Medicine and Health Sciences Commons^™

Apoe Ε2 Resilience For Alzheimer’S Disease Is Mediated By Plasma Lipid Species: Analysis Of Three Independent Cohort Studies, Tingting Wang, Kevin Huynh, Corey Giles, Natalie A. Mellett, Thy Duong, Anh Nguyen, Wei L. F. Lim, Alex A. T. Smith, Gavriel Olshansky, Gemma Cadby, Joseph Hung, Jennie Hui, John Beilby, Gerald F. Watts, Pratishtha Chatterjee, Ian Martins, Simon Laws, Ashley I. Bush, Christopher C. Rowe, Victor L. Villemagne, David Ames, Colin L. Masters, Kevin Taddei, Vincent Doré, Jürgen Fripp, Matthias Arnold, Gabi Kastenmüller, Kwangsik Nho, Andrew J. Saykin, Rebecca Baillie, Xianlin Han, Ralph N. Martins, Eric K. Moses, Rima Kaddurah-Daouk, Peter J. Meikle

Research outputs 2022 to 2026

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 …

Plasma High-Density Lipoprotein Cargo Is Altered In Alzheimer's Disease And Is Associated With Regional Brain Volume, Steve Pedrini, James D. Doecke, Eugene Hone, Penghao Wang, Rohith Thota, Ashley I. Bush, Christopher C. Rowe, Vincent Dore, Victor L. Villemagne, David Ames, Stephanie Rainey-Smith, Giuseppe Verdile, Hamid R. Sohrabi, Manfred R. Raida, Kevin Taddei, Sam Gandy, Colin L. Masters, Pratishtha Chatterjee, Ralph N. Martins, Aibl Research Group

Research outputs 2022 to 2026

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) …

Understanding The Relationship Between Age-Related Hearing Loss And Alzheimer's Disease: A Narrative Review, Hadeel Y. Tarawneh, Dona M. P. Jayakody, Hamid R. Sohrabi, Ralph N. Martins, Wilhelmina H.A.M. Mulders

Research outputs 2022 to 2026

Evidence suggests that hearing loss (HL), even at mild levels, increases the long-term risk of cognitive decline and incident dementia. Hearing loss is one of the modifiable risk factors for dementia, with approximately 4 million of the 50 million cases of dementia worldwide possibly attributed to untreated HL. This paper describes four possible mechanisms that have been suggested for the relationship between age-related hearing loss (ARHL) and Alzheimer's disease (AD), which is the most common form of dementia. The first mechanism suggests mitochondrial dysfunction and altered signal pathways due to aging as a possible link between ARHL and AD. The …

Systemic Perturbations Of The Kynurenine Pathway Precede Progression To Dementia Independently Of Amyloid-Β, Marcela Cespedes, Kelly R. Jacobs, Paul Maruff, Alan Rembach, Christopher J. Fowler, Brett Trounson, Kelly K. Pertile, Rebecca L. Rumble, Stephanie R. Rainey-Smith, Christopher C. Rowe, Victor L. Villemagne, Pierrick Bourgeat, Chai K. Lim, Pratishtha Chatterjee, Ralph N. Martins, Arne Ittner, Colin L. Masters, James D. Doecke, Gilles J. Guillemin, David B. Lovejoy

Research outputs 2022 to 2026

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild …

The Association Between Alzheimer's Disease-Related Markers And Physical Activity In Cognitively Normal Older Adults, Steve Pedrini, Pratishtha Chatterjee, Akinori Nakamura, Michelle Tegg, Eugene Hone, Stephanie R. Rainey-Smith, Christopher C. Rowe, Vincent Dore, Victor L. Villemagne, David Ames, Naoki Kaneko, Samantha L. Gardener, Kevin Taddei, Binosha Fernando, Ian Martins, Prashant Bharadwaj, Hamid R. Sohrabi, Colin L. Masters, Belinda Brown, Ralph N. Martins, Aibl Research Group

Research outputs 2022 to 2026

Previous studies have indicated that physical activity may be beneficial in reducing the risk for Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. The goal of this study was to evaluate the relationship between habitual physical activity levels and brain amyloid deposition and AD-related blood biomarkers (i.e., measured using a novel high-performance mass spectrometry-based assay), in apolipoprotein E (APOE) ε4 carriers and noncarriers. We evaluated 143 cognitively normal older adults, all of whom had brain amyloid deposition assessed using positron emission tomography and had their physical activity levels measured using the International Physical Activity Questionnaire (IPAQ). We …

A Large-Scale Genome-Wide Cross-Trait Analysis Reveals Shared Genetic Architecture Between Alzheimer’S Disease And Gastrointestinal Tract Disorders, Emmanuel O. Adewuyi, Eleanor K. O'Brien, Dale R. Nyholt, Tenielle Porter, Simon Laws

Research outputs 2022 to 2026

Consistent with the concept of the gut-brain phenomenon, observational studies suggest a relationship between Alzheimer’s disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analyse several genome-wide association studies (GWAS) summary statistics (N = 34,652–456,327), to assess the relationship of AD with GIT disorders. Findings reveal a positive significant genetic overlap and correlation between AD and gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis-duodenitis, irritable bowel syndrome and diverticulosis, but not inflammatory bowel disease. Cross-trait meta-analysis identifies several loci (P_{meta-analysis} < 5 × 10⁻⁸) shared by AD and GIT disorders (GERD and PUD) including …

Exploring Discordant Low Amyloid Beta And High Neocortical Tau Positron Emission Tomography Cases, Natasha Krishnadas, Vincent Doré, Simon M. Laws, Tenielle Porter, Fiona Lamb, Svetlana Bozinovski, Victor L. Villemagne, Christopher C. Rowe

Research outputs 2022 to 2026

Introduction: Neocortical 3R4R (3-repeat/4-repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aβ). 18F-MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aβ, but positive tau positron emission tomography (PET) findings. Methods: All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aβ (18F-NAV4694) and tau (18F-MK6240) PET scans were included. Centiloid < 25 defined negative Aβ PET (Aβ–). The presence of neocortical tau was defined quantitatively and visually. Results: Aβ– PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2, and MAPT genes did not identify relevant functional mutations. Discussion: Discordant cases were infrequent (1.4% of all Aβ– participants). In these cases, the Aβ PET ligand may not be detecting the Aβ that is present.

Plasma P-Tau181/Aβ1-42 Ratio Predicts Aβ-Pet Status And Correlates With Csf-P-Tau181/Aβ1-42 And Future Cognitive Decline, Christopher J. Fowler, Erik Stoops, Stephanie R. Rainey-Smith, Eugeen Vanmechelen, Jeroen Vanbrabant, Nele Dewit, Kimberley Mauroo, Paul Maruff, Christopher C. Rowe, Jurgen Fripp, Qiao-Xin Li, Pierrick Bourgeat, Steven J. Collins, Ralph N. Martins, Colin L. Masters, James D. Doecke

Research outputs 2022 to 2026

Background: In Alzheimer's disease (AD), plasma amyloid beta (Aβ)1-42 and phosphorylated tau (p-tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown. Methods: Prototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Results: The p-tau181/Aβ1-42 ratio showed the best prediction of Aβ-PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86–0.95) and in CN (AUC = …

An Il1rl1 Genetic Variant Lowers Soluble St2 Levels And The Risk Effects Of Apoe-Ε4 In Female Patients With Alzheimer’S Disease, Yuanbing Jiang, Xiaopu Zhou, Hiu Yi Wong, Li Ouyang, Fanny C. F. Ip, Vicky M. N. Chau, Shun-Fat Lau, Wei Wu, Daniel Y. K. Wong, Heukjin Seo, Wing-Yu Fu, Nicole C. H. Lai, Yuewen Chen, Yu Chen, Estella P.S. Tong, Alzheimer’S Disease Neuroimaging Initiative, Vincent C. T. Mok, Timothy C. Y. Kwok, Kin Y. Mok, Maryam Shoai, Benoit Lehallier, Patricia Morán Losada, Eleanor O'Brien, Tenielle Porter, Simon Laws, John Hardy, Tony Wyss-Coray, Colin L. Masters, Amy K.Y. Fu, Nancy Y. Ip

Research outputs 2022 to 2026

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD …

Plasma P217+Tau Versus Nav4694 Amyloid And Mk6240 Tau Pet Across The Alzheimer's Continuum, Vincent Doré, James D. Doecke, Ziad S. Saad, Gallen Triana-Baltzer, Randy Slemmon, Natasha Krishnadas, Pierrick Bourgeat, Kun Huang, Samantha Burnham, Christopher Fowler, Stephanie R. Rainey-Smith, Ashley I. Bush, Larry Ward, Jo Robertson, Ralph N. Martins, Colin L. Masters, Victor L. Villemagne, Jurgen Fripp, Hartmuth C. Kolb, Christopher C. Rowe

Research outputs 2022 to 2026

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 …

Cerebrospinal Fluid Levels Of Fatty Acid–Binding Protein 3 Are Associated With Likelihood Of Amyloidopathy In Cognitively Healthy Individuals, Kunal Dhiman, Victor L. Villemagne, Christopher Fowler, Pierrick Bourgeat, Qiao-Xin Li, Steven Collins, Christopher C. Rowe, Colin L. Masters, David Ames, Kaj Blennow, Henrik Zetterberg, Ralph N. Martins, Veer Gupta

Research outputs 2022 to 2026

Introduction: Fatty acid–binding protein 3 (FABP3) is a biomarker of neuronal membrane disruption, associated with lipid dyshomeostasis—a notable Alzheimer's disease (AD) pathophysiological change. We assessed the association of cerebrospinal fluid (CSF) FABP3 levels with brain amyloidosis and the likelihood/risk of developing amyloidopathy in cognitively healthy individuals. Methods: FABP3 levels were measured in CSF samples of cognitively healthy participants, > 60 years of age (n = 142), from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results: FABP3 levels were positively associated with baseline brain amyloid beta (Aβ) load as measured by standardized uptake value ratio (SUVR, standardized β …