Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study

  • Author Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Robert H. Pietrzak
    Correspondence
    Address correspondence to: Robert H. Pietrzak, Ph.D., M.P.H., U.S. Department of Veterans Affairs National Center for PTSD, Clinical Neurosciences Division, VA Connecticut Healthcare System, 950 Campbell Ave 161E, West Haven, CT; .
    Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Affiliations
    U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author
  • Author Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Simon M. Laws
    Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Affiliations
    Centre of Excellence for Alzheimer’s Disease Research and Care, Edith Cowan University, Joondalup, Western Australia

    Co-operative Research Centre for Mental Health
    Search for articles by this author
  • Yen Ying Lim
    Affiliations
    The Florey Institute, The University of Melbourne, Parkville, Victoria
    Search for articles by this author
  • Sophie J. Bender
    Affiliations
    School of Health Sciences, University of Notre Dame Australia, Fremantle, Western Australia
    Search for articles by this author
  • Tenielle Porter
    Affiliations
    Centre of Excellence for Alzheimer’s Disease Research and Care, Edith Cowan University, Joondalup, Western Australia

    Co-operative Research Centre for Mental Health
    Search for articles by this author
  • James Doecke
    Affiliations
    The Commonwealth Scientific and Industrial Research Organization, Canberra
    Search for articles by this author
  • David Ames
    Affiliations
    Academic Unit for Psychiatry of Old Age, St. Vincent’s Health, Department of Psychiatry, The University of Melbourne, Kew

    National Ageing Research Institute, Parkville, Victoria
    Search for articles by this author
  • Christopher Fowler
    Affiliations
    The Florey Institute, The University of Melbourne, Parkville, Victoria
    Search for articles by this author
  • Colin L. Masters
    Affiliations
    The Florey Institute, The University of Melbourne, Parkville, Victoria
    Search for articles by this author
  • Lidija Milicic
    Affiliations
    Centre of Excellence for Alzheimer’s Disease Research and Care, Edith Cowan University, Joondalup, Western Australia
    Search for articles by this author
  • Stephanie Rainey-Smith
    Affiliations
    Centre of Excellence for Alzheimer’s Disease Research and Care, Edith Cowan University, Joondalup, Western Australia
    Search for articles by this author
  • Victor L. Villemagne
    Affiliations
    The Florey Institute, The University of Melbourne, Parkville, Victoria

    Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia

    Department of Nuclear Medicine and Centre for PET, Austin Health
    Search for articles by this author
  • Christopher C. Rowe
    Affiliations
    Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia

    Department of Nuclear Medicine and Centre for PET, Austin Health
    Search for articles by this author
  • Author Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Ralph N. Martins
    Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Affiliations
    Centre of Excellence for Alzheimer’s Disease Research and Care, Edith Cowan University, Joondalup, Western Australia

    Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia
    Search for articles by this author
  • Author Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Paul Maruff
    Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
    Affiliations
    The Florey Institute, The University of Melbourne, Parkville, Victoria

    Department of Medicine, Austin Health, The University of Melbourne, Heidelberg

    Cogstate Ltd., Melbourne, Victoria, Australia
    Search for articles by this author
  • for the Australian Imaging, Biomarkers and Lifestyle Research Group
  • Author Footnotes
    1 RHP and SML are joint first authors. PM and RNM are joint senior authors.
Published:September 07, 2016DOI:https://doi.org/10.1016/j.bpsc.2016.08.006

      Abstract

      Background

      Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer’s disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention.

      Methods

      Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults.

      Results

      Results revealed that Aβ+ older adults experienced faster decline than Aβ− older adults in all cognitive domains (Cohen’s d at 6-year assessment = 0.37–0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition (d = 0.32), episodic memory (d = 0.50), and executive function (d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type.

      Conclusions

      In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD.

      Keywords

      To read this article in full you will need to make a payment

      References

        • Caselli R.J.
        • Reiman E.M.
        Characterizing the preclinical stages of Alzheimer׳s disease and the prospect of presymptomatic intervention.
        J Alzheimers Dis. 2013; 33: S405-S416
        • Langbaum J.B.
        • Fleisher A.S.
        • Chen K.
        • Ayutyanont N.
        • Lopera F.
        • Quiroz Y.T.
        • et al.
        Ushering in the study and treatment of preclinical Alzheimer disease.
        Nat Rev Neurol. 2013; 9: 371-381
        • Chetelat G.
        • Villemagne V.L.
        • Pike K.E.
        • Ellis K.A.
        • Bourgeat P.
        • Jones G.
        • et al.
        Independent contribution of temporal beta-amyloid deposition to memory decline in the pre-dementia phase of Alzheimerʼs disease.
        Brain. 2011; 134: 798-807
        • Doraiswamy P.M.
        • Sperling R.A.
        • Johnson K.
        • Reiman E.M.
        • Wong T.Z.
        • Sabbagh M.N.
        • et al.
        Florbetapir F 18 amyloid PET and 36-month cognitive decline:a prospective multicenter study.
        Mol Psychiatry. 2014; 19: 1044-1051
        • Ellis K.A.
        • Lim Y.Y.
        • Harrington K.
        • Ames D.
        • Bush A.I.
        • Darby D.
        • et al.
        Decline in cognitive function over 18 months in healthy older adults with high amyloid-beta.
        J Alzheimers Dis. 2013; 34: 861-871
        • Lim Y.Y.
        • Ellis K.A.
        • Pietrzak R.H.
        • Ames D.
        • Darby D.
        • Harrington K.
        • et al.
        Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults.
        Neurology. 2012; 79: 1645-1652
        • Lim Y.Y.
        • Maruff P.
        • Pietrzak R.H.
        • Ames D.
        • Ellis K.A.
        • Harrington K.
        • et al.
        Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer׳s disease.
        Brain. 2014; 137: 221-231
        • Lim Y.Y.
        • Maruff P.
        • Pietrzak R.H.
        • Ellis K.A.
        • Darby D.
        • Ames D.
        • et al.
        Aβ and cognitive change: Examining the preclinical and prodromal stages of Alzheimer׳s disease.
        Alzheimers Dement. 2014; 10: 743-751
        • Villemagne V.L.
        • Burnham S.
        • Bourgeat P.
        • Brown B.
        • Ellis K.A.
        • Salvado O.
        • et al.
        Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer׳s disease: A prospective cohort study.
        Lancet Neurol. 2013; 12: 357-367
        • Lim Y.Y.
        • Villemagne V.L.
        • Laws S.M.
        • Pietrzak R.H.
        • Snyder P.J.
        • Ames D.
        • et al.
        APOE and BDNF polymorphisms moderate amyloid beta-related cognitive decline in preclinical Alzheimerʼs disease.
        Mol Psychiatry. 2015; 20: 1322-1328
        • Landau S.M.
        • Marks S.M.
        • Mormino E.C.
        • Rabinovici G.D.
        • Oh H.
        • O׳Neil J.P.
        • et al.
        Association of lifetime cognitive engagement and low beta-amyloid deposition.
        Arch Neurol. 2012; 69: 623-629
        • Schultz S.A.
        • Boots E.A.
        • Almeida R.P.
        • Oh J.M.
        • Einerson J.
        • Korcarz C.E.
        • et al.
        Cardiorespiratory fitness attenuates the influence of amyloid on cognition.
        J Int Neuropsychol Soc. 2015; 21: 841-850
        • Catania C.
        • Sotiropoulos I.
        • Silva R.
        • Onofri C.
        • Breen K.C.
        • Sousa N.
        • et al.
        The amyloidogenic potential and behavioral correlates of stress.
        Mol Psychiatry. 2009; 14: 95-105
        • Dong H.
        • Csernansky J.G.
        Effects of stress and stress hormones on amyloid-beta protein and plaque deposition.
        J Alzheimers Dis. 2009; 18: 459-469
        • Hebda-Bauer E.K.
        • Simmons T.A.
        • Sugg A.
        • Ural E.
        • Stewart J.A.
        • Beals J.L.
        • et al.
        3xTg-AD mice exhibit an activated central stress axis during early-stage pathology.
        J Alzheimers Dis. 2013; 33: 407-422
        • Wang Y.
        • Li M.
        • Tang J.
        • Song M.
        • Xu X.
        • Xiong J.
        • et al.
        Glucocorticoids facilitate astrocytic amyloid-beta peptide deposition by increasing the expression of APP and BACE1 and decreasing the expression of amyloid-beta-degrading proteases.
        Endocrinology. 2011; 152: 2704-2715
        • Geerlings M.I.
        • Sigurdsson S.
        • Eiriksdottir G.
        • Garcia M.E.
        • Harris T.B.
        • Gudnason V.
        • et al.
        Salivary cortisol, brain volumes, and cognition in community-dwelling elderly without dementia.
        Neurology. 2015; 85: 976-983
        • Lupien S.J.
        • de Leon M.
        • de Santi S.
        • Convit A.
        • Tarshish C.
        • Nair N.P.
        • et al.
        Cortisol levels during human aging predict hippocampal atrophy and memory deficits.
        Nat Neurosci. 1998; 1: 69-73
        • Popp J.
        • Wolfsgruber S.
        • Heuser I.
        • Peters O.
        • Hull M.
        • Schroder J.
        • et al.
        Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer׳s type.
        Neurobiol Aging. 2015; 36: 601-607
        • Hinterberger M.
        • Zehetmayer S.
        • Jungwirth S.
        • Huber K.
        • Krugluger W.
        • Leitha T.
        • et al.
        High cortisol and low folate are the only routine blood tests predicting probable Alzheimer׳s disease after age 75-results of the Vienna Transdanube Aging Study.
        J Am Geriatr Soc. 2013; 61: 648-651
        • Toledo J.B.
        • Toledo E.
        • Weiner M.W.
        • Jack Jr, C.R.
        • Jagust W.
        • Lee V.M.
        • et al.
        Cardiovascular risk factors, cortisol, and amyloid-beta deposition in Alzheimer׳s Disease Neuroimaging Initiative.
        Alzheimers Dement. 2012; 8: 483-489
        • Pietrzak R.H.
        • Lim Y.Y.
        • Neumeister A.
        • Ames D.
        • Ellis K.A.
        • Harrington K.
        • et al.
        Amyloid-beta, anxiety, and cognitive decline in preclinical Alzheimer disease: A multicenter, prospective cohort study.
        JAMA Psychiatry. 2015; 72: 284-291
        • Faravelli C.
        • Lo Sauro C.
        • Godini L.
        • Lelli L.
        • Benni L.
        • Pietrini F.
        • et al.
        Childhood stressful events, HPA axis and anxiety disorders.
        World J Psychiatry. 2012; 22: 13-25
        • Elnazer H.Y.
        • Baldwin D.S.
        Investigation of cortisol levels in patients with anxiety disorders: a structured review.
        Curr Top Behav Neurosci. 2014; 18: 191-216
        • Sapolsky R.M.
        Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders.
        Arch Gen Psychiatry. 2000; 57: 925-935
        • Byers A.L.
        • Yaffe K.
        Depression and risk of developing dementia.
        Nat Rev Neurol. 2011; 7: 323-331
        • Knoops A.J.
        • Gerritsen L.
        • van der Graaf Y.
        • Mali W.P.
        • Geerlings M.I.
        Basal hypothalamic pituitary adrenal axis activity and hippocampal volumes: The SMART-Medea study.
        Biol Psychiatry. 2010; 67: 1191-1198
        • McEwen B.S.
        Stress and the aging hippocampus.
        Front Neuroendocrinol. 1999; 20: 49-70
        • Sapolsky R.M.
        • Krey L.C.
        • McEwen B.S.
        The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis.
        Endocr Rev. 1986; 7: 284-301
        • Ellis K.A.
        • Rainey-Smith S.R.
        • Rembach A.
        • Macaulay S.L.
        • Villemagne V.L.
        Enabling a multidisciplinary approach to the study of ageing and Alzheimer׳s disease: An update from the Australian Imaging Biomarkers and Lifestyle (AIBL) study.
        Int Rev Psychiatry. 2013; 25: 699-710
        • Brown B.M.
        • Bourgeat P.
        • Peiffer J.J.
        • Burnham S.
        • Laws S.M.
        • Rainey-Smith S.R.
        • et al.
        Influence of BDNF Val66Met on the relationship between physical activity and brain volume.
        Neurology. 2014; 83: 1345-1352
        • Lim Y.Y.
        • Villemagne V.L.
        • Laws S.M.
        • Ames D.
        • Pietrzak R.H.
        • Ellis K.A.
        • et al.
        BDNF Val66Met, Abeta amyloid, and cognitive decline in preclinical Alzheimer׳s disease.
        Neurobiol Aging. 2013; 34: 2457-2464
        • Lim Y.Y.
        • Villemagne V.L.
        • Laws S.M.
        • Ames D.
        • Pietrzak R.H.
        • Ellis K.A.
        • et al.
        Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer׳s disease: A preliminary study.
        PloS One. 2014; 9: e86498
        • Farrington D.P.
        • Loeber R.
        Some benefits of dichotomization in psychiatric and criminological research.
        Crim Behav Ment Health. 2000; 10: 100-122
        • Yates P.A.
        • Desmond P.M.
        • Phal P.M.
        • Steward C.
        • Szoeke C.
        • Salvado O.
        • et al.
        Incidence of cerebral microbleeds in preclinical Alzheimer disease.
        Neurology. 2014; 82: 1266-1273
        • Wiederkehr S.
        • Laurin D.
        • Simard M.
        • Verreault R.
        • Lindsay J.
        Vascular risk factors and cognitive functions in nondemented elderly individuals.
        J Geriatr Psychiatry Neurol. 2009; 22: 196-206
        • Bjelland I.
        • Dahl A.A.
        • Haug T.T.
        • Neckelmann D.
        The validity of the Hospital Anxiety and Depression Scale. An updated literature review.
        J Psychosom Res. 2002; 52: 69-77
        • Crook 3rd, T.H.
        • Feher E.P.
        • Larrabee G.J.
        Assessment of memory complaint in age-associated memory impairment: The MAC-Q.
        Int Psychogeriatr. 1992; 4: 165-176
        • Wechsler D.
        Wechsler Test of Adult Reading: Examiner׳s Manual.
        Psychological Corporation, San Antonio, TX2001
        • Harrington K.D.
        • Lim Y.Y.
        • Ellis K.A.
        • Copolov C.
        • Darby D.
        • Weinborn M.
        • et al.
        The association of Abeta amyloid and composite cognitive measures in healthy older adults and MCI.
        Int Psychogeriatr. 2013; 25: 1667-1677
        • Cohen J.
        Statistical Power Analysis for the Behavioral Sciences.
        2nd ed. Lawrence Erlbaum Associates, Mahwah, New Jersey1988
        • Maeda K.
        • Tanimoto K.
        • Terada T.
        • Shintani T.
        • Kakigi T.
        Elevated urinary free cortisol in patients with dementia.
        Neurobiol Aging. 1991; 12: 161-163
        • McEwen B.S.
        Brain on stress: How the social environment gets under the skin.
        Proc Natl Acad Sci U S A. 2012; 109: 17180-17185
        • Jacobson L.
        • Sapolsky R.
        The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis.
        Endocr Rev. 1991; 12: 118-134
        • Bratt A.M.
        • Kelley S.P.
        • Knowles J.P.
        • Barrett J.
        • Davis K.
        • Davis M.
        • et al.
        Long term modulation of the HPA axis by the hippocampus. Behavioral, biochemical and immunological endpoints in rats exposed to chronic mild stress.
        Psychoneuroendocrinology. 2001; 26: 121-145
        • Zhu L.J.
        • Liu M.Y.
        • Li H.
        • Liu X.
        • Chen C.
        • Han Z.
        • et al.
        The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.
        PloS One. 2014; 9: e97689
        • de Kloet E.R.
        • Joels M.
        • Holsboer F.
        Stress and the brain: From adaptation to disease.
        Nat Rev Neurosci. 2005; 6: 463-475
        • Sooy K.
        • Noble J.
        • McBride A.
        • Binnie M.
        • Yau J.L.
        • Seckl J.R.
        • et al.
        Cognitive and disease-modifying effects of 11beta-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer׳s disease.
        Endocrinology. 2015; 156: 4592-4603
        • Aboulafia-Brakha T.
        • Suchecki D.
        • Gouveia-Paulino F.
        • Nitrini R.
        • Ptak R.
        Cognitive-behavioural group therapy improves a psychophysiological marker of stress in caregivers of patients with Alzheimer׳s disease.
        Aging Ment Health. 2014; 18: 801-808
        • Gaab J.
        • Blattler N.
        • Menzi T.
        • Pabst B.
        • Stoyer S.
        • Ehlert U.
        Randomized controlled evaluation of the effects of cognitive-behavioral stress management on cortisol responses to acute stress in healthy subjects.
        Psychoneuroendocrinology. 2003; 28: 767-779
        • Sotiropoulos I.
        • Catania C.
        • Pinto L.G.
        • Silva R.
        • Pollerberg G.E.
        • Takashima A.
        • et al.
        Stress acts cumulatively to precipitate Alzheimer׳s disease-like tau pathology and cognitive deficits.
        J Neurosci. 2011; 31: 7840-7847
        • Srivareerat M.
        • Tran T.T.
        • Alzoubi K.H.
        • Alkadhi K.A.
        Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer’s disease.
        Biol Psychiatry. 2009; 65: 918-926
        • Dedovic K.
        • Ngiam J.
        The cortisol awakening response and major depression: Examining the evidence.
        Neuropsychiatr Dis Treat. 2015; 11: 1181-1189
        • Veen G.
        • van Vliet I.M.
        • DeRijk R.H.
        • Giltay E.J.
        • van Pelt J.
        • Zitman F.G.
        Basal cortisol levels in relation to dimensions and DSM-IV categories of depression and anxiety.
        Psychiatry Res. 185. 2011: 121-128
        • Wardenaar K.J.
        • Vreeburg S.A.
        • van Veen T.
        • Giltay E.J.
        • Veen G.
        • Penninx B.W.
        • et al.
        Dimensions of depression and anxiety and the hypothalamo-pituitary-adrenal axis.
        Biol Psychiatry. 2011; 69: 366-373
      1. Alzheimer Research Forum: Meta-analyses of apolipoprotein E AD association studies.http://www.alzgene.org/meta.asp?geneID=83. Accessed April 19, 2016.

        • Griffing G.T.
        • Staros E.B.
        Serum cortisol. Reference range. 2016; (Accessed January 14, 2016)
        • Doecke J.D.
        • Laws S.M.
        • Faux N.G.
        • Wilson W.
        • Burnham S.C.
        • Lam C.P.
        • et al.
        Blood-based protein biomarkers for diagnosis of Alzheimer disease.
        Arch Neurol. 2012; 69: 1318-1325
        • Lehallier B.
        • Essioux L.
        • Gayan J.
        • Alexandridis R.
        • Nikolcheva T.
        • Wyss-Coray T.
        • et al.
        Combined plasma and cerebrospinal fluid signature for the prediction of midterm progression from mild cognitive impairment to Alzheimer disease.
        JAMA Neurol. 2016; 73: 203-212