Authors: Milicic, Lidija | Porter, Tenielle | Vacher, Michael | Laws, Simon M.
Article Type: Review Article
Abstract: 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. Show more
Keywords: Aging, Alzheimer’s disease, dementia, DNA methylation, epigenetics
DOI: 10.3233/ADR-220109
Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 475-503, 2023
Authors: Porter, Tenielle | Bharadwaj, Prashant | Groth, David | Paxman, Adrian | Laws, Simon M. | Martins, Ralph N. | Verdile, Giuseppe
Article Type: Research Article
Abstract: Latrepirdine (Dimebon™) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer’s disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was …assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties. Show more
Keywords: Alzheimer’s disease, amyloid-beta, latrepirdine, neurotoxicity, Thiofavin T
DOI: 10.3233/JAD-150790
Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 895-905, 2016
Authors: Mehramiz, Mehrane | Porter, Tenielle | O’Brien, Eleanor K. | Rainey-Smith, Stephanie R. | Laws, Simon M.
Article Type: Review Article
Abstract: Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer’s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement …of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid-β and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia. Show more
Keywords: Alzheimer’s disease, dementia, lifestyle, SIRT1, sirtuin-1
DOI: 10.3233/ADR-220088
Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 823-843, 2023
Authors: Brown, Belinda M. | de Frutos Lucas, Jaisalmer | Porter, Tenielle | Frost, Natalie | Vacher, Michael | Peiffer, Jeremiah J. | Laws, Simon M.
Article Type: Research Article
Abstract: Background: Previous research suggests physical activity attenuates grey and white matter loss; however, there appears to be individual variability in this effect. Understanding factors that can influence the relationship between physical activity and brain volume may enable prediction of individual response. Objective: The current study examined the relationship between objectively-measured physical activity and brain volume; and whether this relationship is moderated by age, sex, or a priori candidate genetic factors, brain-derived neurotrophic factor (BDNF ) Val66Met, or apolipoprotein (APOE ) ɛ4 allele carriage. Methods: Data from 10,083 men and women (50 years and over) of the UK Biobank were used …to examine the study objectives. All participants underwent a magnetic resonance imaging scan to quantify grey and white matter volumes, physical activity monitoring via actigraphy, and genotyping. Results: Physical activity was associated with total grey matter volume, total white matter volume, and right hippocampal volume. Only males had an association between higher physical activity levels and greater cortical grey matter volume, total grey matter volume, and right hippocampal volume. Age moderated the relationship between physical activity and white matter volume. Conclusion: Our results indicate that in males, but not females, an association exists between objectively-measured physical activity and grey matter volume. Age may also play a role in impacting the relationship between physical activity and brain volume. Future research should evaluate longitudinal brain volumetrics to better understand the nature of age and sex-effects on the physical activity and brain volume relationship. Show more
Keywords: Dementia, genotype, hippocampus, sex differences
DOI: 10.3233/JAD-220114
Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1091-1101, 2022
Authors: Vacher, Michael | Porter, Tenielle | Milicic, Lidija | Bourgeat, Pierrick | Dore, Vincent | Villemagne, Victor L | Laws, Simon M. | Doecke, James D.
Article Type: Research Article
Abstract: 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 APOE ɛ 4 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. Show more
Keywords: Alzheimer’s disease, blood-brain barrier, brain atrophy, linear mixed model, MRI, single nucleotide polymorphisms
DOI: 10.3233/JAD-210644
Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1817-1829, 2022
Authors: Schäfer Hackenhaar, Fernanda | Josefsson, Maria | Nordin Adolfsson, Annelie | Landfors, Mattias | Kauppi, Karolina | Porter, Tenielle | Milicic, Lidija | Laws, Simon M. | Hultdin, Magnus | Adolfsson, Rolf | Degerman, Sofie | Pudas, Sara
Article Type: Research Article
Abstract: 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 APOE ɛ 4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for ɛ 4-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. Show more
Keywords: Alzheimer’s disease, biomarkers, DNA methylation, epigenomics, longitudinal studies
DOI: 10.3233/JAD-230039
Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1443-1464, 2023
Authors: Roberts, Blaine R. | Laffoon, Scott B. | Roberts, Anne M. | Porter, Tenielle | Fowler, Chris | Masters, Colin L. | Dratz, Edward A. | Laws, Simon M.
Article Type: Short Communication
Abstract: After age, polymorphisms of the Apolipoprotein E (APOE ) gene are the biggest risk factor for the development of Alzheimer’s disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ɛ 2, ɛ 3, and ɛ 4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ɛ 4 (Q222K) mutation did not form dimers or complexes observed for apoE ɛ 2 & ɛ 3 proteins.
Keywords: Alzheimer’s disease, APOE, biomarkers, 2D PAGE, mutation, plasma, proteogenomics
DOI: 10.3233/ADR-220075
Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 165-172, 2023
Authors: Moussavi Nik, Seyyed Hani | Porter, Tenielle | Newman, Morgan | Bartlett, Benjamin | Khan, Imran | Sabale, Miheer | Eccles, Melissa | Woodfield, Amy | Groth, David | Dore, Vincent | Villemagne, Victor L. | Masters, Colin L. | Martins, Ralph N. | Laws, Simon M. | Lardelli, Michael | Verdile, Giuseppe
Article Type: Research Article
Abstract: Background: The PRESENILIN genes (PSEN1 , PSEN2 ) encoding for their respective proteins have critical roles in many aspects of Alzheimer’s disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. Objective: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. Methods: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem brain tissue (frontal cortex and hippocampus) from control, AD, …frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. Results: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V /PSEN2 ratios were increased in mild cognitive impairment (p = 0.024) and AD (p = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n = 62, β= –0.269, p = 0.03). Conclusion: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration. Show more
Keywords: Alzheimer’s disease, frontotemporal dementia, Lewy body dementia, lymphocytes, neurodegeneration, Presenilin 2
DOI: 10.3233/JAD-201133
Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1479-1489, 2021
Authors: Porter, Tenielle | Burnham, Samantha C. | Milicic, Lidija | Savage, Greg | Maruff, Paul | Lim, Yen Ying | Li, Qiao-Xin | Ames, David | Masters, Colin L. | Rainey-Smith, Stephanie | Rowe, Christopher C. | Salvado, Olivier | Groth, David | Verdile, Giuseppe | Villemagne, Victor L. | Laws, Simon M. | for the AIBL Research Group
Article Type: Research Article
Abstract: 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. Show more
Keywords: Alzheimer’s disease, amyloid-β, cognitive decline, episodic memory, polygenic risk scores
DOI: 10.3233/JAD-180713
Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1193-1211, 2018
Authors: Hollands, Simone | Lim, Yen Ying | Laws, Simon M. | Villemagne, Victor L. | Pietrzak, Robert H. | Harrington, Karra | Porter, Tenielle | Snyder, Peter | Ames, David | Fowler, Christopher | Rainey-Smith, Stephanie R. | Martins, Ralph N. | Salvado, Olivier | Robertson, Joanne | Rowe, Christopher C. | Masters, Colin L. | Maruff, Paul | for the AIBL Research Group
Article Type: Research Article
Abstract: Background: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE ) ɛ 4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOE ɛ 4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ. Objective: To determine the extent and nature to which APOE ɛ 4 increases risk for clinical disease progression in CN older adults. Methods: Data from the total (n = 765) and Aβ-imaged (n = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox …proportional hazard models to estimate ɛ 4 risk for clinical disease progression over a 72-month follow-up. Results: With Aβ status unknown and risk from demographic characteristics controlled, ɛ 4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ 4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ 4 carriage was no longer predictive of clinical disease progression. Conclusion: In CN older adults, the risk of ɛ 4 for clinical disease progression occurs through the effect of ɛ 4 increasing Aβ levels. Show more
Keywords: Alzheimer’s disease, Alzheimer type dementia, amyloid-β, apolipoprotein E4, positron emission tomography
DOI: 10.3233/JAD-161019
Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 411-422, 2017
