Long-term cortisol measures predict Alzheimer disease risk
Abstract
Objective:
To examine whether long-term measures of cortisol predict Alzheimer disease (AD) risk.
Method:
We used a prospective longitudinal design to examine whether cortisol dysregulation was related to AD risk. Participants were from the Baltimore Longitudinal Study of Aging (BLSA) and submitted multiple 24-hour urine samples over an average interval of 10.56 years. Urinary free cortisol (UFC) and creatinine (Cr) were measured, and a UFC/Cr ratio was calculated to standardize UFC. To measure cortisol regulation, we used within-person UFC/Cr level (i.e., within-person mean), change in UFC/Cr over time (i.e., within-person slope), and UFC/Cr variability (i.e., within-person coefficient of variation). Cox regression was used to assess whether UFC/Cr measures predicted AD risk.
Results:
UFC/Cr level and UFC/Cr variability, but not UFC/Cr slope, were significant predictors of AD risk an average of 2.9 years before AD onset. Elevated UFC/Cr level and elevated UFC/Cr variability were related to a 1.31- and 1.38-times increase in AD risk, respectively. In a sensitivity analysis, increased UFC/Cr level and increased UFC/Cr variability predicted increased AD risk an average of 6 years before AD onset.
Conclusions:
Cortisol dysregulation as manifested by high UFC/Cr level and high UFC/Cr variability may modulate the downstream clinical expression of AD pathology or be a preclinical marker of AD.
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Information & Authors
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Published In
Copyright
© 2016 American Academy of Neurology.
Publication History
Received: May 31, 2016
Accepted: October 17, 2016
Published online: December 16, 2016
Published in issue: January 24, 2017
Disclosure
G. Ennis was supported by a Ruth L. Kirschstein PHS training grant (T32 AG000175). She reports no other disclosures. Y. An, S. Resnick, L. Ferrucci, R. O'Brien, and S. Moffat report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Study Funding
This research was supported by a grant from the National Institute on Aging of the NIH (R01-AG028466; Scott D. Moffat, principal investigator) and a Ruth L. Kirschstein Public Health Service training grant (T32 AG000175). This study was also supported in part by the Intramural Research Program, National Institute on Aging, NIH.
Authors
Author Contributions
Gilda E. Ennis drafted the manuscript and analyzed and interpreted study data. Yang An analyzed and interpreted study data and reviewed the content of the manuscript. Susan M. Resnick contributed to the study concept and design and the writing of the manuscript. Luigi Ferrucci contributed to the study concept and design and reviewed the manuscript. Richard J. O'Brien was responsible for the diagnosis of AD onset, a major study variable, and reviewed the manuscript. Scott D. Moffat contributed to the study concept and design, analysis, and writing of the manuscript and is principal investigator on the grant that funded the research.
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We thank Drs. Lattanzi and Silvestrini for the thoughtful response to our article. [1] We fully agree with their suggested mechanisms of action by which cortisol may increase risk for Alzheimer disease (AD). In our sample, we had very few non-AD dementias which precluded a more comprehensive assessment of how cortisol dysregulation may affect risk for other dementias, though it is a fascinating question.
1. Ennis GE, An Y, Resnick SM, et al. Long-term cortisol measures predict Alzheimer disease risk. Neurology Epub 2016 Dec 16.
For disclosures, please contact the editorial office at [email protected].
We read with great interest the article by Ennis et al. which found cortisol dysregulation to be related with an increased risk for Alzheimer disease (AD), and built on the unresolved question of whether systemic homeostasis primarily contributes to AD expression or represents an epiphenomenon of the underlying brain pathology. [1] Additional considerations might provide useful insights toward a better and more comprehensive understanding of this issue. Within their pleiotropic effects, corticosteroids can greatly influence metabolic functions as well as blood pressure levels and fluctuations, all of which play key roles in dementia onset and course. [2] In the CNS, corticosteroid receptors are not uniformly localized and abnormal glucocorticoid signalling can result in cell-type and site-specific differences. [3] Accordingly, it would be of great interest to address the interrelationships between cortisol dysregulation, insulin resistance, and blood pressure variability, [4] and to investigate the associations between cortisol exposure and the risk of non-AD dementias. [5]
1. Ennis GE, An Y, Resnick SM, et al. Long-term cortisol measures predict Alzheimer disease risk. Neurology Epub 2016 Dec 16.
2. Lattanzi S, Luzzi S, Provinciali L, Silvestrini M. Blood pressure variability predicts cognitive decline in Alzheimer's disease patients. Neurobiol Aging 2014;35:2282-2287.
3. Herman JP. Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system. Cell Mol Neurobiol 1993;13:349-372.
4. Lattanzi S, Viticchi G, Falsetti L, et al. Visit-to-visit blood pressure variability in Alzheimer disease. Alzheimer Dis Assoc Disord 2014;28:347-351.
5. Lattanzi S, Luzzi S, Provinciali L, Silvestrini M. Blood pressure variability in Alzheimer's disease and frontotemporal dementia: the effect on the rate of cognitive decline. J Alzheimers Dis 2015;45:387-394.
For disclosures, please contact the editorial office at [email protected].