Cortisol, Amyloid-β, and Reserve Predicts Alzheimer’s Disease Progression for Cognitively Normal Older Adults

Article type: Research Article

Authors: Udeh-Momoh, Chinedu T.^{a; b; *} | Su, Bowen^{a; c} | Evans, Stephanie^d | Zheng, Bang^a | Sindi, Shireen^{a; e} | Tzoulaki, Ioanna^c | Perneczky, Robert^{a; f; g} | Middleton, Lefkos T.^a | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK | [b] Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK | [c] Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK | [d] Department of Infectious Disease Epidemiology, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK | [e] Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden | [f] Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany | [g] German Center for Neurodegenerative Disorders (DZNE), Munich, Germany

Correspondence: [*] Correspondence to: Dr. Chi Udeh-Momoh, PhD, Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK. Tel.: +44 20 3311 0320; Fax: +44 20 8846 7739; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer’s disease (AD), in conjunction with amyloid-β (Aβ) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aβ and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and Aβ42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aβ42, reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal Aβ42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aβ/ reserve interaction for clinical progression was noted (adjusted HR = 0.15, p < 0.001), suggesting a moderating effect of reserve on the association between cortisol/Aβ+ and clinical progression. Our findings indicate that cortisol hypersecretion accelerates clinical progression in CN individuals presenting with pathological Aβ42. High reserve reduces the associated AD progression risk in these high-risk individuals.

Keywords: Alzheimer’s disease, amyloid, cognitive reserve, cortisol

DOI: 10.3233/JAD-181030

Journal: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 553-562, 2019