Medicine and Health Sciences Commons^™

The Impact Of Exercise On Blood-Based Biomarkers Of Alzheimer’S Disease In Cognitively Unimpaired Older Adults, Kelsey R. Sewell, Stephanie R. Rainey-Smith, Steve Pedrini, Jeremiah J. Peiffer, Hamid R. Sohrabi, Kevin Taddei, Shaun J. Markovic, Ralph N. Martins, Belinda M. Brown

Research outputs 2022 to 2026

Physical activity is a promising preventative strategy for Alzheimer’s disease: it is associated with lower dementia risk, better cognition, greater brain volume and lower brain beta-amyloid. Blood-based biomarkers have emerged as a low-cost, non-invasive strategy for detecting preclinical Alzheimer’s disease, however, there is limited literature examining the effect of exercise (a structured form of physical activity) on blood-based biomarkers. The current study investigated the influence of a 6-month exercise intervention on levels of plasma beta-amyloid (A 42, A 40, A 42/40), phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) chain in cognitively unimpaired older adults, and …

A Systematic Review Of Dementia Research Priorities, Manonita Ghosh, Pelden Chejor, Melanie Baker, Davina Porock

Research outputs 2022 to 2026

Introduction: Patient involvement is a critical component of dementia research priority-setting exercises to ensure that research benefits are relevant and acceptable to those who need the most. This systematic review synthesises research priorities and preferences identified by people living with dementia and their caregivers. Methods: Guided by Joanna Briggs Institute methodology, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework, we conducted a systematic search in five electronic databases: CINAHL, Medline, PsycINFO, Web of Science and Scopus. The reference lists of the included studies were also manually searched. We combined quantitative and qualitative data for synthesis and descriptive thematic …

Large Multi-Ethnic Genetic Analyses Of Amyloid Imaging Identify New Genes For Alzheimer Disease, Muhammad Ali, Derek B. Archer, Priyanka Gorijala, Daniel Western, Jigyasha Timsina, Maria V. Fernández, Ting Chen Wang, Claudia L. Satizabal, Qiong Yang, Alexa S. Beiser, Ruiqi Wang, Gengsheng Chen, Brian Gordon, Tammie L.S. Benzinger, Chengjie Xiong, John C. Morris, Randall J. Bateman, Celeste M. Karch, Eric Mcdade, Alison Goate, Sudha Seshadri, Richard P. Mayeux, Reisa A. Sperling, Rachel F. Buckley, Keith A. Johnson, Hong-Hee Won, Sang-Hyuk Jung, Hang-Rai Kim, Sang W. Seo, Hee J. Kim, Elizabeth Mormino, Simon M. Laws, Kang-Hsien Fan, M. Ilyas Kamboh, Prashanthi Vemuri, Vijay K. Ramanan, Hyun-Sik Yang, Allen Wenzel, Hema S. R. Rajula, Aniket Mishra, Carole Dufouil, Stephanie Debette, Oscar L. Lopez, Steven T. Dekosky, Feifei Tao, Michael W. Nagle, Timothy J. Hohman, Yun J. Sung, Logan Dumitrescu, Carlos Cruchaga, Knight Alzheimer Disease Research Center (Knight Adrc), The Dominantly Inherited Alzheimer Network (Dian), Alzheimer's Disease Neuroimaging Initiative (Adni), Adni-Dod, A4 Study Team, The Australian Imaging Biomarkers, Lifestyle (Aibl) Study

Research outputs 2022 to 2026

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (AB) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE 4; rs429358; = 0.35, SE = 0.01, P = 6.2 × 10–311, MAF = 0.19), driven by APOE 4, and five additional novel associations (APOE 2/rs7412; rs73052335/rs5117, rs1081105, …

Alzheimer’S Disease Genetic Risk And Cognitive Reserve In Relationship To Long-Term Cognitive Trajectories Among Cognitively Normal Individuals, Corinne Pettigrew, Jurijs Nazarovs, Anja Soldan, Vikas Singh, Jiangxia Wang, Timothy Hohman, Logan Dumitrescu, Julia Libby, Brian Kunkle, Alden L. Gross, Sterling Johnson, Qiongshi Lu, Corinne Engelman, Colin L. Masters, Paul Maruff, Simon M. Laws, John C. Morris, Jason Hassenstab, Carlos Cruchaga, Susan M. Resnick, Melissa H. Kitner-Triolo, Yang An, Marilyn Albert

Research outputs 2022 to 2026

Background:

Both Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition.

Methods:

Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by …

How Does Apolipoprotein E Genotype Influence The Relationship Between Physical Activity And Alzheimer’S Disease Risk? A Novel Integrative Model, Jaisalmer De Frutos Lucas, Kelsey R. Sewell, Alejandra García-Colomo, Shaun Markovic, Kirk I. Erickson, Belinda M. Brown

Research outputs 2022 to 2026

Background:

Wide evidence suggests that physical activity (PA) confers protection against Alzheimer’s disease (AD). On the other hand, the apolipoprotein E gene (APOE) ε₄ allele represents the greatest genetic risk factor for developing AD. Extensive research has been conducted to determine whether frequent PA can mitigate the increased AD risk associated with APOE ε₄. However, thus far, these attempts have produced inconclusive results. In this context, one possible explanation could be that the influence of the combined effect of PA and APOE ε₄ carriage might be dependent on the specific outcome measure utilised.

Main body:

In …

Early Visual Alterations In Individuals At-Risk Of Alzheimer’S Disease: A Multidisciplinary Approach, Inés López-Cuenca, Alberto Nebreda, Alejandra García-Colomo, Elena Salobrar-García, Jaisalmer De Frutos-Lucas, Ricardo Bruña, Ana I. Ramírez, Federico Ramirez-Toraño, Juan J. Salazar, Ana Barabash, Pedro Gil, Fernando Maestú, José M. Ramírez, Rosa De Hoz

Research outputs 2022 to 2026

Background: The earliest pathological features of Alzheimer’s disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease. …

Ketone Bodies Mediate Alterations In Brain Energy Metabolism And Biomarkers Of Alzheimer’S Disease, Matin Ramezani, Malika Fernando, Shaun Eslick, Prita R. Asih, Sina Shadfar, Ekanayaka M. S. Bandara, Heidi Hillebrandt, Silochna Meghwar, Maryam Shahriari, Pratishtha Chatterjee, Rohith Thota, Cintia B. Dias, Manohar L. Garg, Ralph N. Martins

Research outputs 2022 to 2026

Alzheimer’s disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta () plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including A , phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and …

Two-Year Prognostic Utility Of Plasma P217+Tau Across The Alzheimer’S Continuum, A. Feizpour, V. Doré, J. D. Doecke, Z. S. Saad, G. Triana-Baltzer, R. Slemmon, P. Maruff, N. Krishnadas, P. Bourgeat, K. Huang, C. Fowler, S. R. Rainey-Smith, A. I. Bush, L. Ward, J. Robertson, R. N. Martins, C. L. Masters, V. L. Villemagne, J. Fripp, H. C. Kolb, C. C. Rowe

Research outputs 2022 to 2026

Background: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid- (A ) and tau in Alzheimer’s Disease (AD). However, its association with longitudinal cognition and comparative performance to PET A and tau in predicting cognitive decline are unknown. Objectives: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on A (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost …

Utility Of Dna Methylation As A Biomarker In Ageing And Alzheimer’S Disease, Lidija Milicic, Tenielle Porter, Michael Vacher, Simon M. Laws

Research outputs 2022 to 2026

Epigenetic mechanisms such as DNA methylation have been implicated in a number of diseases including cancer, heart disease, autoimmune disorders, and neurodegenerative diseases. While it is recognized that DNA methylation is tissue-specific, a limitation for many studies is the ability to sample the tissue of interest, which is why there is a need for a proxy tissue such as blood, that is reflective of the methylation state of the target tissue. In the last decade, DNA methylation has been utilized in the design of epigenetic clocks, which aim to predict an individual’s biological age based on an algorithmically defined set …

Sixteen-Year Longitudinal Evaluation Of Blood-Based Dna Methylation Biomarkers For Early Prediction Of Alzheimer's Disease, Fernanda Schäfer Hackenhaar, Maria Josefsson, Annelie Nordin Adolfsson, Mattias Landfors, Karolina Kauppi, Tenielle Porter, Lidija Milicic, Simon M. Laws, Magnus Hultdin, Rolf Adolfsson, Sofie Degerman, Sara Pudas, Australian Imaging Biomarkers And Lifestyle Study

Research outputs 2022 to 2026

BACKGROUND: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer's disease (AD) prediction. OBJECTIVE: Testing long-term predictive ability ( > 15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers. METHODS: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares …

Tackling Dementia Together Via The Australian Dementia Network (Adnet): A Summary Of Initiatives, Progress And Plans, Sharon L. Naismith, Johannes C. Michaelian, Cherry Santos, Inga Mehrani, Joanne Robertson, Kasey Wallis, Xiaoping Lin, Stephanie A. Ward, Ralph Martins, Colin L. Masters, Michael Breakspear, Susannah Ahern, Jurgen Fripp, Peter R. Schofield, Perminder S. Sachdev, Christopher C. Rowe

Research outputs 2022 to 2026

In 2018, the Australian Dementia Network (ADNeT) was established to bring together Australia's leading dementia researchers, people with living experience and clinicians to transform research and clinical care in the field. To address dementia diagnosis, treatment, and care, ADNeT has established three core initiatives: the Clinical Quality Registry (CQR), Memory Clinics, and Screening for Trials. Collectively, the initiatives have developed an integrated clinical and research community, driving practice excellence in this field, leading to novel innovations in diagnostics, clinical care, professional development, quality and harmonization of healthcare, clinical trials, and translation of research into practice. Australia now has a national …

Relationship Of Cognition And Alzheimer’S Disease With Gastrointestinal Tract Disorders: A Large-Scale Genetic Overlap And Mendelian Randomisation Analysis, Emmanuel O. Adewuyi, Eleanor K. O’Brien, Tenielle Porter, Simon M. Laws

Research outputs 2022 to 2026

Emerging observational evidence suggests links between cognitive impairment and a range of gastrointestinal tract (GIT) disorders; however, the mechanisms underlying their relationships remain unclear. Leveraging large-scale genome-wide association studies’ summary statistics, we comprehensively assessed genetic overlap and potential causality of cognitive traits and Alzheimer’s disease (AD) with several GIT disorders. We demonstrate a strong and highly significant inverse global genetic correlation between cognitive traits and GIT disorders — peptic ulcer disease (PUD), gastritis-duodenitis, diverticulosis, irritable bowel syndrome, and gastroesophageal reflux disease (GERD), but not inflammatory bowel disease (IBD). Further analysis detects 35 significant (p < 4.37 × 10 ^{− 5}) bivariate local genetic …

Current Insights On The Use Of Insulin And The Potential Use Of Insulin Mimetics In Targeting Insulin Signalling In Alzheimer’S Disease, Amy Woodfield, Tatiana Gonzales, Erik Helmerhorst, Simon Laws, Philip Newsholme, Tenielle Porter, Giuseppe Verdile

Research outputs 2022 to 2026

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of …

Assessment Of A Polygenic Hazard Score For The Onset Of Pre-Clinical Alzheimer’S Disease, Michael Vacher, Vincent Doré, Tenielle Porter, Lidija Milicic, Victor L. Villemagne, Pierrick Bourgeat, Sam C. Burnham, Timothy Cox, Colin L. Masters, Christopher C. Rowe, Jurgen Fripp, James D. Doecke, Simon M. Laws

Research outputs 2022 to 2026

Background: With a growing number of loci associated with late-onset (sporadic) Alzheimer’s disease (AD), the polygenic contribution to AD is now well established. The development of polygenic risk score approaches have shown promising results for identifying individuals at higher risk of developing AD, thereby facilitating the development of preventative and therapeutic strategies. A polygenic hazard score (PHS) has been proposed to quantify age-specific genetic risk for AD. In this study, we assessed the predictive power and transferability of this PHS in an independent cohort, to support its clinical utility. Results: Using genotype and imaging data from 780 individuals enrolled in …

Analysis Of Plasma Proteins Using 2d Gels And Novel Fluorescent Probes: In Search Of Blood Based Biomarkers For Alzheimer’S Disease, Scott B. Laffoon, James D. Doecke, Anne M. Roberts, Jennifer A. Vance, Benjamin D. Reeves, Kelly K. Pertile, Rebecca L. Rumble, Chris J. Fowler, Brett Trounson, David Ames, Ralph Martins, Ashley I. Bush, Colin L. Masters, Paul A. Grieco, Edward A. Dratz, Blaine R. Roberts

Research outputs 2022 to 2026

Background: The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer’s disease. Methods: The concentration of proteins in plasma covers a vast range of 12 orders of magnitude. Therefore, to search for medium to low abundant biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3400 protein species resolved on the 2D …

Sleep, Sirtuin 1 And Alzheimer’S Disease: A Review, Mehrane Mehramiz, Tenielle Porter, Simon Laws, Stephanie R. Rainey-Smith

Research outputs 2022 to 2026

Sleep plays a major role in brain health, and cognition. Disrupted sleep is a well-described symptom of Alzheimer’s disease (AD). However, accumulating evidence suggests suboptimal sleep also increases AD risk. The deacetylase Sirtuin 1 (Sirt 1), encoded by the SIRT1 gene, impacts sleep via its relationship to wake-sleep neurotransmitters and somnogens. Evidence from animal and human studies supports a significant and complex relationship between sleep, Sirt 1/ SIRT1 and AD. Numerous hypotheses attempt to explain the critical impact of Sirt 1/ SIRT1 on wake- and sleep- promoting neurons, their related mechanisms and neurotransmitters. However, there is a paucity of studies …

Visually Identified Tau 18f-Mk6240 Pet Patterns In Symptomatic Alzheimer's Disease, Natasha Krishnadas, Kun Huang, Stephanie A. Schultz, Vincent Doré, Pierrick Bourgeat, Anita M. Y. Goh, Fiona Lamb, Svetlana Bozinovski, Samantha C. Burnham, Joanne S. Robertson, Simon M. Laws, Paul Maruff, Colin L. Masters, Victor L. Villemagne, Christopher C. Rowe

Research outputs 2022 to 2026

Background: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. Objective: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. Methods : Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), …

Characterization Of Retinal Drusen In Subjects At High Genetic Risk Of Developing Sporadic Alzheimer’S Disease: An Exploratory Analysis, Inés López-Cuenca, Elena Salobrar-García, Inés Gil-Salgado, Lidia Sánchez-Puebla, Lorena Elvira-Hurtado, José A. Fernández-Albarral, Federico Ramírez-Toraño, Ana Barabash, Jaisalmer De Frutos-Lucas, Juan J. Salazar, José M. Ramírez, Ana I. Ramírez, Rosa De Hoz

Research outputs 2022 to 2026

Having a family history (FH+) of Alzheimer’s disease (AD) and being a carrier of at least one ε4 allele of the ApoE gene are two of the main risk factors for the development of AD. AD and age-related macular degeneration (AMD) share one of the main risk factors, such as age, and characteristics including the presence of deposits (Aβ plaques in AD and drusen in AMD); however, the role of apolipoprotein E isoforms in both pathologies is controversial. We analyzed and characterized retinal drusen by optical coherence tomography (OCT) in subjects, classifying them by their AD FH (FH-or FH+) and …

Comprehensive Analysis Of Epigenetic Clocks Reveals Associations Between Disproportionate Biological Ageing And Hippocampal Volume, Lidija Milicic, Michael Vacher, Tenielle Porter, Vincent Doré, Samantha C. Burnham, Pierrick Bourgeat, Rosita Shishegar, James Doecke, Nicola J. Armstrong, Rick Tankard, Paul Maruff, Colin L. Masters, Christopher C. Rowe, Victor L. Villemagne, Simon M. Laws, Alzheimer’S Disease Neuroimaging Initiative, Australian Imaging Biomarkers And Lifestyle (Aibl) Study

Research outputs 2022 to 2026

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant …

Mitoprotective Effects Of A Synergistic Nutraceutical Combination: Basis For A Prevention Strategy Against Alzheimer’S Disease, Dona P.W. Jayatunga, Eugene Hone, Binosha W.M.A. Fernando, Manohar L. Garg, Giuseppe Verdile, Ralph N. Martins

Research outputs 2022 to 2026

Evidence to date suggests the consumption of food rich in bioactive compounds, such as polyphenols, flavonoids, omega-3 fatty acids may potentially minimize age-related cognitive decline. For neurodegenerative diseases, such as Alzheimer’s disease (AD), which do not yet have definitive treatments, the focus has shifted toward using alternative approaches, including prevention strategies rather than disease reversal. In this aspect, certain nutraceuticals have become promising compounds due to their neuroprotective properties. Moreover, the multifaceted AD pathophysiology encourages the use of multiple bioactive components that may be synergistic in their protective roles when combined. The objective of the present study was to determine …

A Synergistic Combination Of Dha, Luteolin, And Urolithin A Against Alzheimer’S Disease, Dona P.W. Jayatunga, Eugene Hone, Binosha W.M.A. Fernando, Manohar L. Garg, Giuseppe Verdile, Ralph N. Martins

Research outputs 2022 to 2026

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-β (Aβ) protein aggregates as senile plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated forms of the microtubule-associated protein Tau. There has been limited success in clinical trials for some proposed therapies for AD, so attention has been drawn toward using alternative approaches, including prevention strategies. As a result, nutraceuticals have become attractive compounds for their potential neuroprotective capabilities. The objective of the present study was to derive a synergistic nutraceutical combination in …

Evaluation Of Virtual Screening Strategies For The Identification Of Γ-Secretase Inhibitors And Modulators, Alicia Ioppolo, Melissa Eccles, David Groth, Giuseppe Verdile, Mark Agostino

Research outputs 2022 to 2026

γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer’s disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized …