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Introduction: Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation., Methods: We examined cross-sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD-related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3-year follow-up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol., Results: Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD-related biomarkers., Discussion: Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients., Highlights: Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve [CR]) in memory clinic patients. Cortisol awakening response modified the relation between CR and P-tau 181 , a marker of Alzheimer's disease (AD). Effective stress management techniques for AD and related dementia prevention are warranted., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Neuroinflammation is a hallmark of the Alzheimer's disease (AD) pathogenic process. Cortisol dysregulation may increase AD risk and is related to brain atrophy. This cross-sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates., Method: 134 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden). Four visual rating scales were applied to magnetic resonance imaging or computed tomography scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. Participants provided saliva samples for assessment of diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Three cortisol measures were used: the cortisol awakening response, total daily output, and the ratio of awakening to bedtime levels. Nineteen CSF neuroinflammation markers were categorized into five composite scores: proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers. Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation scores in relation to visual rating scales., Result: Higher levels of angiogenesis markers were associated with more severe WML. Some evidence was found for interactions between dysregulated diurnal cortisol patterns and greater neuroinflammation-related biomarkers in relation to more severe GCA and WML. No associations were found between cortisol patterns and visual rating scales., Conclusion: This study suggests an interplay between diurnal cortisol patterns and neuroinflammation in relation to brain structure. While this cross-sectional study does not provide information on causality or temporality, these findings suggest that neuroinflammation may be involved in the relationship between HPA-axis functioning and AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Aims: To examine associations of life-course stress with cognition and diurnal cortisol patterns in older adulthood, as well as potential mediation effects of diurnal cortisol patterns and perceived stress on the association between life-course stress and cognition., Methods: 127 participants without dementia were selected from a cohort of Swedish memory clinic patients. Cross-sectional associations between scores on two chronic stress questionnaires (perceived stress, stressful life events (SLEs)), five cognitive domains (overall cognition, memory, working memory, processing speed, perceptual reasoning), and two measures of diurnal cortisol patterns (total daily output, diurnal cortisol slope), as well as potential mediation effects of diurnal cortisol patterns and perceived stress on associations between life-course stress and cognition, were assessed using linear regressions., Results: Greater lifetime exposure to SLEs was associated with worse memory, working memory, and processing speed performance, but not with diurnal cortisol patterns. A greater number of SLEs in late childhood was associated with worse working memory and processing speed, while a greater number of SLEs in non-recent adulthood were associated with better overall cognition and perceptual reasoning. Greater perceived stress was associated with a flattened diurnal cortisol slope, but not with cognition. No evidence for interplay between self-reported and physiological stress markers was found in relation to cognition, although there appeared to be a significant positive indirect association between economic/legal SLEs and the diurnal cortisol slope via perceived stress., Conclusions: The associations between SLEs and cognition depend on the period during which SLEs occur, but seem independent of late-life cortisol dysregulation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To determine whether hypothalamus-pituitary-adrenal axis (HPAA) dysfunction is prospectively associated with global cognitive impairment in later life., Methods: This cross-cohort study integrates 2 large longitudinal datasets, Whitehall II and the National Survey for Health and Development (NSHD), on data collected in the Whitehall II study between 2002-2004, 2007-2009, and 2012-2013; and for NSHD between 2006-2010 and in 2015. Serial salivary cortisol samples were collected multiple times within a 24-hour period at mean ages 61.2 and 65.9 years in Whitehall II and at age 60-64 years from NSHD participants. Cortisol profile is defined using cortisol awakening response and am:pm ratio. Cognitive function was measured using the Mini-Mental State Examination in Whitehall II and Addenbrooke's Cognitive Examination, third version, in NSHD, harmonized into a 30-point score. Models were adjusted for age, sex, diagnoses of hypertension and diabetes, body mass index (BMI), educational attainment, and interval between HPAA and cognitive assessments., Results: In fully adjusted models, increased am:pm cortisol ratio was prospectively associated with better later-life cognitive function years later (0.02 fewer errors per SD increase in am:pm cortisol ratio, p < 0.01) and verbal fluency (0.03 SD increase in verbal fluency per SD increase in am:pm ratio, p < 0.01). Increasing age, lower educational attainment, diagnosis of hypertension, diagnosis of diabetes, and increased BMI were associated with worse cognitive function and poorer verbal fluency. There were no associations between depression and later-life cognition or reverse associations between cognition and later-life cortisol profiles., Conclusions: Loss of diurnal HPAA variation is evident in individuals subsequently experiencing more cognitive impairment. It may serve as an early preclinical marker of cognitive decline., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.

• Patients with Alzheimer's disease had higher morning cortisol level than controls. • Clinically meaningful AD-related increases of morning cortisol level were quantified. • People with mild cognitive impairment had higher CSF cortisol than normal controls. • High cortisol is associated with accelerated cognitive decline in people with MCI. • Predictive value of cortisol for cognitive decline in preclinical adults is unclear. Morning cortisol levels have been reported to be elevated among patients with Alzheimer's disease (AD); yet no meta-analysis has been conducted to confirm the existence and magnitude of this association. It also remains unclear whether hypercortisolism is a risk factor for AD. PubMed, EMBASE, and PsycINFO were systematically searched for eligible studies. Cross-sectional data were pooled using random-effects meta-analyses; the differences in morning cortisol levels between patients and cognitively normal controls were quantified. Longitudinal studies were qualitatively synthesised due to methodological heterogeneity. 17,245 participants from 57 cross-sectional studies and 19 prospective cohort studies were included. Compared with cognitively normal controls, AD patients had moderately increased morning cortisol in blood (g = 0.422, P < 0.001; I2 = 48.5 %), saliva (g = 0.540, P < 0.001; I2 = 13.6 %), and cerebrospinal fluids (g = 0.565, P = 0.003; I2 = 75.3 %). A moderate elevation of morning cortisol was also detected in cerebrospinal fluids from patients with mild cognitive impairment (MCI) versus controls (g = 0.309, P = 0.001; I2 = 0.0 %). Cohort studies suggested that higher morning cortisol may accelerate cognitive decline in MCI or mild AD patients, but the results in cognitively healthy adults were inconsistent. Morning cortisol was confirmed to be moderately elevated in AD patients and may have diagnostic and prognostic values for AD. [ABSTRACT FROM AUTHOR]