Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study

• Published in: Translational psychiatry 2024-09, Vol.14 (1), p.364-11, Article 364
• Main Authors: Daniilidou, Makrina, Holleman, Jasper, Hagman, Göran, Kåreholt, Ingemar, Aspö, Malin, Brinkmalm, Ann, Zetterberg, Henrik, Blennow, Kaj, Solomon, Alina, Kivipelto, Miia, Sindi, Shireen, Matton, Anna
• Format: Article
• Language: English
• Subjects: 692/53/2421; 692/699/476; 82/56; 82/58; 96/1; 96/21; Aged; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - metabolism; Behavioral Sciences; Biological Psychology; Biomarkers; Biomarkers - cerebrospinal fluid; Biomarkers - metabolism; C-Reactive Protein - analysis; C-Reactive Protein - metabolism; Cerebrovascular Disorders - cerebrospinal fluid; Cerebrovascular Disorders - metabolism; Chemokine CXCL10 - cerebrospinal fluid; Chemokine CXCL10 - metabolism; Circadian Rhythm - physiology; Clinical Medicine; Cognitive Dysfunction - cerebrospinal fluid; Cognitive Dysfunction - metabolism; Cohort Studies; Female; Hormones; Humans; Hydrocortisone - metabolism; Intercellular Adhesion Molecule-1 - metabolism; Klinisk medicin; Male; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Middle Aged; Neuroinflammatory Diseases - cerebrospinal fluid; Neuropsychological Tests; Neurosciences; Pharmacotherapy; Psychiatry; Saliva - chemistry; Saliva - metabolism; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-024-03072-x

Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer’s disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer’s Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.