not observe higher FA or lower MD in the PHCB of APOE ε4 carriers relative to non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. In addition, we observed no APOE ε4-related differences in PHCB HMOA. Our findings indicate that young adult APOE ε4 carriers and non-carriers do not differ in PHCB microstructure, casting some doubt on the notion that early-life variation in PHCB tract microstructure might enhance vulnerability to amyloid-β accumulation and/or tau spread

Tract-specific differences in white matter microstructure between young adult APOE ε4 carriers and non-carriers: A replication and extension study

The parahippocampal cingulum bundle (PHCB) interconnects regions known to be vulnerable to early Alzheimer's disease (AD) pathology, including posteromedial cortex and medial temporal lobe. While AD-related pathology has been robustly associated with alterations in PHCB microstructure, specifically lower fractional anisotropy (FA) and higher mean diffusivity (MD), emerging evidence indicates that the reverse pattern is evident in younger adults at increased risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) ε4 allele – the strongest common genetic risk factor for AD – showed higher FA and lower MD in the PHCB but not the inferior longitudinal fasciculus (ILF). These results are consistent with proposals claiming that heightened neural activity and intrinsic connectivity play a significant role in increasing posteromedial cortex vulnerability to amyloid-β and tau spread beyond the medial temporal lobe. Given the implications for understanding AD risk, here we sought to replicate Hodgetts et al.‘s finding in a larger sample (N = 128; 40 APOE ε4 carriers, 88 APOE ε4 non-carriers) of young adults (age range = 19–33). Extending this work, we also conducted an exploratory analysis using a more advanced measure of white matter microstructure: hindrance modulated orientational anisotropy (HMOA). Contrary to the original study, we did not observe higher FA or lower MD in the PHCB of APOE ε4 carriers relative to non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. In addition, we observed no APOE ε4-related differences in PHCB HMOA. Our findings indicate that young adult APOE ε4 carriers and non-carriers do not differ in PHCB microstructure, casting some doubt on the notion that early-life variation in PHCB tract microstructure might enhance vulnerability to amyloid-β accumulation and/or tau spread

Imaging biomarkers in neurodegeneration: current and future practices

Abstract: There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course “Biomarkers in neurodegenerative diseases”. In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis

Tract-specific differences in white matter microstructure between young adult APOE ε4 carriers and non-carriers: A replication and extension study

This repository contains R code used to analyse and visualise data in Lissaman et al. (2022), NeuroImage: Reports (https://doi.org/10.1016/j.ynirp.2022.100126). For more information, please contact: [email protected] / [email protected]

Imaging biomarkers in neurodegeneration: current and future practices

Abstract: There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course “Biomarkers in neurodegenerative diseases”. In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis