Abstract
Background
In addition to being the greatest risk factor for Alzheimer's disease (AD), ageing also results in the deregulation of hormonal homeostasis. The steroidogenesis pathway describes the synthesis of the steroid hormones (progestagens, androgens, estrogens, mineralo- and gluco- corticoids) from cholesterol. Changes in hormone levels, in particular cortisol, testosterone and oestrogen, have been associated with the promotion of neurodegeneration and the aggregation of beta amyloid and tau. This suggests that alterations in steroid synthesis could be associated with an increased risk of developing AD. The study described below aimed to further investigate steroidogenesis with regards to AD.
Methods
Through a fine-mapping approach, using tagSNPs (Haploview, r 2 cut-off 0.9), 88 polymorphisms across 15 genes were selected and genotyped within the Australian Imaging, Biomarkers & Lifestyle (AIBL) Study of Aging cohort (1473 samples) and investigated in relation to AD-risk and clinical phenotypes (i.e. neocortical amyloid burden, hippocampal volume and cognitive performance). Variants were also investigated with regards to endogenous hormone levels (i.e. circulating free testosterone (cFT), cortisol, and estradiol).
Results
Risk association analyses yielded positive associations between two variants within steroid 5-aplpha-reductase (SRD5A1; rs518763 & rs248803; increased risk; FDR corrected P value (Q)=0.045) and one variant within Aldo-keto Reductase family 1, member C3 (AKR1C3; rs4881400; decreased risk; Q=0.045) and AD in a dominant model. Additionally, in a recessive model a variant (rs6203) in 3-Beta-hydroxysteroid dehydrogenase gene (HSD3B1) was also associated with increased AD-risk (Q=0.034). Regression analysis revealed that increased amyloid burden was associated with carrying the minor allele for SRD5A1 rs518763 (P=0.031), whereas rs248803 within that same gene was associated with decreased hippocampal volume (P=0.013). Both rs518673 (P=0.035) and rs248803 (P=0.044) polymorphisms within SRD5A1 in addition to rs6203 (P=0.010) in HSD3B1 were associated to poorer cognitive performance on a memory task. Only trends towards associations with measured hormone levels were observed.
Conclusions
This project suggests that variations within the steroidogenic pathway modulates the risk towards developing AD and is associated with AD phenotypes. This project is also the first to identify variants within SRD5A1, AKR1C3 and HSD3B1 as having an association with the modulation of AD risk and clinical phenotypes.