Abstract
Background
A major research focus of the Australian Imaging Biomarkers and Lifestyle (AIBL) study of ageing is the identification of biomarkers, whose measurable levels are altered during the development of AD. We have previously reported on panel of biomarkers that allow for the classification of AD with high sensitivity and specificity. One of the members of this panel was Cortisol, a primary steroid hormone, which was elevated in AD. This study reports on the validation of cortisol levels in the AIBL study cohort and its association with cognition and neuropathology at baseline and 18-month follow-up time points. Genes involved in cortisol biosynthesis were investigated to determine any genetic underpinning to this association.
Methods
Baseline cortisol levels in the AIBL study cohort, initially assayed on the RBM xMAP panel, were validated and 18-month levels determined using a commercial Cortisol Enzyme-linked immunosorbent assay. Levels at baseline and 18-month time points were then analysed with respect to measures of cognition and neuropathology (hippocampal volume and neocortical Aβ burden). SNP data allowing for the fine mapping of genes involved in cortisol biosynthesis (e.g. 17±OH, 11±OH and others) was derived from a custom Illumina GoldenGate assay or via the OpenArray Platform.
Results
Results from this study confirmed the initial association of elevated cortisol levels in AD, with significant differences observed between HC/MCI and AD groups (no significant differences were observed between HC and MCI groups). Further, this study demonstrated several overall significant correlations between cortisol and measures of neuropathology and cognition. Single marker and haplotype associations with AD risk and quantitative phenotypes were identified using GoldenHelix SVS7 software.
Conclusions
These findings suggest that initial subtle changes in cortisol levels reflect changes in neuropathology rather than the cause thereof. However, the combination of significant elevations between MCI and AD groups and the more pronounced relationship between cortisol and neuropathology in the MCI group, in the context of current literature, provides evidence to suggest that chronic elevated cortisol exposure imparts neurotoxicity. This may result in exacerbated neuropathology, which in a viscous cycle of hippocampal atrophy and over activation of the HPA-axis manifests in overt clinical symptomology and the development of AD.