Florey Department of Neuroscience and Mental Health - Research Publications
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ItemNo Preview AvailableLipidomic signatures for APOE genotypes provides new insights about mechanisms of resilience in Alzheimer’s disease(Wiley, 2021-12)Background The apolipoprotein E gene (APOE) genotype is the first and strongest genetic risk factor for late‐onset Alzheimer’s disease and has emerged as a novel therapeutic target for AD. The encoded protein (Apolipoprotein E, APOE) is well‐known to be involved in lipoprotein transport and metabolism, but its effect on lipid metabolic pathways and the potential mediating effect of these on disease risk have not been fully defined. Method We performed lipidomic analysis on three independent cohorts (AIBL, n = 693; ADNI, n=207; BHS, n=4,384) and defined the association between APOE polymorphisms (ε4 and ε2) and plasma lipid species. To identify associations independent of lipoprotein metabolism, the analyses was performed with adjustment for clinical lipids (total cholesterol, HDL‐C and triglycerides). Causal mediation analysis was performed to estimate the proportion of risk in the outcome model explained by a direct effect of APOE genotype on prevalent AD — the average direct effect (ADE) — and the proportion that was mediated by lipid species or lipidomic risk models — the average causal mediation effect (ACME). Result We identified multiple associations of species from lipid classes such as ceramide, hexosylceramide, sphingomyelin, plasmalogens, alkyldiacylglycerol and cholesteryl esters with APOE polymorphisms (ε4 and ε2) that were independent of clinical lipoprotein measurements. There were 104 and 237 lipid species associated with APOE ε4 and ε2 respectively which were largely discordant. Of these 116 were also associated with Alzheimer’s disease. Individual lipid species (notably the alkyldiacylglycerol subspecies) or lipidomic risk models of APOE genotypes mediated up to 10% and 30% of APOE ε4 and ε2 treatment effect on AD risks respectively. Conclusion We demonstrate a strong relationship between APOE polymorphisms and peripheral lipid species. Lipids species mediate a proportion of the effects of APOE genotypes in risk of AD, particularly resilience with e2. Our results highlight the involvement of lipids in how APOE e2 mediates its resilience to AD and solidify their involvement with the disease pathway.
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ItemPlasma high-density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume(WILEY, 2022-10)Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data.
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ItemComprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease(NATURE PORTFOLIO, 2022-06-06)We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
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ItemCerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study(MDPI, 2022-05)Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03−2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31−17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.
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ItemAPOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies(WILEY, 2022-11)INTRODUCTION: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. METHODS: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. RESULTS: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. DISCUSSION: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.
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ItemPlasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum(WILEY, 2022)INTRODUCTION: We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau). METHODS: Plasma p217+tau levels were compared to 18F-NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. RESULTS: Compared to Aβ- CU, the plasma levels of p217+tau increased 2-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ- the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVRMT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ- CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ- PET was 0.89, and for tau+ versus tau- PET was 0.89. DISCUSSION: Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.
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ItemFifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease(IOS PRESS, 2021)BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer's disease dementia (AD)) as an 'Inception cohort' who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an 'Enrichment cohort' (as of 10 April 2019). OBJECTIVE: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. METHODS: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. RESULTS: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. CONCLUSION: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.
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ItemAsymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer's disease(NATURE PORTFOLIO, 2021-02-01)Aging and Alzheimer's disease (AD) are associated with progressive brain disorganization. Although structural asymmetry is an organizing feature of the cerebral cortex it is unknown whether continuous age- and AD-related cortical degradation alters cortical asymmetry. Here, in multiple longitudinal adult lifespan cohorts we show that higher-order cortical regions exhibiting pronounced asymmetry at age ~20 also show progressive asymmetry-loss across the adult lifespan. Hence, accelerated thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This organizational principle showed high consistency across cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Asymmetry-change was further accelerated in AD. Results suggest a system-wide dedifferentiation of the adaptive asymmetric organization of heteromodal cortex in aging and AD.
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ItemConcordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease(NATURE PORTFOLIO, 2020-11-10)Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer's disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.
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ItemReduced striatal vesicular monoamine transporter 2 in REM sleep behavior disorder: imaging prodromal parkinsonism(NATURE RESEARCH, 2020-10-23)Motor deficits in parkinsonism are caused by degeneration of dopaminergic nigral neurons. The success of disease-modifying therapies relies on early detection of the underlying pathological process, leading to early interventions in the disease phenotype. Healthy (n = 16), REM sleep behavior disorder (RBD) (n = 14), dementia with Lewy bodies (n = 10), and Parkinson's disease (PD) (n = 20) participants underwent 18F-AV133 vesicular monoamine transporter type-2 (VMAT2) PET to determine the integrity of the nigrostriatal pathway. Clinical, neurophysiological and neuropsychological testing was conducted to assess parkinsonian symptoms. There was reduced VMAT2 levels in RBD participants in the caudate and putamen, indicating nigrostriatal degeneration. RBD patients also presented with hyposmia and anxiety, non-motor symptoms associated with parkinsonism. 18F-AV133 VMAT2 PET allows identification of underlying nigrostriatal degeneration in RBD patients. These findings align with observations of concurrent non-motor symptoms in PD and RBD participants of the Parkinson's Progression Markers Initiative. Together, these findings suggest that RBD subjects have prodromal parkinsonism supporting the concept of conducting neuroprotective therapeutic trials in RBD-enriched cohorts. Ongoing longitudinal follow-up of these subjects will allow us to determine the time-window of clinical progression.