Florey Department of Neuroscience and Mental Health - Theses
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ItemThe nature of memory decline and learning dysfunction in preclinical Alzheimer’s disease( 2019)Background: In cognitively normal (CN) older adults, abnormal levels of amyloid-beta indicates that the pathophysiological process of Alzheimer’s disease (AD) has begun, although it may be up to 20 years before these individuals meet clinical criteria for dementia Measurement of episodic memory is a cornerstone of neuropsychological assessment in AD, which is consistent with clinicopathological studies showing that the earliest neuronal loss begins within the medial temporal lobe (MTL), a brain region crucial for learning and memory. Neuropsychological compendia detail many tests of episodic memory well validated for use in AD, however, there are fewer standardized neuropsychological tests of learning validated for use in AD. The overarching aim of this thesis was to investigate the relationship between AD pathological markers such as beta-amyloid, and trajectories of neuropsychological performance on memory and learning tasks in CN older adults. Methods: The nature and magnitude of cognitive impairment and decline associated with abnormal levels of amyloid beta in CN older adults was determined via meta-analysis of studies published from 2012 to 2016. Indices of memory and learning on computerised cognitive tests were examined in amyloid negative and amyloid positive CN older adults, with estimates of impairment and decline reported over periods of 18 and 36 months. Finally, a novel web-based learning task was designed and validated to enable the modelling of learning and memory in amyloid negative and amyloid positive CN older adults. Results: Meta-analytic estimates showed significant impairments of small to moderate magnitude (Cohen’s d’s 0.15-0.32) associated with abnormal amyloid in CN older adults in the domains of visuospatial function, processing speed, episodic memory, executive function, and global cognition. Significant decline of small-to-moderate magnitude associated with abnormal amyloid in CN older adults were found for semantic memory, visuospatial function, episodic memory, and global cognition (Cohen’s d’s 0.24-0.30). Rates of learning on the computerised cognitive tests at baseline were equivalent between the amyloid negative and amyloid positive CN groups, while significant differences in longitudinal trajectory of performance was evident. The amyloid negative group showed significant practice effects over time, which were absent in the amyloid positive group, suggesting an inability to learn from repeated exposure. Daily measurement of cognition via a remote, online assessment was sensitive to both age and pathology related changes in ability to learn new information over one week in CN older adults. The magnitude of this effect was very large (Cohen’s d = 1.50), approximately three times larger than current longitudinal estimates of cognitive decline in amyloid positive CN individuals over a year or more. Conclusions: Results indicated that the presence of abnormal amyloid in CN older adults has a significant, negative effect on a range of cognitive domains, although the magnitude of this effect is only small-to-moderate and is largest for memory. Furthermore, amyloid positive CN older adults display aberrant performance on memory and learning tasks over time in the form of a lack of practice effects. This suggests that in amyloid positive CN individuals, the processes by which learning occurs as a function of repeated exposure and presentation to stimuli may be compromised. The large magnitude of impairment in daily learning on the web-based task highlights that the ability to learn new information is dysfunctional in the preclinical stage of AD, and that a sensitive way of measuring cognition in very early disease stages is via repeatable learning assessments. This suggests the need for a paradigm shift towards understanding cognitive dysfunction in preclinical AD as dysfunctional learning, rather than memory.
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ItemComprehensive touchscreen characterisation of the APP/PS1 mouse model of Alzheimer’s disease( 2019)Alzheimer’s disease is the most common form of dementia, and represents one of the biggest health challenges of our time. As such, it has been the subject of intense research for the past 20 years, but, as of yet, no effective disease-modifying treatments have passed clinical trials. The use of AD mouse models to identify potential treatments is a predominant method used by the field, but cognition is not assessed in these models in a comparable way to the clinic. This body of work was interested in using rodent touchscreen technology to comprehensively characterise clinically relevant cognitive domains in the APP/PS1 mouse model of AD. Four cohorts of APP/PS1 mice (and wild-type littermate controls) from 8-26 months of age underwent touchscreen tasks assessing attention, impulsive and compulsive behaviours and executive function, as well as hippocampal-dependent associative learning, pattern separation and working memory. Additionally, a touchscreen-exposed and naïve cohort of 12-month-old animals underwent 2 traditional behavioural tasks that are well characterised in the literature, the Morris water maze and forced alternation. APP/PS1 mice showed slightly increased impulsive and compulsive behaviour at 11 months of age, as well as a subtle executive function deficit at 16 months of age that became increasingly severe to 26 months of age. At 12 months of age, APP/PS1 mice showed no changes on touchscreen-assessed associative learning or attention, nor in Morris water maze or forced alternation. Furthermore, APP/PS1 mice showed no changes in basic learning or vision function up to 26 months of age, nor in working memory or pattern separation up to 16 months of age. Cell proliferation in the hippocampus was affected by age but not genotype at 12 and 21 months of age. As one would expect hippocampal-dependent deficits to occur prior to executive dysfunction, we became interested in how environmental factors may change disease progression in AD mouse models. We completed a systematic review on the effects of exercise and environmental enrichment (EE) on AD mouse models, and found that both EE and exercise consistently improved cognition and increased neurogenesis and synaptic plasticity markers, while the effects on amyloid were inconsistent. Thus, we hypothesized that the touchscreen testing paradigm may have improved hippocampal function and thus delayed onset of symptoms in the APP/PS1 mice. This body of work provides the first full characterization of any AD mouse model across various ages, and the battery developed can be used for future studies.
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ItemProbing white matter pathology in Alzheimer's disease using advanced diffusion MRI( 2019)Alzheimer’s disease is increasingly conceptualised as a disease of network dysfunction, which is likely underpinned by substantial white matter degeneration. Indeed, white matter is known to exhibit disruption in Alzheimer’s disease, both at microstructural and macroscopic levels, and has been reported in pathological and imaging studies. However, these white matter changes across the Alzheimer’s disease spectrum have been poorly described thus far, largely due to methodological limitations. In this thesis, advanced diffusion MRI methods were applied to investigate white matter changes in Alzheimer’s disease patients, as well as in mild cognitive impairment patients, who represent an at-risk cohort for developing Alzheimer’s disease. There were three major research questions for this thesis, which formed the basis of three major studies: (1) What are the specific white matter pathways that degenerate in mild cognitive impairment and Alzheimer’s disease? (2) To what extent does the degeneration of these fibre structures relate to cognitive decline? (3) What are the in vivo microstructural characteristics of white matter lesions in Alzheimer’s disease? To address the first research question, the first study utilised a novel method known as fixel-based analysis to investigate fibre tract-specific white matter degeneration in a cohort of Alzheimer’s disease, mild cognitive impairment, and healthy elderly control participants from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) study. Using this approach, specific fibre pathways that exhibited degeneration in Alzheimer’s disease subjects compared to control subjects were identified. Of these fibre pathways, only select fibre tracts exhibited degeneration in mild cognitive impairment patients, and this degeneration did not appear to be associated with high amyloid accumulation. The findings supported a structural basis to theories of network-wide disruption in Alzheimer’s disease. In a related second study, the associations between tract-specific degeneration and decline across a number of cognitive domains were then investigated, in a similar cohort of Alzheimer’s disease, mild cognitive impairment, and healthy elderly control participants. Tract-specific degeneration was closely associated to cognitive impairment across all cognitive domains, and interestingly, certain pathways in particular (namely, the posterior cingulum and inferior fronto-occipital fasciculus) appeared to be most closely associated with all domains. This suggested that network-wide dysfunction is mediated by degeneration of specific fibre structures. Finally, the third study in this thesis aimed to investigate white matter lesions, which are commonly reported in elderly individuals, but are increased in Alzheimer’s disease. By applying novel diffusion MRI methods to characterise the diffusion profile of lesions, microstructural heterogeneity could be observed within these macroscopic lesions, which has previously been reported in post-mortem studies but has not been described in vivo. Different lesion classes were shown to exhibit distinct diffusional properties, and the findings of this work highlighted the need to account for microstructural heterogeneity when investigating the relevance of lesions to disease. The overall findings of this thesis offer disease-specific insight that highlights the crucial importance of white matter degeneration in Alzheimer’s disease. Moreover, the findings demonstrate the ability of advanced diffusion MRI to non-invasively investigate white matter changes in vivo, thus providing the potential to further our understanding of this disease in the future.
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ItemN-truncation of Aβ peptides and Cu(II) binding: affinity, structures, reactivity( 2018)Alzheimer's disease is a neurodegenerative condition characterized by progressive cognitive decline and cerebral deposition of fibrillar plaques comprised of the β–amyloid (Aβ) peptide. According to the current state of knowledge, aggregation of Aβ is responsible for the onset and development of symptoms of AD. The first protein sequencing studies of the plaque core of AD patients identified a significant proportion of Aβ peptides with ragged N–termini, with Aβ4–x and Aβ12–x (x – different length of amino acid chain e.g. 16, 28, 40, 42) isoforms accounting for more than 60% and 8% of brain amyloid, respectively. This finding was largely overlooked until recently, when mass spectroscopic studies identified Aβ4–42 and Aβ1–42 as the dominant isoforms present in the hippocampus and cortex of sporadic AD patients, as well as in healthy brains. In the same papers, another minor form was identified – Aβ11–42. Unlike the commonly studied Aβ1–42 and Aβ1–40, all of these peptides contain the amino–terminal (H2N–Xaa–Yaa–His–) copper binding motif (ATCUN) characterised by the His residue at the third position from the N–terminus which enables high affinity Cu(II) binding. Moreover, Aβ12–x and Aβ11–x contain another His residue at the second or fourth position, respectively, which can affect their coordination properties. Additionally, Aβ11–x contains a glutamic acid residue at the first position, which can spontaneously cyclise into pyroglutamic acid. Aβ5–x is another N–terminally truncated form present in Aβ deposits in brains of sporadic and familial AD patients. It contains His at the second position from the N–terminus (Xaa–His–) which enables another type of high–affinity Cu(II) binding site. Studies presented by Lovell et al. in 1998 demonstrated increased levels of Cu, Fe and Zn ions in amyloid plaques ("Metal Ions Hypothesis"). However, these results were discordant with previous results reported by Deibel et al., where a significant decrease in copper in AD hippocampus and amygdala was reported. In addition, the meta–analysis presented by Schrag et al. showed no evidence for change in neocortical iron but a significant decrease in neocortical copper in AD in comparison with age–matched control tissue. Also, no clear evidence for copper imbalance has been presented using animal models. Therefore, the hypothesis that the total amount of Cu(II) ions present in the brains of AD patients and healthy persons is the same but the extracellular–intracellular copper ratio is increased, has gained more support. Cell–free studies have demonstrated that Cu(II) significantly accelerates Aβ aggregation. The Cu(II) interaction with Aβ peptides has also been linked with the production of free radicals in the presence of natural reductants like ascorbic acid (Asc) or hydrogen peroxide (H2O2). The metal hypothesis proposes that these processes contribute to disease progression and that “therapeutic chelation” could prevent it. Nowadays, it is thought that Aβ aggregation is not the only reason for the development of AD but also a balance between the production of Aβ and their degradation by enzymes is crucial. One of these degrading enzymes is neprilysin (NEP), a zinc–dependent endopeptidase associated with the membrane that cleaves peptides at the amino side of hydrophobic residues. A deep understanding of Cu(II) binding properties of N–truncated Aβ peptides vs. Aβ1–x, together with the knowledge how they interact with other Cu(II) binding partners, such as small molecule chelators, is required to assess their relevance to brain copper homeostasis in health and AD. Besides the Cu(II) coordination properties, it is important to understand the redox activity of these Cu(II) complexes in order to establish their putative role in the development of AD and whether chelators such as PBT2 can protect against the production of ROS. The relationship between various truncations, Cu(II) binding modes and enzymatic degradation of Aβ peptides may also be very important for designing therapies and understanding their outcome. This thesis aims to address many of these fundamental issues. Using spectroscopic methods (UV–Vis, CW–EPR and CD), the present work established the Cu(II) coordination properties of a series of model Aβ peptides (Aβ4–16; Aβ11–16; pAβ11–16; Aβ12–16; Aβ5–x, x = 9, 12, 16). CuAβ4–16 and CuAβ11–16 in the 1:1 peptide: metal ratio form four nitrogen (4N) Cu(II) complexes using their ATCUN motif, which is a high–affinity Cu(II) binding site. We have not observed any direct influence of the His at the fourth position present in Aβ11–16 on the Cu(II) coordination. The CuAβ12–16 complex at low pH (pH 3 – 4) is a 3N complex. At higher pH, it transforms into a 4N complex in the ATCUN motif (accounting for 100% of the Cu(II) speciation at pH ≥ 6.5). In addition, analogously to CuAβ12–16, we have shown that CuAβ5–x (x = 9, 12, 16) yield 3N complexes which are present from low to high pH, proving the important role of the His at the second position for Cu(II) binding in the absence of the ATCUN motif. Aβ5–x peptides are present in brains in low amounts, but are increased in the course of experimental AD treatments using protease inhibitors. We have also investigated the formation of 'internally–ternary' complexes between CuAβ5–x and the His or Tyr present in the same peptide chain. Based on the potentiometric technique, we have reported the binding affinities of these CuAβ complexes, placing them in the picomolar to femtomolar range. This is at least 3–orders of magnitude higher than the affinity of CuAβ1–x peptides considered so far to be key Cu(II) binding species. Further physico–chemical studies in this thesis concern mostly the interactions between Aβ4–16 and other Aβ peptides and a small molecule (a homologue of the experimental therapeutic PBT2). Based upon the results presented by Masters et al. and Portelius et al., we can propose that the 4–x N–terminally truncated Aβ peptides are very significant species in the brains of AD patients. PBT2 was reported to reduce neuropathological AD markers in transgenic animal models but had limited efficacy in human AD trials. The putative benefits of PBT2 were proposed to result from its ability to chelate and transport Cu(II), protecting against oxidative stress triggered by Cu/Aβ ROS production. Previous studies using the PBT2 homolog 2–[(dimethylamino)methyl]–8–hydroxyquinoline (L) showed that such 8–hydroxyquinolines can create a tridentate CuL complex with a conditional Kd value of 0.35 pM at pH 7.4. Moreover, L can form ternary copper complexes with His side chains of the Aβ1–16 peptide and other proteins. These observations suggest the ternary CuL(Aβ) complex is of relevance to any in vivo actions of PBT2 that involve Cu(II). To establish the relative affinity of Aβ4–16 to Cu(II) ions, competition experiments between Aβ4–16 and Aβ1–16 were performed using various spectroscopic methods (CW–EPR, UV–Vis and CD). In all cases, quantitative transfer of Cu(II) from Aβ1–16 to Aβ4–16 suggests the Cu(II) binding affinity of Aβ4–16 is more than an order of magnitude higher, which is consistent with potentiometric results. Given the relatively high binding affinity of Aβ4–16, it was anticipated that the Cu(II) transfer from CuL to Aβ4–16 would be immediate. However, the UV–Vis spectra showed a rapid exchange of Cu(II) from CuL to a ternary CuLAβ4–16 complex, which then slowly transformed into the CuAβ4–16 complex, taking approximately 90 min for complete Cu(II) transfer. Similar results were observed for a competition experiment involving Aβ5–9 and Aβ4–9 where transfer of Cu(II) ions from CuAβ5–9 to Aβ4–9 via a ternary Cu(Aβ5–9)NimAβ4-9 complex was complete only after approximately 23 hours. Using fluorescence spectroscopy, we conducted Cu(II) competition experiments between Aβ12–16 and Aβ4–16. We expected either quenching of the tyrosine fluorescence from Aβ4–16 by transfer of Cu(II) from CuAβ12–16 to Aβ4–16, or a increase of the tyrosine signal by transfer of Cu(II) from CuAβ4–16 to Aβ12–16. We observed both of these processes depending on which form was available in excess, indicating that both of these forms have very similar Cu(II) binding affinities. Moreover, Aβ5–16 and Aβ4–16 can bind a second equivalent of Cu(II) ions via His13/14 but the Cu(II) binding affinity for this site is low and thus its biological relevance doubtful. Next, the redox activity of copper complexes formed in the presence of Aβ4–16 and the PBT2 homolog (L) was examined. ROS production was measured using APF (2–[6–(4’–amino)phenoxy–3H–xanthen–3–on–9–yl]benzoic acid), a fluorescent sensor of hydroxyl radicals. We observed that CuAβ4–16 was redox silent but Cu2Aβ4–16 was redox active. A model system comprising Cu(II)/L/imidazole in a 1:1:20 ratio was used for further characterization of the redox activity of the ternary CuLNim complex where Nim represented His–bearing peptides and proteins. Previous CW–EPR and UV–Vis studies have shown that under these conditions > 95% of Cu(II) is bound by a ternary CuLNim species with the electronic and geometric structure similar to that of CuLNimAβ [11]. In this experiment, we observed ROS production. These findings have important consequences for experimental AD therapeutics based on the structure of L, such as PBT2, since it is highly likely that any Cu(II) intermediate of PBT2 will result in ROS production by the ternary Cu(PBT2)Nim complex. In collaboration with Magdalena Wiloch (Department of Microbioanalysis, Faculty of Chemistry, Warsaw University of Technology) cyclic and square wave voltammetry experiments were performed. These revealed that the 1:1 Cu(II)/Aβ4–16 complex undergoes irreversible oxidation to a Cu(III)/Aβ4–16 species at a potential above 1V. Also, using UV–Vis spectroscopy, the characteristic signal for Cu(III) complexes was observed in the presence of ascorbate (Asc). Using fluorescence spectroscopy and various forms of Aβ (Aβ1–16; Aβ4–x, x = 8, 12, 16), we have investigated the formation of dityrosine in the presence of Asc and H2O2. For CuAβ4–16, we observed a signal characteristic for dityrosine only in the presence of the Asc but not in the presence of H2O2. Also, no dityrosine signal was observed for the sample containing CuAβ4–12 under both conditions. This suggests a crucial role of the His13/14 and Asc in formation of dityrosine, thus indicating that a huge copper overload would have to occur for the CuAβ4–x species to yield this toxic modification. The last part of this project was related to proteolysis of various Aβ peptides (Aβ1–16, Aβ4–16, Aβ5–16) and their Cu(II) complexes by NEP. Using HPLC with TOF ESI–MS, we observed formation of Aβ4–9 and Aβ12–16 fragments from Aβ1–16 and Aβ4–16 in the presence of NEP. Both these fragments contain ATCUN motifs. Moreover, the results obtained for CuAβ4–16 in the presence of NEP revealed the approximately 3–times faster proteolysis of the peptide in comparison to CuAβ1–16 and CuAβ5–16. NEP activity in the presence of metal ions was also measured using fluorescence spectroscopy and the non–fluorescent substrate Mca–RPPGFSAFK(Dnp), which yields a fluorescent product upon NEP cleavage. Results obtained for different substrate and Cu(II) concentrations were fitted to a non–competitive inhibition model with Ki ~ 1 μM. Taking into account that peak extracellular Cu(II) in glutamatergic synapses may be as high as 200 – 300 μM, this result suggests that NEP may also be inhibited by Cu(II) in vivo. Addition of excess Zn(II) did not show restoration of the enzyme activity, but also inhibited NEP. Similar to Cu(II) experiments, fluorescence assays were performed with different substrate and Zn(II) concentrations and fitted to a non–competitive inhibition model with Ki ~ 20 μM.
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ItemFunctional characterisation of Intersectin-1, a gene over-expressed in Down syndrome and analysis of intrinsic metals in the Down syndrome brain( 2017)Individuals with Down syndrome (DS) have an extra copy of chromosome 21. Over-expression of the genes on this chromosome results in intellectual disability, a structurally abnormal brain, and many other congenital disorders, and Alzheimer’s disease (AD) neuropathology. However, it is hard to determine which of the genes on chromosome 21 contributes to the phenotype of DS. The role of the intersectin-1 (ITSN1) gene was examined in this study as it has a role in endocytic membrane trafficking, a process disrupted in DS. Enlarged early endosomes, the hallmark of disturbance in endocytosis, have been observed in both the DS and AD brain. Metal dyshomeostasis is another hallmark of AD brain. Hence, we examined metal homeostasis in the DS brain to test if AD and DS share this hallmark as well. To examine the consequences of over-expression of ITSN1 in DS, mice that over-express ITSN1 (ITSN1-Tg) were examined. In addition, an ITSN1-LKO mouse, where the long isoform has been deleted, was used to study biological functions of the ITSN1 long isoform. In the DS brain, iron was high, and calcium was low in the hippocampus, and the frontal and temporal cortices in the DS brain compared to the controls. The level of zinc was also lower in the temporal cortex of the DS brain compared with the controls. However, the levels of Zinc and copper were elevated in the DS frontal cortex compared with the controls. It was revealed that ITSN1 over-expression does not seem to contribute to the cognitive deficits observed in DS that we focussed on. There were no differences in long term memory, short term memory, long term potentiation (LTP) or the MAPK/ERK and AKT signalling pathways in ITSN1-Tg mice compared with their wild-type counterparts. However, blood test results in ITSN1-Tg mice, revealed that ITSN1 over-expression might contribute to microcytic anaemia and polycythaemia, both of which have been observed in DS individuals. Phenotyping ITSN1-LKO mice revealed that short and long term memory, LTP, MAPK/ERK and AKT signalling pathways were all compromised in the absence of the ITSN1 long isoform, compared with the WT control. There was also a cognitive decline with age in the ITSN1-LKO mice. In addition, both over-expression of ITSN1 and the absence of ITSN1-L seemed to disrupt kidney filtration at different stages of this process. In summary, this thesis concluded that metals, as well as metals in metal-containing proteins, are dysregulated in the DS brain, and ITSN1 over-expression may contribute to blood disorders of DS but not to DS cognitive deficits. We also conclude ITSN1-L is required for normal learning and memory.
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ItemMemory changes in community-based older adults: subjective memory complaints, personal memory and their relationship with Alzheimer’s disease biomarkers( 2015)Subjective concerns of memory decline (or subjective memory complaints) are a common phenomenon in the normal population, particularly in older adults. Complaints arise from a negative self-appraisal of memory performance, and form the bridge that connects an individual to clinical attention. The experience of memory failure, whether momentary, gradually progressive, or sudden and acute, is universal and inherently subjective. Within this experiential realm lies rich and complex subjective detail. A threshold exists at which point self-appraised memory dysfunction becomes intolerable, and most individuals seek diagnostic resolution for their symptoms. Alzheimer’s disease (AD) is the most common form of dementia, which is characterised by early impairment in objective memory performance, and gradual accrual of in vivo biological markers. The current trend in the literature is to assume a monotonic relationship between memory complaint severity and level of objective memory impairment, but in general studies have been unable to find a consistent association. The relationship between subjective memory complaining and biomarkers of AD, such as neocortical β-amyloid (Aβ) burden, measured via positron emission tomography (PET) imaging, and brain atrophy, measured via magnetic resonance imaging (MRI), is gathering pace. Brain atrophy in the medial temporal lobes (MTL) is consistently related to memory complaining, but the literature relating to neocortical Aβ burden is less clear; recent studies have shown a relationship, but the effect sizes are small. Autobiographical (ABM) and personal semantic memories (PSM), along with their autonoetic re-experiencing, form the foundation of everyday personal memory. An assessment of personal memory impairment does not feature in the mainstream diagnostic approach to mild cognitive impairment (MCI), the clinical transitional stage prior to a diagnosis of AD. ABM, or the highly contextualised details related to a personal event, are consistently found to be impaired in individuals with MCI, but the pattern of impairment of PSM is less understood. As the most ecologically valid form of memory, it is possible that a breakdown in ABM and PSM is the main driver for subsequent memory complaining. To the candidate’s knowledge, there is no literature which has yet examined a possible connection between memory complaining and personal memory function. It is also unclear how markers of AD pathology, such as Aβ burden and brain atrophy, may be related to ABM and PSM, but functional MRI studies of these personal memory systems suggest they are supported by differing functional networks. ABM is related to a core functional network that primarily involves the MTL, frontal, and posterior cingulate regions, while PSM has been attributed to networks in the lateral temporal lobe. The current inquiry is aimed at describing the phenomenological experience of memory change in non-demented older adults in order to elucidate complaints in those at greater risk of AD, such as individuals with evidence of biological markers of AD, or those with MCI. The specific objectives of this these were: 1) to determine cognitive, affective and AD biological marker correlates of SMCs in healthy older adults and individuals with MCI examined via a commonly-used subjective memory complaint questionnaire (SMCQ), 2) to characterise the phenomenological experiences of memory loss in the earliest stages of Alzheimer’s disease, such as healthy older adults with evidence of AD biological markers and those with MCI, and 3) to examine the pattern of ABM and PSM impairment and its relationship with AD biomarkers in healthy memory complainers and individuals with MCI. The first study (Chapter 4), investigated memory, affective and AD biomarker correlates of SMC severity as measured via a commonly-used SMCQ, the Memory Assessment Clinics Questionnaire (MAC-Q), in healthy older adults and individuals with MCI. Participants were healthy controls (n = 674) and individuals with MCI (n = 66) in the Australian Imaging, Biomarker and Lifestyle (AIBL) study of ageing, who responded to the MAC-Q. Scores from measures of new learning and retention, as well as mood (anxiety and depression), age, education and diagnostic category, were regressed onto the total MAC-Q score, to determine whether memory would relate to SMC severity over and above the other variables. Diagnostic category, depressive symptomatology, and age, were the strongest correlates. In healthy older adults, the strongest driver of greater MAC-Q score was depressive symptomatology, while in individuals with MCI, the sole correlate was age. Aβ deposition, grey matter volumes, and APOE ε4 carrier status were regressed onto MAC-Q total score in both diagnostic groups, but no correlates were found. A strong relationship between depression and memory complaint severity in healthy older adults aligns with other studies using SMCQs. The relationship with age in MCI supports the notion of an underlying organic driver of memory complaining, and a transition from affectively-driven phenomena. The second study (Chapter 5), addressed the characterisation of SMCs in different AD-risk groups, such as healthy older adults with high Aβ load, healthy memory complainers (identified by asking “do you have difficulties with your memory, yes or no?”), and individuals with MCI. Healthy control (n = 80) and MCI (n = 43) participants were randomly recruited from the AIBL study for the next three studies. A semi-structured interview was developed by the candidate, in conjunction with supervisor, MS to probe the phenomenological experience of memory loss. A thematic analysis was conducted and meaningful phrases were extracted, and grouped similar phrases into what ultimately became twelve themes. A comparison between healthy individuals with high and low Aβ load showed that greater Aβ deposition was related to greater acknowledgement of a progressive memory decline. Complaint themes in healthy memory complainers closely aligned to those expressed by MCI individuals, suggesting that a single SMC question has the potential to uncover individuals with subjectively similar experiences of memory loss as those with a diagnosed memory dysfunction. Individuals with MCI diverged from healthy memory complainers in their greater acknowledgement of dependency on a significant other, and the implementation of burdensome coping strategies. Thus, an increasing acknowledgement of dysfunction in daily activities may well signify an interim early stage outcome of accumulating memory problems. The pattern of ABM and PSM impairment in healthy memory complainers and those with MCI was examined in the third study (Chapter 6). The Episodic Autobiographical Memory Interview, a validated semi-structured interview, measured the spatiotemporal and emotional details of a recent personal event (ABM) and personally factual knowledge from the recent past (PSM). Individuals with MCI showed a deficit in both ABM and PSM, supporting conceptual notions of a dynamic and interactive overlap between these two memory systems. Healthy memory complainers did not show a deficit compared to non-complaining healthy older adults, raising the question as to whether current measures of memory complaining are sensitive to the subjective experience of memory decline. In the fourth and final study, AD biomarkers were considered in relation to personal memory performance, namely ABM, PSM and the conscious re-experiencing connected with ABM (Chapter 7). Aβ deposition, grey matter volumes and APOE ε4 carrier status were regressed onto each form of personal memory. PSM was negatively associated with neocortical Aβ burden in healthy older adults, but neither ABM nor autonoetic consciousness were related to any AD biomarkers. ABM impairment exerted a large magnitude of effect on MCI unlike PSM, so there are potentially other underlying neurodegenerative processes affecting ABM performance. The prevailing assumption in the literature is to treat subjective memory complaining as a unidimensional proxy for neuropsychological measures of memory impairment. The problem with this assumption is that it does not recognise the complex, and often counter-intuitive, nature of subjective experiences. SMCQs, such as the MAC-Q, are structured as screening tools in that they are non-interactive, non-specific and designed for quick self-administration. This approach provides no diagnostic information over and above a quantified score, and neglects the possibility that phenomenological experiences contain important clinical information. The impairment to both ABM and PSM in MCI, highlighting that both personal memory systems are affected by underlying AD-related neuropathology. Specifically, findings from this thesis suggest that ABM and PSM are affected by differential disease mechanisms, with PSM strongly influenced by neocortical Aβ burden in healthy older adults, and ABM showing a trend towards association with hippocampal volume. Thus, elevated AD biomarkers were found to have an effect on the subjective experience (via complaints) and expression (via autobiographical narratives) of memory, supporting the notion that these phenomena are affected in the early stages of AD. This thesis highlights the subjective experience of memory change in non-demented older adults, which will help to inform future approaches to the clinical evaluation of memory complaints prior to diagnosis.