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    Higher coffee consumption is associated with slower cognitive decline and Aβ‐amyloid accumulation over 126 months: Data from the AIBL study
    Gardener, SL ; Rainey‐Smith, SR ; Villemagne, VLL ; Fripp, J ; Dore, V ; Bourgeat, P ; Taddei, K ; Masters, CL ; Maruff, PT ; Rowe, CC ; Ames, D ; Martins, RN (Wiley, 2021-12)
    Background Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer’s disease (AD). However, there is limited longitudinal data available in cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning these associations. Method The aim of the current study was to investigate the relationship between self‐reported baseline coffee intake (mean = 280 ± 323 g/day) and cognitive decline assessed using a comprehensive neuropsychological battery, over 126 months, in 227 cognitively normal individuals from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study. We also sought to investigate the relationship between coffee intake and cerebral Aβ‐amyloid accumulation and brain volumes in a subset of individuals (n=60; and n=51, respectively) over 126 months. Result Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown to reliably measure the first signs of cognitive decline in at‐risk cognitively normal populations) over 126 months. Higher baseline coffee consumption was also associated with slower Aβ‐amyloid accumulation over 126 months, and lower risk of transitioning from ‘negative’ Aβ‐amyloid status to ‘moderate’, and ‘very high’ Aβ‐amyloid burden over the same time period. There were no associations between coffee intake and atrophy in total grey matter, white matter, or hippocampal volume. Conclusion Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption reducing cognitive decline potentially by slowing cerebral Aβ‐amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ‐amyloid‐mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate how coffee intake could be incorporated as one modifiable lifestyle factor aimed at delaying AD onset.
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    How lifestyle shapes the brain: Associations between physical activity, sleep, beta‐amyloid and cognitive function in older adults
    Sewell, KR ; Rainey‐Smith, SR ; Villemagne, VLL ; Peiffer, JJ ; Sohrabi, HR ; Taddei, K ; Ames, D ; Maruff, PT ; Laws, SM ; Masters, CL ; Rowe, CC ; Martins, RN ; Erickson, KI ; Brown, BM (Wiley, 2021-12)
    Abstract Background Lifestyle factors such as sleep and physical activity influence risk of cognitive decline and dementia. Higher habitual physical activity and optimal sleep are associated with better cognitive function and lower levels of Alzheimer’s disease biomarkers, including beta‐amyloid (Aß). There is currently a poor understanding of how physical activity may influence the relationship between sleep and cognition, and whether exercise and sleep interact to influence cognition and Aß. Developing this understanding is crucial for creating effective lifestyle interventions for dementia prevention. Method Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised to determine whether self‐reported physical activity moderates the cross‐sectional relationship between self‐reported sleep parameters (duration, efficiency, latency, disturbance, quality), cognitive function (episodic memory, attention and processing speed, executive function), and brain Aß (quantified by amyloid positron emission tomography, using the Centiloid scale). Analyses were adjusted for age, sex, APOE ε4 carriage, mood, premorbid intelligence, and collection point. Participants were 404 community‐dwelling cognitively normal older adults aged 60 and above (75.3 5.7 years). Data from a subset of participants (n = 220, aged 75.2 5.6 years) were used for analyses with AB as the outcome. Result Physical activity moderated the relationship between sleep duration and episodic memory (ß = ‐.09, SE = .03, p = .005), and sleep efficiency and episodic memory (ß = ‐.08, SE = .03, p = .016). Physical activity moderated the relationship between sleep duration and A® (ß = ‐.12, SE = .06, p = .036), and sleep quality and Aß (ß = .12, SE = .06, p = .029). Conclusion Physical activity may play an important role in the relationship between sleep and cognitive function, and sleep and brain Aß. Future longitudinal and intervention studies in this area are crucial for informing interventions for dementia prevention.
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    Non-negative matrix factorisation improves Centiloid robustness in longitudinal studies
    Bourgeat, P ; Dore, V ; Doecke, J ; Ames, D ; Masters, CL ; Rowe, CC ; Fripp, J ; Villemagne, VL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-02-01)
    BACKGROUND: Centiloid was introduced to harmonise β-Amyloid (Aβ) PET quantification across different tracers, scanners and analysis techniques. Unfortunately, Centiloid still suffers from some quantification disparities in longitudinal analysis when normalising data from different tracers or scanners. In this work, we aim to reduce this variability using a different analysis technique applied to the existing calibration data. METHOD: All PET images from the Centiloid calibration dataset, along with 3762 PET images from the AIBL study were analysed using the recommended SPM pipeline. The PET images were SUVR normalised using the whole cerebellum. All SUVR normalised PiB images from the calibration dataset were decomposed using non-negative matrix factorisation (NMF). The NMF coefficients related to the first component were strongly correlated with global SUVR and were subsequently used as a surrogate for Aβ retention. For each tracer of the calibration dataset, the components of the NMF were computed in a way such that the coefficients of the first component would match those of the corresponding PiB. Given the strong correlations between the SUVR and the NMF coefficients on the calibration dataset, all PET images from AIBL were subsequently decomposed using the computed NMF, and their coefficients transformed into Centiloids. RESULTS: Using the AIBL data, the correlation between the standard Centiloid and the novel NMF-based Centiloid was high in each tracer. The NMF-based Centiloids showed a reduction of outliers, and improved longitudinal consistency. Furthermore, it removed the effects of switching tracers from the longitudinal variance of the Centiloid measure, when assessed using a linear mixed effects model. CONCLUSION: We here propose a novel image driven method to perform the Centiloid quantification. The methods is highly correlated with standard Centiloids while improving the longitudinal reliability when switching tracers. Implementation of this method across multiple studies may lend to more robust and comparable data for future research.
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    Increased cerebral blood flow with increased amyloid burden in the preclinical phase of alzheimer's disease
    Fazlollahi, A ; Calamante, F ; Liang, X ; Bourgeat, P ; Raniga, P ; Dore, V ; Fripp, J ; Ames, D ; Masters, CL ; Rowe, CC ; Connelly, A ; Villemagne, VL ; Salvado, O (WILEY, 2020-02)
    BACKGROUND: Arterial spin labeling (ASL) is an emerging MRI technique for noninvasive measurement of cerebral blood flow (CBF) that has been used to show hemodynamic changes in the brains of people with Alzheimer's disease (AD). CBF changes have been measured using positron emission tomography (PET) across the AD spectrum, but ASL showed limited success in measuring CBF variations in the preclinical phase of AD, where amyloid β (Aβ) plaques accumulate in the decades prior to symptom onset. PURPOSE: To investigate the relationship between CBF measured by multiphase-pseudocontinuous-ASL (MP-PCASL) and Aβ burden as measured by 11 C-PiB PET imaging in a study of cognitively normal (CN) subjects age over 65. STUDY TYPE: Cross-sectional. POPULATION: Forty-six CN subjects including 33 with low levels of Aβ burden and 13 with high levels of Aβ. FIELD STRENGTH/SEQUENCE: 3T/3D MP-PCASL. ASSESSMENT: The MP-PCASL method was chosen because it has a high signal-to-noise ratio. Furthermore, the data were analyzed using an efficient processing pipeline consisting of motion correction, ASL motion correction imprecision removal, temporal and spatial filtering, and partial volume effect correction. STATISTICAL TESTS: General Linear Model. RESULTS: In CN subjects positive for Aβ burden (n = 13), we observed a positive correlation between CBF and Aβ burden in the hippocampus, amygdala, caudate (P < 0.01), frontal, temporal, and insula (P < 0.05). DATA CONCLUSION: To the best of our knowledge, this is the first study using MP-PCASL in the study of AD, and the results suggest a potential compensatory hemodynamic mechanism that protects against pathology in the early stages of AD. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:505-513.
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    Fifteen 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
    Fowler, C ; Rainey-Smith, SR ; Bird, S ; Bomke, J ; Bourgeat, P ; Brown, BM ; Burnham, SC ; Bush, A ; Chadunow, C ; Collins, S ; Doecke, J ; Dore, V ; Ellis, KA ; Evered, L ; Fazlollahi, A ; Fripp, J ; Gardener, SL ; Gibson, S ; Grenfell, R ; Harrison, E ; Head, R ; Jin, L ; Kamer, A ; Lamb, F ; Lautenschlager, NT ; Laws, SM ; Li, Q-X ; Lim, L ; Lim, YY ; Louey, A ; Macaulay, SL ; Mackintosh, L ; Martins, RN ; Maruff, P ; Masters, CL ; McBride, S ; Milicic, L ; Peretti, M ; Pertile, K ; Porter, T ; Radler, M ; Rembach, A ; Robertson, J ; Rodrigues, M ; Rowe, CC ; Rumble, R ; Salvado, O ; Savage, G ; Silbert, B ; Soh, M ; Sohrabi, HR ; Taddei, K ; Taddei, T ; Thai, C ; Trounson, B ; Tyrrell, R ; Vacher, M ; Varghese, S ; Villemagne, VL ; Weinborn, M ; Woodward, M ; Xia, Y ; Ames, D (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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    Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals
    Van der Kall, LM ; Thanh, T ; Burnham, SC ; Dore, V ; Mulligan, RS ; Bozinovski, S ; Lamb, F ; Bourgeat, P ; Fripp, J ; Schultz, S ; Lim, YY ; Laws, SM ; Ames, D ; Fowler, C ; Rainey-Smith, SR ; Martins, RN ; Salvado, O ; Robertson, J ; Maruff, P ; Masters, CL ; Villemagne, VL ; Rowe, CC (LIPPINCOTT WILLIAMS & WILKINS, 2021-02-02)
    OBJECTIVE: To determine the effect of β-amyloid (Aβ) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals. METHODS: All CN from the Australian Imaging Biomarkers and Lifestyle study with Aβ PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aβ positive; follow-up 5.3 ± 1.7 years). Aβ level was divided using the standardized 0-100 Centiloid scale: <15 CL negative, 15-25 CL uncertain, 26-50 CL moderate, 51-100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline. RESULTS: Aβ levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aβ, the hazard ratio for progression for moderate Aβ was 3.2 (95% confidence interval [CI] 1.3-7.6; p < 0.05), for high was 7.0 (95% CI 3.7-13.3; p < 0.001), and for very high was 11.4 (95% CI 5.1-25.8; p < 0.001). Decline in cognitive composite score was minimal in the moderate group (-0.02 SD/year, p = 0.05), while the high and very high declined substantially (high -0.08 SD/year, p < 0.001; very high -0.35 SD/year, p < 0.001). CONCLUSION: The risk of MCI or dementia over 5 years in older CN is related to Aβ level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26-50 CL to 28% if 51-100 CL and 50% if >100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials.
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    Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease
    Huynh, K ; Lim, WLF ; Giles, C ; Jayawardana, KS ; Salim, A ; Mellett, NA ; Smith, AAT ; Olshansky, G ; Drew, BG ; Chatterjee, P ; Martins, I ; Laws, SM ; Bush, AI ; Rowe, CC ; Villemagne, VL ; Ames, D ; Masters, CL ; Arnold, M ; Nho, K ; Saykin, AJ ; Baillie, R ; Han, X ; Kaddurah-Daouk, R ; Martins, RN ; Meikle, PJ (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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    Plasma High Density Lipoprotein Small Subclass is Reduced in Alzheimer's Disease Patients and Correlates with Cognitive Performance
    Pedrini, S ; Hone, E ; Gupta, VB ; James, I ; Teimouri, E ; Bush, A ; Rowe, CC ; Villemagne, VL ; Ames, D ; Masters, CL ; Rainey-Smith, S ; Verdile, G ; Sohrabi, HR ; Raida, MR ; Wenk, MR ; Taddei, K ; Chatterjee, P ; Martins, I ; Laws, SM ; Martins, RN ; Pasinetti, G (IOS PRESS, 2020)
    BACKGROUND: The link between cholesterol and Alzheimer's disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a "good" lipid complex due to its ability to enable clearance of excess cholesterol via 'cholesterol reverse transport', although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL. OBJECTIVE: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition. METHODS: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1-42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. RESULTS: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels. CONCLUSION: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.
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    Evaluation of GammaH2AX in Buccal Cells as a Molecular Biomarker of DNA Damage in Alzheimer's Disease in the AIBL Study of Ageing
    Siddiqui, MS ; Francois, M ; Rainey-Smith, S ; Martins, R ; Masters, CL ; Ames, D ; Rowe, CC ; Macaulay, LS ; Fenech, MF ; Leifert, WR (MDPI, 2020-08)
    In response to double-stranded breaks (DSBs) in chromosomal DNA, H2AX (a member of histone H2A family) becomes phosphorylated to form γH2AX. Although increased levels of γH2AX have been reported in the neuronal nuclei of Alzheimer's disease (AD) patients, the understanding of γH2AX responses in buccal nuclei of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In the current study, endogenous γH2AX was measured in buccal cell nuclei from MCI (n = 18) or AD (n = 16) patients and in healthy controls (n = 17) using laser scanning cytometry (LSC). The γH2AX level was significantly elevated in nuclei of the AD group compared to the MCI and control group, and there was a concomitant increase in P-trend for γH2AX from the control group through MCI to the AD group. Receiver-operating characteristic curves were carried out for different γH2AX parameters; γH2AX in nuclei resulted in the greatest area under the curve value of 0.7794 (p = 0.0062) with 75% sensitivity and 70% specificity for the identification of AD patients from control. In addition, nuclear circularity (a measure of irregular nuclear shape) was significantly higher in the buccal cell nuclei from the AD group compared with the MCI and control groups. Additionally, there was a positive correlation between the nuclear circularity and γH2AX signals. The results indicated that increased DNA damage is associated with AD.
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    Relationships Between Plasma Lipids Species, Gender, Risk Factors, and Alzheimer's Disease
    Lim, WLF ; Huynh, K ; Chatterjee, P ; Martins, I ; Jayawardana, KS ; Giles, C ; Mellett, NA ; Laws, SM ; Bush, AI ; Rowe, CC ; Villemagne, VL ; Ames, D ; Drew, BG ; Masters, CL ; Meikle, PJ ; Martins, RN ; Götz, J (IOS PRESS, 2020)
    BACKGROUND: Lipid metabolism is altered in Alzheimer's disease (AD); however, the relationship between AD risk factors (age, APOEɛ4, and gender) and lipid metabolism is not well defined. OBJECTIVE: We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals. METHODS: We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and interaction analysis were used to explore the relationship between risk factors and plasma lipid species. RESULTS: We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOEɛ4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOEɛ4 may, in part, be mediated by changes in lipid metabolism. CONCLUSION: This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways.