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The paper considers the procedure for determining the brachistochronic motion of the Chaplygin sleigh in a vertical plane, where the blade is such that it prevents the motion of the contact point in one direction only. The position of the sleigh mass center and orientation at the final positions is specified, as well as the initial value of mechanical energy. The simplest formulation of a corresponding optimal control problem is given and it is solved by applying Pontryagin’s maximum principle. For some cases, analytical solutions of differential equations of the two-point boundary value problem (TPBVP) of the maximum principle were found. Numerical integration was carried out for other cases using the shooting method, where the assessment of missing terminal conditions was given and it was shown that the solution obtained represents the global minimum time for the brachistochronic motion. The method of the brachistochronic motion by means of a single holonomic and a single unilateral nonholonomic mechanical constraint is presented.

Rare earth elements (REE) are frequently referred to as ingredients for enhancements in modern industry, as they are extensively applied in many industrial branches due to their accented electro-magnetic and optical properties. REE have end-utilizations as catalysts, magnets, and as dopants for ceramic materials. Rare earth minerals are scarce therefore the unconventional REE-containing resources such as waste materials and industrial byproducts are continuously being investigated. Coal combustion products comprise REE concentrations varying between 200 ppm and 1500 ppm. This quantity can be isolated though the extraction procedure. In this study, the five stages extraction was conducted on the coal combustion ash from the selected landfill site. The extractions of 32 elements (As, Ga, Ce, Be, Ge, Nd, Cr, Zr, Eu, Cu, Nb, Gd, Co, Mo, Dy, Li, Ag, W, Mn, Cd, Au, Ni, In, Hg, Pb, Sn, Tl, V, Sb, Th, Zn, and La) were conveyed. Chemical analyses were conducted via XRF, ICP-OES, ICP-MS, and AAS techniques. The complexity of the obtained data was examined by Principal component analysis and Cluster analysis in order to derive interconnections between quantity of elements and landfill characteristics, as well as mutual relationships among the elements of interest, and to assess the accomplishment of REE recovery from the coal ash.

Micro-silica is a highly efficient mineral additive whose role is reflected in improvements of microstructure packing, strength and durability of non-shaped composite building materials such as concrete and mortar. A comparative study of performances of rendering mortars with different quantities of micro silica was conducted. The experimental program included production of reference mortar based on Portland cement and quartz sand (CM) and three mortars with 5, 10, and 15 % addition of micro silica (SCM-5, SCM-10, and SCM-15). The effect that micro silica addition has on the thermal behavior and mechanical properties of mortars was discussed. Hydration mechanisms and thermally induced reactions were studied at temperatures ranging from ambient to 1100 °C by differential thermal analysis. The results were supported by X-ray diffraction analysis. The cementing efficiency of micro silica was assessed by cavitation erosion test. The changes in the morphology of mortar samples prior and upon cavitation testing were monitored by means of the scanning electron microscope imagining. It was found that 5 % of superfine micro silica (SCM-5 mortar) has positive effects on mechanical strengths (15 % increase in compressive strength) due to microstructure densification arising from the successive filling of voids by the micro silica. Addition of micro silica also improved the cavitation erosion resistance in comparison with reference cement mortar (SCM-5 showed cavitation velocity as low as 0.09 mg/min). This qualifies mortars with micro silica addition as building materials which can be safely employed in potential hydro-demolition environment.

A modification of an analytical procedure for the energy-dispersive X-ray fluorescence (EDXRF) quantification of ten chemical elements (As, Ba, Cd, Co, Cr, Cu, Mo, Ni, Pb and Zn) in the leachates obtained from cement binders was developed. Twenty-nine testing samples were used in the experiment. All samples were based on Portland cement. Fly ash of different origin, zeolite and bentonite were employed as mineral additives in the cement binders. Distilled water was used as the leachate. Validation of the modified EDXRF procedure was conducted in terms of limits of detection and quantification, working range, linearity, selectivity, precision, trueness, and robustness. Traceability of the procedure was established using certified reference materials. Uncertainty of measurement was confirmed via an “in-house” laboratory validation approach. The expanded uncertainties for the ten analysed elements were obtained for the entire working range of the EDXRF method. Robustness of the modified EDXRF procedure was assessed by means of a chemometric in-house approach. The results obtained by the modified X-ray fluorescence method were additionally correlated to those acquired by inductively coupled plasma optical emission spectrometry to confirm that EDXRF could be used as an effective and reliable alternative method for analysis of cement leachates.

This experimental study was conducted with an aim to investigate the effect of the elevated temperature on the mineral phase composition, microstructure and mechanical properties of the thermal insulation lightweight concretes. The first group of experimental concretes was based on the expanded vermiculite and expanded perlite used as lightweight aggregates (in 65 wt%) in combination with either ordinary Portland cement or refractory calcium aluminate cement. The mix-design of the second group of concretes comprised standard quartz aggregate, vermiculite or perlite as aggregate replacement (25 wt%) and binder (PC or CAC). A total of 10 concrete mix-designs were fabricated in form of 40×40×160 mm samples which were submitted to heat-treatment at 400°, 600°, 800° and 1000°C upon standard 28-days period of curing and hardening. The changes in crystallinity and mineral phase composition induced by temperature were monitored by X-ray diffraction technique. Microstructural visualizations of the non-fired and fired concrete samples were conducted by scanning electron microscopy accompanied with EDX analysis. The results indicated that despite the decrease in compressive strengths upon firing, investigated lightweight concretes can be categorized both as thermal insulators and structural materials.

New global tendencies for waste materials reusing in building materials are imposing the request for improved performances of chemical analysis methods and the improvements of matrices used. A new method for optical emission spectrometry with inductively coupled plasma (ICP-OES) is developed and validated for the chemical analysis (35 elements: Al, Be, Cd, So, Cr, Cu, Fe, Mn, Mo, Ni, V, Mo, Zn, Pb , Bi, Si, Zr, W, As, Se, Sb, Sn, Ti, Ba, B, Ag, Mg, Ca, K, Na, S, P, Ga, In, Li) in leachate of fly ash. Validation performances and the uncertainty оf measurement were resolved. Uncertainty оf measurements were resolved by three routes: validation procedure, participation in proficiency testing (PT) schemes and standard method. The obtained method is a new simple and effective analyzing route for determination of undesired trace elements and their quantity comprised in leachates of fly ash, and leachates of building materials with addition of fly ash (cement binders and mortars). In order to prove its accuracy and precision, the developed method was employed on laboratory samples of cement binders and mortars. Results were compared with limit values provided in the standard. Multivariate analyses, i.e. cluster analysis and principal component analysis, were applied to establish interrelations between analyzed samples, and to certify the developed ICP-OES method. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 45008 and Grant no. OI 172057]

Mineral additives are extensively applied as cement replacement materials in both construction concrete and mortar. Fly ash is one of the most commonly utilized additives which improve rheological properties, as well as thermal and mechanical behavior of mortar, and as such it has been widely investigated. This industrial byproduct comprises heavy metals in its composition; therefore further research is needed to optimize its effective dosage. Moreover, certain sorptive clays, such as natural zeolite and bentonite, can prevent migration of toxic elements from fly ash by immobilizing them in their structure. Ten experimental mortars are prepared with Portland cement, river sand and addition of fly ash, zeolite and/or bentonite in accordance with chemometric experimental design rules. The aim of the study was to investigate the effect of mineral additives on thermal and mechanical performances of mortar. Thermal characteristics were monitored via dilatometric analysis and DTA method. Principal component analysis was used on the results of physico-mechanical testing (workability, bulk density, water absorption, shrinkage, compressive and flexural strength) to enable the divisions of the observed samples into groups in the factor space. The performance of Artificial Neural Network was compared with the experimental data in order to develop rapid and accurate method for prediction of mechanical parameters of mortar. The ANN model showed high overall prediction accuracy (r2 = 0.989, during training cycle). The test results indicate that incorporation of the mineral additives gave cost effective mortars with sufficiently good properties. However, tools of analytical modeling highlighted mortar with zeolite and fly ash as the optimal composition regarding its mechanical performance. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 45008 and Grant no. ON 172057]

Mineral additives are extensively applied as cement replacements in building concretes and mortars. Fly ash is one of the most commonly used additives which enhance rheological, mechanical and thermal properties of material. However, this industrial byproduct comprises heavy metals; therefore the optimization of its effective dosage is necessary. Clayey materials, such as zeolite and bentonite, can prevent migration of toxic elements from fly ash by immobilizing them in their structure. In this paper, three experimental mortars where designed, prepared and investigated. Mortars were based on Portland cement, river sand and mineral additive - fly ash, zeolite and bentonite. Mortar M1 comprised all three additives used in 1:1:1 ratio, mortar M2 contained zeolite and bentonite in 1:2 ratio, while ratio of zeolite and bentonite in M3 mortar was 2:1. The aim of the study was to investigate the effect of mineral additives on physico-chemical, thermal and mechanical performances of mortar. X-ray diffraction, DTA, dilatometry and FRIR analyses were applied on mortar samples. The results of the investigation highlighted that economical mortar with good properties can be obtained by application of these mineral additives.

Amount of fly ash which is and yet to be generated in the coming years highlights the necessity of developing new methods of the recycling where this waste can be reused in significant quantity. A new possibility for fly ash utilization is in high-temperature application (thermal insulators or/and refractory material products). As such, fly ash has to adequately answer the mechanical and thermal stability criteria. One of the ways of achieving it is by applying mechanical activation procedure on fly ash. In present study, fly ashes from two different power plants were mechanically activated in a planetary ball mill. Mechanically treated fly ashes were cemented with two different binders: standard Portland cement and high-aluminates cement. Physico-chemical analysis and investigation of mineralogical components of composites are emphasized, due to the changes occurred in fly ash during mechanical activation and sintering of composites. Macro-performance of the composites was correlated to the microstructure of fly ash studied by means of XRD and SEM analysis. Thermal stability of crystalline phases was investigated with DTA. Highlight was placed on determination of relationship between mechanically activated fly ash and obtained composites microstructure on one side and behavior of sintered composites on the other side. [Projekat Ministarstva nauke Republike Srbije, br. 172057, 45008 and a project F-198, financed by Serbian Academy of Sciences and Arts]

The disposal of the fly ash generated in coal based power-plants may pose a significant risk to the environment due to the possible leaching of hazardous pollutants, such as toxic metals. Also, there is a risk of leaching even when fly ash is built-in the construction composites. Fly ashes from various landfills were applied in several composite samples (mortar, concrete and brick) without any physical or thermal pre-treatment. The leachability of the potentially toxic pollutants from the fly ash based products was investigated. The leaching behavior and potential environmental impact of the 11 potentially hazardous elements was tracked: Pb, Cd, Zn, Cu, Ni, Cr, Hg, As, Ba, Sb and Se. A detailed study of physico-chemical characteristics of the fly ash, with accent on trace elements and the chemical composition investigation is included. Physico/chemical properties of fly ash were investigated by means of X-ray fluorescence, differential thermal analysis and X-ray diffraction methods. Scanning electron microscope was used in microstructural analysis. The results show that most of the elements are more easily leachable from the fly ash in comparison with the fly ash based composites. The leaching of investigated pollutants is within allowed range thus investigated fly ashes can be reused in construction materials production.

The metakaolin was produced by thermal treatment (calcination) of the starting high-quality kaolin clay from Serbia. The optimal calcination parameters, for which nearly complete dehydroxylation of the material was achieved, are: temperature 650°C and heating time of 90 min. The conversion of the kaolinite to metakaolin was confirmed by XRD and IR analyses of the starting and thermally treated kaolin samples. The pozzolanic activity was determined by Chapelle test. The obtained value 0.65 g Ca(OH)2/g of metakaolin indicates that produced metakaolin may be used as supplementary cementitious material.

Objectives: There are currently 29 genome regions that demonstrate associations with Alzheimer's disease (AD) risk. Regular physical exercise can promote systemic change in gene expression and may modify the risk of cognitive decline and AD. This study is a secondary analysis of a randomised controlled trial and examines the effect of a six-month exercise intervention versus control on AD-related gene expression., Design: Single-site parallel pilot randomised controlled trial., Methods: 91 cognitively unimpaired older adults were enrolled in the Intense Physical Activity and Cognition (IPAC) study. Participants were randomised into one of three groups: high-intensity exercise, moderate-intensity exercise, or inactive control for six months. Blood samples were collected prior to, and within two weeks of intervention completion, for later expression analysis of 96 genes. To explore the relationship between changes in gene expression and the intervention groups, an interaction term ("time point × intervention group") was subsequently used., Results: There were no significant differences in gene expression between the three intervention groups at baseline, nor after the intervention. Within groups, five genes were upregulated, seven were downregulated and the remainder remained unchanged. None of the examined genes showed significant change from pre- to post-intervention in the exercise groups compared to the control., Conclusions: Exercise does not change AD-related gene expression in cognitively unimpaired older adults. Several gene expression targets have been identified for further study., Competing Interests: Declaration of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Belinda M. Brown reports that financial support was provided by National Health and Medical Research Council. Belinda M. Brown reports that financial support was provided by Brain Foundation. Simon M. Laws reports a relationship with Cytox Group Limited that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 of CpGs. A number of studies have found associations between disease and/or disease risk with increased biological age, adding weight to the theory of increased biological age being linked with disease processes. Hence, this review takes a closer look at the utility of DNA methylation as a biomarker in aging and disease, with a particular focus on Alzheimer's disease., Competing Interests: The authors have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)

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 Discriminant Analysis applied at pre- (10-16 years), and post-AD-onset time-points., Results: EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOEɛ4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for ɛ4-allele carriage; AUCs = 77.2% versus 87.0%). Literature review showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.

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 associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes., (© 2022. The Author(s).)

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 the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we investigated associations between the PHS and several AD-related traits, including 1) cross-sectional Aβ-amyloid (Aβ) deposition, 2) longitudinal brain atrophy, 3) longitudinal cognitive decline, 4) age of onset. Except in the cognitive domain, we obtained results that were consistent with previously published findings. The PHS was associated with increased Aβ burden, faster regional brain atrophy and an earlier age of onset., Conclusion: Overall, the results support the predictive power of a PHS, however, with only marginal improvement compared to apolipoprotein E alone., (© 2022. The Author(s).)

Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens., Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP)., Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change., Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOEɛ4 allele and were significant post correction for multiple comparisons., Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation.

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., Competing Interests: The following authors have no CoI to declare: CF, SRRS, SB, JB, PB, BMB, SCB, CC, JD, VD, KAE, LE, AF, JF, SLG, SG, RG, EH, RH, LJ, AK, FL, NTL, QXL, LL, YYL, AL, SLM, LMa, SM, LMi, MP, KP, TP, MRa, AR, JR, MRo, RR, OS, GS, BS, MS, HRS, KT, TT, CT, BT, RT, MV, MWe, MWo, YX. AIB is a shareholder in Alterity Therapeutics Ltd, Cogstate Ltd, Mesoblast Ltd, and is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd. SC has received payments from Biogen for advice in relation to CSF biomarkers of Alzheimer’s disease. SML has previously been a paid consultant to Alzhyme. RNM is founder of, and owns stock in, Alzhyme, and is a co-founder of the KaRa Institute of Neurological Diseases. PM is a full-time employee of Cogstate Ltd. CLM is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. CCR has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare and AstraZeneca, has received speaker honoraria from Bayer Pharma and GE Healthcare, and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. VLV has served as a consultant for Bayer Pharma and received research support from a NEDO grant from Japan. DA has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, and Pfizer Inc., (© 2021 – The authors. Published by IOS Press.)

Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

., Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer's disease., Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults., Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study., Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ 4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ 4/rs11023139-A carriers declined significantly faster than APOE ɛ 4/rs11023139-G&#95;G carriers in measures of global cognition ( p  = 0.011) and verbal episodic memory ( p  = 0.020)., Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ 4 cognitively normal older adults with a high neocortical amyloid-β burden., Competing Interests: CLM is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. PM is a full-time employee of Cogstate Ltd. DA has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, and Pfizer Inc. RNM is a consultant to Alzhyme. HRS has received/is receiving remuneration from activities with Pfizer and Takeda pharmaceuticals. CCR has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare and AstraZeneca; has received speaker honoraria from Bayer Pharma and GE Healthcare; and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. VLV served as a consultant for Bayer Pharma; and received research support from a NEDO grant from Japan. SML serves on the scientific advisory board of Cytox Ltd. All other authors have no conflicts of interest to report., (© 2021 – The authors. Published by IOS Press.)

The accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer's disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ-) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts.

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol- O -methyltransferase ( COMT ) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E ( APOE) ε4 allele on cognition in preclinical Alzheimer's disease (AD). In 598 cognitively normal older adults with known neocortical Aβ levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aβ-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults.

The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-β (Aβ) burden, and carriage of the apolipoprotein E (APOE) ε4 allele on cognitive decline. This study involved 581 Aβ-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aβ burden and APOE ε4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aβ burden and APOE ε4-driven cognitive decline in preclinical AD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS ( em PRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample ( n = 151). These were then summed to generate a em PRS either including APOE ( em PRS c̅ APOE ) or excluding APOE ( em PRS s̅ APOE ). Resultant em PRS were then evaluated, in a test sample ( n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of em PRSs were observed with baseline cognition, the em PRS c̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The em PRS s̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the em PRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The em PRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel em PRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.

The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.

A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer's disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Aβ-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aβ-amyloid levels across study duration. In comparison to APOE ε4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE ε4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aβ-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aβ-amyloid and APOE ε4.

Background: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood., Objective: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline., Methods: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC)., Results: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype., Conclusions: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Background: Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer's disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention., Methods: Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults., Results: Results revealed that Aβ+ older adults experienced faster decline than Aβ- older adults in all cognitive domains (Cohen's d at 6-year assessment = 0.37-0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type., Conclusions: In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD., (Published by Elsevier Inc.)