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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological features, including abnormal deposition of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles, and neuronal death. Identifying therapeutics which can reduce memory deficits at an early stage of the disease has the advantage of slowing or even reversing disease progression before irreversible brain damage has occurred. Consequently, in this study, we investigated the ability of the histone deacetylase inhibitor sodium butyrate (NaB) to attenuate memory deficits in the 5xFAD mouse model of AD following a 12-week feeding regimen. 5xFAD mice demonstrate a unique time course of Aβ pathology, developing Aβ plaques as early as 2 months. Male mice were assigned to either a control diet or a NaB-supplemented diet which was administered at either 5 mg/kg/day, or 15 mg/kg/day for 12 weeks (each group, N = 15). Supplementation commenced at an early disease stage (8-10 weeks of age). Behavioral testing (contextual and cued fear conditioning) was undertaken, and brain Aβ levels measured, at the end of the 12-week intervention. NaB had profound effects on Aβ levels and on associative learning and cognitive functioning. A 40% reduction in brain Aβ levels and a 25% increase in fear response in both the cued and contextual testing was observed in the NaB-treated animals compared to the control group. These findings suggest that NaB warrants further investigation as a potential therapeutic agent in the treatment of cognitive deficits associated with early stages of AD. © 2020 - IOS Press and the authors. All rights reserved.

Background: Lipid metabolism is altered in Alzheimer’s disease (AD); however, the relationship between AD risk factors (age, APOE ɛ4, and gender) and lipid metabolism is not well defined. Objective: We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals. Methods: We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and interaction analysis were used to explore the relationship between risk factors and plasma lipid species. Results: We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOE ɛ4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOE ɛ4 may, in part, be mediated by changes in lipid metabolism. Conclusion: This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways.

Background: Changes to lipid metabolism are tightly coupled to the onset and pathology of Alzheimer’s disease (AD). Lipidomics has allowed for unprecedented characterisation of the lipidome within biological systems. To explore the lipid dysregulation associated with AD, we utilised our expanded lipidomics platform, examining 569 lipid species across 32 lipid classes, and applied it to the Australian Imaging, Biomarker & Lifestyle Study of Ageing (AIBL) study and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Method: We examined over 4000 samples between the AIBL and ADNI studies. Baseline samples comprises of 1112 and 804 from the AIBL and ADNI respectively. Univariate associations between lipids and AD were examined using logistic or linear regressions accounting for variables including anthropometric measures and APOE genotype. Cox regression analysis was used to identify lipids associated with future onset of AD from baseline samples. We utilised a fixed effect model to meta analyse the results, identifying lipids which are concordantly associated between the two studies. Result: Exploratory analysis of the data identified strong associations between plasma lipids and AD risk factors such as age (increasing acylcarnitine species), sex (sphingoid base specific) and APOE genotype (ether lipids). Combined meta‐analysis of the two cohorts identified lipid class and subclass‐specific associations with incident and established AD. In the fully adjusted analysis (anthropometric measures, APOE genotype, clinical lipids and medication), a total of 218 species were associated with established AD and 71 with incident AD after correction for FDR. Sphingomyelin, ceramide, ganglioside, plasmalogen and other ether lipids were concordantly associated with AD and its risk factors in both studies. In particular, ether lipids were consistently associated with both established and future AD independent of their subclass (plasmalogen vs non‐plasmalogen) highlighting i

Alzheimer’s disease (AD) is the major form of dementia in the elderly, characterised by progressive decline in cognitive function and the gradual build-up of A amyloid deposits and neurofibrillary tangles in the brain. Due to our aging population, and increasing lifespans, this disease is reaching epidemic proportions: currently 35 million people are estimated to have AD worldwide and within a generation this figure is predicted to increase to 115 million. Although considerable progress has been made into our understanding of AD there is still no effective treatment and no definitive diagnostic test during life. It is now generally recognized that for any drug treatment to be effective, an early diagnostic test for AD is essential. This study investigated the effects of low testosterone and high levels of dietary fats that have been associated with the pathogenesis of AD, and determined whether their effects were more pronounced in APOE e4 carriers, using an animal model of AD. Cholesterol and certain cholesterol metabolite levels were altered by these factors and with age., The findings help demonstrate the inter-relationships between lifestyle factors, age-associated hormone changes in men and APOE genotype on the development of AD and indicate they exert their effects via modulation of brain lipid metabolism. Changes in levels of selected human plasma protein biomarkers were measured in the hope of finding protein changes that indicate AD pathogenesis or pathology. Similarly, a comprehensive screen of plasma lipid levels in AD and control subjects identified several potential novel lipid biomarkers, which together with apoE genotype and protein biomarkers such as the 430kDa reelin protein were analysed to determine their diagnostic significance. The work presented in this thesis supports the theory of a concurrence of changes in multiple factors in the pathogenesis of late onset AD and has identified a selection of candidate biomarkers, which potentially could produce a preliminary biomarker panel for the detection of AD., Thesis (Ph.D.)--University of Western Australia, 2011

Huynh, K., Lim, W. L. F., Giles, C., Jayawardana, K. S., Salim, A., Mellett, N. A., … Meikle, P. J. (2020). Identification of concordant plasma lipid signatures in Alzheimer’s disease: Validation between two independent studies of Alzheimer’s disease. Alzheimer's & Dementia, Biomarkers - Part 2, 16(S5 Supplement), article e042275. https://doi.org/10.1002/alz.042275

Huynh, K., Lim, W. L. F., Giles, C., Jayawardana, K. S., Salim, A., Mellett, N. A., … Meikle, P. J. (2020). Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease. Nature Communications, 11, article 5698. https://doi.org/10.1038/s41467-020-19473-7