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Association of Genes Related to Amyloid-β and Tau Clearance with Alzheimer's Disease Markers

Student thesis: Doctoral ThesisDoctor of Philosophy

Alzheimer’s disease (AD) is an age-related neurodegenerative illness and the most common form of dementia. Patients experience cognitive and functional impairment linked to neuronal loss and brain atrophy. Mild cognitive impairment (MCI) is considered a prodromal stage of AD characterised by problems with cognition. Neuropathological hallmarks of AD include amyloid-beta (Aβ) neuritic plaques and neurofibrillary tangles of hyperphosphorylated tau. A breakdown in central nervous system (CNS) pathways that clear accumulated proteins from the brain (including Aβ and tau) may therefore contribute to AD pathogenesis.

The water channel aquaporin-4 (AQP4), localised to perivascular endfeet of astrocytes, CNS glial support cells, is a key component of the glymphatic system. This is a hypothesised brain waste drainage pathway for solutes, including extracellular Aβ and tau, driven by interstitial bulk flow. Ventricular aquaporin-1 (AQP1) may influence the drainage of waste solutes from the brain, albeit indirectly. By facilitating cell motility, AQP1 expressed on astrocytes could contribute to astrocytic Aβ reactivity and clearance, whereas LDL receptor-related protein 1 (LRP1) on astrocytes or microglia, CNS immune cells, can be important to the phagocytic uptake and degradation of Aβ. LRP1 at the blood brain barrier (BBB) endothelium facilitates the efflux of Aβ to the blood, whilst neuronal LRP1 modulates the uptake of Aβ and tau.

In AD, AQP4, AQP1, or LRP1 can undergo impairments, including a loss of AQP4 polarisation to astrocytic endfeet or declines in CNS AQP1 or LRP1 expression. These may result in reduced Aβ or tau clearance from the brain, which in turn could lead to neurodegeneration and clinical symptomatology. Moreover, under pathogenic conditions consistent with ageing, a breakdown in or prolonged activation of CNS clearance mechanisms for Aβ or tau, such as the glymphatic system, astrocytic reactivity, or BBB transport that incorporate AQP4, AQP1, and/or LRP1, may be linked to chronic sleep problems, which can then contribute to the risk of AD. However, these areas of research remain under-investigated in living subjects.

The work presented in this thesis aimed to indirectly explore whether there is a relationship between AQP4, AQP1, and LRP1 and neuropathological and clinical outcomes for living subjects on the spectrum of AD. Associations were tested between genetic variation at the AQP4, LRP1, and AQP1 loci and in vivo CSF and neuroimaging biomarkers, in addition to clinical and cognitive measures, in subjects from the Alzheimer’s disease neuroimaging initiative (ADNI). To confirm the associations found, significant variants were further tested in two independent AD-research and population cohorts – AddNeuroMed and UK Biobank, in which structural MRI data was available. Using a cohort of older adults from the UK Biobank with available subjective sleep data, associations between AQP4, AQP1, or LRP1 genetic variation and sleep disturbance traits were investigated. It was also examined whether abnormal sleep in ageing could mediate potential associations between variants and AD risk.

In MCI/AD subjects from ADNI, genetic variants in AQP1 and LRP1 were associated with Aβ pathology, whereas variants in AQP4 were associated with tau pathology in the CNS. Variants in all three genes were associated with glucose hypometabolism or changes in brain volume, suggesting Aβ or tau clearance mechanisms are an important contributor to AD pathologies. AQP4 and LRP1 genetic variants were associated with cognitive performance, which may be reflective of a progression of neuropathology due to altered Aβ or tau brain efflux. Moreover, one AQP1 variant was associated with depressive symptomatology, a risk factor for AD, which may have been attributable to fluctuations in Aβ clearance. In UK Biobank subjects with a parental diagnosis of AD, associations were found between AQP4 genetic variants rs335930 and rs162007 and grey matter volume in middle temporal gyrus subdivisions. This finding may have signalled subtle impairments in the glymphatic system linked to neuronal loss for individuals at high risk of developing AD. Finally, in older adults from the UK Biobank, AQP4, AQP1, and LRP1 genetic variation was respectively associated with shorter sleep duration, excessive daytime sleepiness, and insomnia. These relationships could indicate that sleep disturbances in ageing were occurring through influences of CNS mechanisms involved in pathological protein clearance.

Findings from the current thesis implicate AQP4, AQP1, and LRP1 in pathophysiological processes and clinical disease traits linked to AD. Results indirectly suggest that AQP4 is involved in the clearance of tau from the brain, potentially by facilitating its movement through glymphatic pathways, whereas AQP1 and LRP1 have a greater role in the removal of Aβ from the brain, possibly through multiple clearance routes. Altered Aβ or tau retention in the brain modulated by AQP4, AQP1, or LRP1 may result in downstream neuropathological sequalae and clinical symptomatology, including abnormal sleep. With further validation, the use of AQP4, AQP1, or LRP1 genetic variants and more direct markers for these proteins in research may provide additional insight into their precise involvement in CNS pathways for Aβ or tau removal, which could have potential diagnostic and therapeutic applications. 
Original languageEnglish
Awarding Institution
Award date1 Aug 2022


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