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Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants.

ABSTRACT: 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 ?4 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 ?4. In our results, the increase in CSF cortisol associated with the presence of the APOE ?4 allele was only detected when a short TOMM40 poly-T variant, shown to associate with later age of onset of AD in ?4 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.

SUBMITTER: Bruno D

PROVIDER: S-EPMC3207029 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants.

Bruno Davide D Nierenberg Jay J JJ Ritchie James C JC Lutz Michael W MW Pomara Nunzio N

Psychoneuroendocrinology 20110730 3

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 ...[more]

PMID: 21803501

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Project description:IntroductionElevated cortisol levels have been reported in Alzheimer's disease (AD) and may accelerate the development of brain pathology and cognitive decline. Dehydroepiandrosterone sulfate (DHEAS) has anti-glucocorticoid effects and it may be involved in the AD pathophysiology.ObjectivesTo investigate associations of cerebrospinal fluid (CSF) cortisol and DHEAS levels with (1) cognitive performance at baseline; (2) CSF biomarkers of amyloid pathology (as assessed by CSF Aβ levels), neuronal injury (as assessed by CSF tau), and tau hyperphosphorylation (as assessed by CSF p-tau); (3) regional brain volumes; and (4) clinical disease progression.Materials and methodsIndividuals between 49 and 88 years (n = 145) with mild cognitive impairment or dementia or with normal cognition were included. Clinical scores, AD biomarkers, brain MRI volumetry along with CSF cortisol and DHEAS were obtained at baseline. Cognitive and functional performance was re-assessed at 18 and 36 months from baseline. We also assessed the following covariates: apolipoprotein E (APOE) genotype, BMI, and education. We used linear regression and mixed models to address associations of interest.ResultsHigher CSF cortisol was associated with poorer global cognitive performance and higher disease severity at baseline. Cortisol and cortisol/DHEAS ratio were positively associated with tau and p-tau CSF levels, and negatively associated with the amygdala and insula volumes at baseline. Higher CSF cortisol predicted more pronounced cognitive decline and clinical disease progression over 36 months. Higher CSF DHEAS predicted more pronounced disease progression over 36 months.ConclusionIncreased cortisol in the CNS is associated with tau pathology and neurodegeneration, and with decreased insula and amygdala volume. Both CSF cortisol and DHEAS levels predict faster clinical disease progression. These results have implications for the identification of patients at risk of rapid decline as well as for the development of interventions targeting both neurodegeneration and clinical manifestations of AD.

Dataset Information

Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants.

Publications

Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants.

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