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Increased CSF cortisol in AD is a function of APOE genotype

From the Mental Illness Research, Education, and Clinical Center (MIRECC) (Drs. Peskind and Raskind) and Geriatric Research, Education, and Clinical Center (GRECC) (Drs. Wilkinson and Schellenberg), VA Puget Sound Health Care System; and Departments of Psychiatry and Behavioral Sciences (Drs. Peskind, Wilkinson, Petrie, and Raskind) and Medicine (Dr. Schellenberg), University of Washington School of Medicine, Seattle.

Address correspondence and reprint requests to Dr. E.R. Peskind, Mental Illness Research, Education, and Clinical Center (116MIRECC), VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108; e-mail: peskind.elaine{at}seattle.va.gov

BACKGROUND: Increased hypothalamic–pituitary–adrenal (HPA) axis activity manifested by elevated cortisol levels is observed in AD and may contribute to AD by lowering the threshold for neuronal degeneration. Presence of the APOE-4 allele increases risk for AD. Increased cortisol concentrations in apoE-deficient mice suggest that APOE genotype may influence cortisol concentrations in AD.

METHODS: The authors measured cortisol levels in CSF and determined APOE genotypes for 64 subjects with AD and 34 nondemented older control subjects.

RESULTS: CSF cortisol was significantly higher in AD than in control subjects. CSF cortisol concentrations differed with respect to APOE genotype in both subjects with AD (4/4 > 3/4 > 3/3) and normal older control subjects (3/4 > 3/3 > 2/3). Comparison of CSF cortisol concentrations within the 3/4 and 3/3 genotypes revealed no differences between AD and control subject groups.

CONCLUSIONS: Higher CSF cortisol concentrations were associated with increased frequency of the APOE-4 allele and decreased frequency of the APOE-2 allele in AD subjects relative to control subjects. This effect of APOE genotype on HPA axis activity may be related to the increased risk for AD in persons carrying the APOE-4 allele and decreased risk for AD in persons carrying the APOE-2 allele.

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