Novel biomarkers associated with stress : from normal aging to Alzheimer's disease

The burden of Alzheimer’s disease (AD) and dementia can be reduced through the elimination of modifiable lifestyle risk factors. Chronic stress is an emerging risk factor which has received significant focus in research in recent years. While indicators of stress have been found to be associated with AD and AD-related outcomes, findings have been mixed, and limited research has examined these associations in patients within the AD continuum. The aim of this thesis was to contribute to a more comprehensive understanding of the potential relationship between indicators of chronic stress and AD. This was achieved through the examination of associations between indicators of chronic stress and both established and novel markers of AD in memory clinic patients, a population in which these associations have not widely been studied. Additionally, to examine potential pathways linking chronic stress and AD, interactions between diurnal patterns of the stress hormone cortisol and other AD-related pathological processes, including amyloid accumulation and neuroinflammation, were explored in relation to AD-related outcomes. Lastly, this thesis aimed to contribute to the understanding of the complex concept of stress by examining the interplay between physiological, self-perceived, and environmental indicators of chronic stress in relation to AD-related outcomes.

The data used in the present thesis was taken from the Cortisol and Stress in Alzheimer’s Disease (Co-STAR) cohort study of memory clinic patients, as well as from the baseline assessments of the Multimodal Prevention Trial for Alzheimer’s Disease – mini (MIND-ADmini) among prodromal AD patients.

Study 1. Data from the Co-STAR study (n = 155) was used to examine associations between diurnal patterns of salivary cortisol and cognitive function at baseline, change in cognitive function over time, as well as AD-biomarkers beta-amyloid [1-42] (Aβ42), total tau, and phosphorylated tau measured in the cerebrospinal fluid (CSF). Dysregulation of cortisol patterns, a potential indicator of stress exposure, is characterized by reduced variation in cortisol levels, a flattened cortisol awakening response, abnormal diurnal cortisol output, and high evening cortisol levels. Greater cortisol levels at awakening were associated with better processing speed performance at baseline. After stratification by normal versus abnormal CSF Aβ42 levels (cut-off 550 ng/L), this association remained present only in participants with normal CSF Aβ42 levels. Additionally, reduced diurnal variation in cortisol levels was associated with worse overall cognition and perceptual reasoning performance in participants with normal CSF Aβ42 levels. No associations were found between diurnal cortisol patterns and CSF AD biomarkers or change in cognition over time.

Study 2. Data from the Co-STAR study (n = 134, based on availability of neuroinflammation data) was used to examine associations between diurnal cortisol patterns and neuroimaging visual rating scales, as well as interactions between diurnal cortisol patterns and neuroinflammation markers in relation to neuroimaging visual rating scales. Visual rating scales based on magnetic resonance imaging (MRI) or computed tomography (CT) were used to assess medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. CSF markers of neuroinflammation-related processes (proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers) were examined. Diurnal cortisol patterns were not found to be associated with neuroimaging visual rating scales. However, some evidence was found for interactions between diurnal cortisol patterns and neuroinflammation in relation to GCA and WML.

Study 3. Data from Co-STAR participants without a dementia diagnosis (n = 127) was used to assess associations between exposure to stressful life events (SLEs) throughout the life course, current perceived stress as assessed using the perceived stress scale (PSS), and cognitive function at baseline. Additionally, potential mediation effects of diurnal cortisol patterns and perceived stress on the association between stress exposure and cognition were examined. Lifetime exposure to SLEs was associated with poorer cognition in the memory, working memory, and processing speed domains, although this association appeared to depend on the period of life in which SLEs occurred. PSS scores were not associated with cognition. Neither diurnal cortisol patterns nor current perceived stress mediated the associations between exposure to SLEs and cognitive function.

Study 4. A small sample of prodromal AD patients from the MIND-ADmini trial and cognitively healthy controls of similar age (n = 21) underwent magnetoencephalography (MEG) functional brain imaging. Participants underwent a tactile working memory task in which stimuli were provided to the fingers of either hand. Attention was paid to one hand at a time. Associations were assessed between current perceived stress as measured using the PSS and attention-related lateralization of oscillatory brain activity in the alpha frequency band (8 – 12 Hz) within the primary somatosensory cortex. Lateralization of alpha band activity did not differ between prodromal AD patients and controls, and was not associated with current perceived stress among prodromal AD patients.

Conclusions. Physiological and self-reported measures of chronic stress appear to be associated with cognition, most notably in the earlier stages of the AD continuum. However, effect sizes are limited, and associations depend on the included measures of stress and cognitive domains. Interactions between cortisol patterns, amyloid pathology, and neuroinflammation in relation to ADrelated outcomes suggest an interplay between the physiological stress response and other pathological processes involved in the development of AD. Longitudinal research on these interactions, as well as a more systematic approach to the assessment of stress in research are needed to further establish the potential role of chronic stress in the development of AD.

List of scientific papers

I. Holleman J, Adagunodo S, Kåreholt I, Hagman G, Aspö M, Udeh-Momoh CT, Solomon A, Kivipelto M, Sindi S. Cortisol, cognition, and Alzheimer’s disease biomarkers among memory clinic patients. BMJ Neurology Open. 2022;4(2): e000344.
https://doi.org/10.1136/bmjno-2022-000344

II. Holleman J*, Daniilidou M*, Kåreholt I, Aspö M, Hagman G, Udeh-Momoh CT, Spulber G, Kivipelto M, Solomon A, Matton A†, Sindi S†. Diurnal cortisol, neuroinflammation, and neuroimaging visual rating scales in memory clinic patients. Brain, Behavior, and Immunity. 2024;118: 499-509. *Shared first author, †Shared last author.
https://doi.org/10.1016/j.bbi.2024.03.024

III. Holleman J, Kåreholt I, Aspö M, Hagman G, Udeh-Momoh CT, Kivipelto M, Solomon A, Sindi S. Life-course stress, cognition, and diurnal cortisol in memory clinic patients without dementia. Archives of Gerontology and Geriatrics. 2024;119: 105316.
https://doi.org/10.1016/j.archger.2023.105316

IV. Holleman J, Thunborg C, Solomon A, Lundqvist D, Kivipelto M, Vinding MC*, Sindi S*. Perceived stress, insomnia symptoms, and attention-related magnetoencephalography alpha power lateralization in prodromal Alzheimer’s disease. *Shared last author. [Manuscript]