Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been reported in subjects with Alzheimer's disease (AD) and may include increased cerebrospinal fluid (CSF) cortisol concentrations. Moreover, presence of the APOE ɛ4 allele, which is an established risk factor for the development of AD, has been shown to associate with higher CSF cortisol levels, especially in AD sufferers. In this study, we examined whether TOMM40 variants, which have been reported to influence age of onset of AD, also had an effect on CSF cortisol levels, in healthy, cognitively intact individuals with or without APOE ɛ4. In our results, the increase in CSF cortisol associated with the presence of the APOE ɛ4 allele was only detected when a short TOMM40 poly-T variant, shown to associate with later age of onset of AD in ɛ4 carriers, was not present. These results are consistent with previous reports (e.g., Roses et al., 2009) suggesting that TOMM40 poly-T variants influence the effects of APOE alleles.

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