Biomarkers.

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.

Alzheimer's Imaging Consortium.

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.

Exploration of Alzheimer's disease-related gene expression following high-intensity and moderate-intensity exercise interventions.

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.

Sixteen-Year Longitudinal Evaluation of Blood-Based DNA Methylation Biomarkers for Early Prediction of Alzheimer's Disease.

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.

Utility of DNA Methylation as a Biomarker in Aging and Alzheimer's Disease.

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.

Assessment of a polygenic hazard score for the onset of pre-clinical Alzheimer's disease.

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.

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume.

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).

A Targeted Association Study of Blood-Brain Barrier Gene SNPs and Brain Atrophy.

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).

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease.

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.

Is Associated with Amyloid-β and ε4-Related Cognitive Decline in Cognitively Normal Adults.

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.

Androgen receptor CAG repeat length as a moderator of the relationship between free testosterone levels and cognition.

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.

Validation of a priori candidate Alzheimer's disease SNPs with brain amyloid-beta deposition.

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.

val158met is not associated with Aβ-amyloid and ε4 related cognitive decline in cognitively normal older adults.

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol--methyltransferase () 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 Val158Met on cognitive performance. In particular, it was hypothesised that Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E ( ε4 allele on cognition in preclinical Alzheimer's disease (AD).

Klotho allele status is not associated with Aβ and APOE ε4-related cognitive decline in preclinical Alzheimer's disease.

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.

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease.

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 genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted.

Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study.

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.

Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden.

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.

KIBRA is associated with accelerated cognitive decline and hippocampal atrophy in APOE ε4-positive cognitively normal adults with high Aβ-amyloid burden.

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.

Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer's Disease: A 6-Year Prospective Cohort Study.

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.