HPA Axis Dysregulation Associated to Apolipoprotein E4 Genotype in Alzheimer's Disease

Article type: Research Article

Authors: Gil-Bea, Francisco J.^{a; b} | Aisa, Barbara^b | Solomon, Alina^a | Solas, Maite^b | del Carmen Mugueta, Maria^c | Winblad, Bengt^a | Kivipelto, Miia^a | Cedazo-Mínguez, Angel^a | Ramírez, María J.^{b; *}

Affiliations: [a] Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, Karolinska Institutet, Stockholm, Sweden | [b] Department of Pharmacology and Department of Neuropharmacology and Behaviour, Center for Applied Medical Research, University of Navarra, Pamplona, Spain | [c] Clinical Chemistry Department, University Clinic of Navarra, University of Navarra, Pamplona, Spain

Correspondence: [*] Correspondence to: Dr. María J. Ramírez, Center for Applied Medical Research, Department of Pharmacology, School of Medicine, University of Navarra, C/ Irunlarrea, 1, 31008 Pamplona, Spain. Tel.: +34 948425600; Fax: +34 948425649; E-mail: mariaja@unav.es.

Note: [] Handling Associate Editor: Gene Bowman

Abstract: The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-β levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD.

Keywords: Aβ, cerebrospinal fluid, cortisol, frontal cortex, glucocorticoid receptor, mild cognitive impairment, mineralocorticoid receptor, Mini-Mental Status Examination

DOI: 10.3233/JAD-2010-100663

Journal: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 829-838, 2010