OML‐Combine: Online Machine Learning tool for Combining datasets to increase power and facilitate multi‐centre collaboration on Alzheimer's disease studies.

Background: Diagnostic and prognostic decisions about Alzheimer’s disease (AD) are more accurate when based on large data sets. We developed and validated a machine learning (ML) data harmonization tool for aggregation of prospective data from neuropsychological tests applied to study AD. The online ML‐combine application (OML‐combine app) allows researchers to utilize the ML‐harmonization method for harmonization of their own data with that from other large available data bases (e.

Plasma phospho‐tau 217 rises with and not before early tau aggregation measured by MK6240 PET.

Background: Rise in plasma phospho‐tau (pTau) is hypothesized to reflect a physiological response to brain Aβ plaques, preceding the formation of neurofibrillary tangles (NFT). An alternate explanation is poor sensitivity of tau PET for detection of early NFT formation. The tau tracer MK6240 has very low background “off‐target” binding and may better detect early tau aggregation.

Plasma p217+tau accurately discriminates Intermediate or Advanced Alzheimer's Disease biological PET stages.

Background: Plasma phospho‐tau biomarkers, such as p217+tau, excel at identifying Alzheimer’s Disease (AD) neuropathology. However, questions remain regarding their capacity to inform AD biological PET stages at group level and maintain the same precision at individual patient level.

Method: Participants included 248 cognitively unimpaired (CU) and 227 cognitively impaired (CI) individuals, with Janssen plasma p217+tau Simoa® assay, F‐NAV4694 Aβ PET (A) and F‐MK6240 tau PET (T) data.

Longitudinal associations between self‐reported exercise levels and Alzheimer’s related biomarkers in Autosomal Dominant Alzheimer’s Disease.

Background: Accumulating evidence indicates exercise may delay or prevent the onset of Alzheimer’s disease (AD). To our knowledge, no study has investigated the longitudinal impact of exercise on AD‐related biomarkers in individuals with Autosomal dominant Alzheimer’s disease (ADAD) mutations who are destined to develop AD. This study examined longitudinal associations between self‐reported exercise levels and AD‐related biomarkers in a cohort of ADAD mutation carriers and investigated whether observed associations depended upon disease stage.

Cross‐cohort epigenome‐wide association study in Alzheimer’s disease risk and related traits.

Background: Epigenome‐wide association studies (EWAS) have identified multiple loci that are differentially methylated in Alzheimer’s disease (AD). However, for complex diseases such as AD, single methylation sites associated with disease and disease‐related traits have relatively low effect sizes. At the genetic level, measures of cumulative genetic risk, such as polygenetic risk scores, have yielded success in risk prediction as well as in association and interaction studies.

Comparing plasma Aβ42/40 and pTau217 to predict Amyloid‐β status across the Alzheimer’s disease continuum.

Background: Recent advances in immunoassays have enabled sensitive detection of Aβ42/40 and pTau217 in plasma, components of Alzheimer’s disease (AD) neuropathological markers. Further characterization of increased diagnostic accuracy with PET Amyloid‐β (Aβ) across the AD continuum is needed for clinical application.

Method: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing (N=197) representing a cross‐sectional population of four clinical and PET‐Aβ subgroups: cognitive unimpaired (CU) Aβ‐ (n=75), CU Aβ+ (n=48), mild cognitive impairment (MCI) Aβ+ (n=26), and AD Aβ+ (n=48).

Plasma metabolites associated with plasma P‐tau181 in preclinical Alzheimer's disease.

Background: Alzheimer's disease (AD) pathogenesis is not restricted to amyloid‐beta, Aβ, and tau pathologies but involves dysregulation in diverse cellular and molecular processes. Numerous metabolomic studies revealed plasma metabolite alterations in AD individuals compared to healthy controls. Nevertheless, plasma P‐tau181, an established biomarker for AD diagnosis and prognosis, has been described to reflect initial multiple cortical region Aβ deposition in cognitively intact adults.

Cross‐cohort epigenome‐wide association study in Alzheimer's disease risk and related traits.

Background: Epigenome‐wide association studies (EWAS) have identified multiple loci that are differentially methylated in Alzheimer’s disease (AD). However, for complex diseases such as AD, single methylation sites associated with disease and disease‐related traits have relatively low effect sizes. At the genetic level, measures of cumulative genetic risk, such as polygenetic risk scores, have yielded success in risk prediction as well as in association and interaction studies.

Plasma phospho‐tau 217 rises with and not before early tau aggregation measured by MK6240 PET.

Background: Rise in plasma phospho‐tau (pTau) is hypothesized to reflect a physiological response to brain Aß plaques, preceding the formation of neurofibrillary tangles (NFT). An alternate explanation is poor sensitivity of tau PET for detection of early NFT formation. The tau tracer MK6240 has very low background “off‐target” binding and may better detect early tau aggregation.

Early identification of participants at risk of cognitive decline: An online tool for patient prediction of cognitive decline.

Background: The success of therapeutic options for treatment of Alzheimer’s disease (AD) and the growing emphasis for such treatment to commence in the pre‐clinical phase makes it necessary to have robust empirical models of clinical disease progression to understand findings from clinical trials, allow clinicians to evaluate effects of new drugs, and to select individuals for future trials. Such models have been developed from relatively small samples, with incomplete data/substantial loss to follow‐up. The ADOPIC consortium provides the largest complete AD natural history sample to date.

Development and Validation of a Tool to Predict Onset of Mild Cognitive Impairment and Alzheimer Dementia.

Importance: The ability to predict the onset of mild cognitive impairment (MCI) and Alzheimer dementia (AD) could allow older adults and clinicians to make informed decisions about dementia care.

Objective: To assess whether the age at onset of MCI and AD can be predicted using a statistical modeling approach.

Design, Setting, And Participants: This prognostic study used data from 2 aging and dementia cohort studies-the Australian Imaging, Biomarker and Lifestyle (AIBL) study and the Alzheimer's Disease Neuroimaging Initiative (ADNI)-for model development and validation of the Florey Dementia Index (FDI), a tool used to predict the age at onset of MCI and AD in older adults.

Sleep discrepancy and brain glucose metabolism in community-dwelling older adults.

Sleep discrepancy (negative discrepancy reflects worse self-reported sleep than objective measures, such as actigraphy, and positive discrepancy the opposite) has been linked to adverse health outcomes. This study is first to investigate the relationship between sleep discrepancy and brain glucose metabolism (assessed globally and regionally via positron emission tomography), and to evaluate the contribution of insomnia severity and depressive symptoms to any associations. Using data from cognitively unimpaired community-dwelling older adults ( = 68), cluster analysis was used to characterise sleep discrepancy (for total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE)), and logistic regression was used to explore sleep discrepancy's associations with brain glucose metabolism, while controlling for insomnia severity and depressive symptoms.

Longitudinal associations between exercise and biomarkers in autosomal dominant Alzheimer's disease.

Introduction: We investigated longitudinal associations between self-reported exercise and Alzheimer's disease (AD)-related biomarkers in individuals with autosomal dominant AD (ADAD) mutations.

Methods: Participants were 308 ADAD mutation carriers aged 39.7 ± 10.

Clearance and transport of amyloid β by peripheral monocytes correlate with Alzheimer's disease progression.

Impaired clearance of amyloid β (Aβ) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aβ clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aβ-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry.

Sleep discrepancy and cognitive function in community-dwelling older adults.

This was the first study to use cluster analysis to characterise sleep discrepancy (the discordance between self-reported and objective sleep) across multiple sleep parameters, in community-dwelling older adults. For sleep efficiency, negative discrepancy (the tendency to self-report worse sleep than objectively-measured) was associated with poorer memory, independent of insomnia severity, depressive symptoms and objective sleep. This suggests a unique role for sleep discrepancy as a possible risk factor for future cognitive decline, and warrants the need for further research.

A comprehensive multi-omics analysis reveals unique signatures to predict Alzheimer's disease.

Background: Complex disorders, such as Alzheimer's disease (AD), result from the combined influence of multiple biological and environmental factors. The integration of high-throughput data from multiple omics platforms can provide system overviews, improving our understanding of complex biological processes underlying human disease. In this study, integrated data from four omics platforms were used to characterise biological signatures of AD.

Suboptimal self-reported sleep efficiency and duration are associated with faster accumulation of brain amyloid beta in cognitively unimpaired older adults.

Introduction: This study investigated whether self-reported sleep quality is associated with brain amyloid beta (Aβ) accumulation.

Methods: Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean ± standard deviation 74.0 ± 6.

Alzheimer's disease biomarker utilization at first referral enhances differential diagnostic precision with simultaneous exclusion of Creutzfeldt-Jakob disease.

Most suspected Creutzfeldt-Jakob disease (CJD) cases are eventually diagnosed with other disorders. We assessed the utility of investigating Alzheimer's disease (AD) biomarkers and neurofilament light (NfL) in patients when CJD is suspected. The study cohort consisted of cerebrospinal fluid (CSF) samples referred for CJD biomarker screening wherein amyloid beta 1-42 (Aβ1-42), phosphorylated tau 181 (p-tau181), and total tau (t-tau) could be assessed via Elecsys immunoassays ( = 419) and NfL via enzyme-linked immunosorbent assay (ELISA;  = 161).

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer's Disease Across Distinct Brain Regions.

Alzheimer's disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) ε4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes in AD have previously been complicated by the influence of apolipoprotein E disparities.

Physical activity and brain amyloid beta: A longitudinal analysis of cognitively unimpaired older adults.

Introduction: The current study evaluated the relationship between habitual physical activity (PA) levels and brain amyloid beta (Aβ) over 15 years in a cohort of cognitively unimpaired older adults.

Methods: PA and Aβ measures were collected over multiple timepoints from 731 cognitively unimpaired older adults participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Aging. Regression modeling examined cross-sectional and longitudinal relationships between PA and brain Aβ.

A pilot study: Metabolic profiling of plasma and saliva samples from newly diagnosed glioblastoma patients.

Background: Despite aggressive treatment, more than 90% of glioblastoma (GBM) patients experience recurrences. GBM response to therapy is currently assessed by imaging techniques and tissue biopsy. However, difficulties with these methods may cause misinterpretation of treatment outcomes.

Diagnostic performance of CSF biomarkers in a well-characterized Australian cohort of sporadic Creutzfeldt-Jakob disease.

The most frequently utilized biomarkers to support a pre-mortem clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) include concentrations of the 14-3-3 and total tau (T-tau) proteins, as well as the application of protein amplification techniques, such as the real time quaking-induced conversion (RT-QuIC) assay, in cerebrospinal fluid (CSF). Utilizing CSF from a cohort of neuropathologically confirmed (definite) sCJD ( = 50) and non-CJD controls ( = 48), we established the optimal cutpoints for the fully automated Roche Elecsys immunoassay for T-tau and the CircuLexTM 14-3-3 Gamma ELISA and compared these to T-tau protein measured using a commercially available assay (INNOTEST hTAU Ag) and 14-3-3 protein detection by western immunoblot (WB). These CSF specimens were also assessed for presence of misfolded prion protein using the RT-QuIC assay.