Peripheral inflammation offers significant but limited explanation for the association between sleep and cognition health: evidence from two longitudinal studies.
Aug 2026· Brain, behavior, and immunity· Vol 139, pp.
106978
· 0 citations· 57 references
Medicine
TL;DR
It is suggested that peripheral inflammation provides a statistically significant but quantitatively limited explanation for the association between sleep and cognitive health.
Abstract
Sleep disturbances can trigger peripheral inflammatory responses, and both poor sleep and inflammation have been linked to cognitive impairment. However, whether peripheral inflammation mediates the association between sleep quality and cognitive health remains insufficiently tested. We analyzed data from two independent cohorts: 259,817 non-demented participants (mean age 58 years, 55.39% female, mean follow-up 10.29 years) from the UK Biobank (UKB) and 1,107 participants (mean age 74 years, 56.82% female, mean follow-up 4.17 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At baseline, sleep quality was assessed using self-reported or caregiver-reported information. Peripheral blood lymphocyte count (LYM), neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and serum C-reactive protein (CRP) were used as pragmatic peripheral inflammatory markers. Causal mediation analyses tested whether peripheral inflammation mediated the associations of sleep quality with cognitive performance and risk of incident dementia. In both cohorts, poor sleep quality was associated with higher levels of LYM, NEU, NLR and CRP (p < 0.001), and with lower cognitive function (p < 0.001). Poor sleep quality was also associated with an increased risk of incident dementia in UKB (p < 0.001), whereas this association was not significant in ADNI (p = 0.33). Higher NEU, NLR, and CRP levels were associated with lower cognitive function (UKB, p < 0.001; ADNI, p < 0.05) and increased risk of dementia (p < 0.001). In UKB, selected markers mediated the associations of sleep quality with fluid intelligence (p < 0.001), numeric memory score (p < 0.05), and risk of incident all-cause dementia and Alzheimer's disease (p < 0.001). However, the mediation proportions were limited (< 10%). In ADNI, no significant mediation was observed. These findings suggest that peripheral inflammation provides a statistically significant but quantitatively limited explanation for the association between sleep and cognitive health. Future studies should investigate additional mechanisms and potential intervention targets in more diverse cohorts.
Strong evidence supports the role of low-grade systemic inflammation in neurodegeneration, including cognitive decline. Given the literature documenting chronic persistent inflammation in older Black adults, we investigated the association between circulating inflammatory proteins and cognitive decline in this high-risk population. We used data (n = 642) from the Minority Aging Research Study (MARS) and the Rush Clinical Core, including plasma samples to assess circulating inflammatory proteins (Olink® Target-96 Inflammation) and cognition (global cognition and five cognitive domains) assessed annually following proteomics measurement using previously stored blood samples. Linear mixed-effect and latent class mixed models (age at blood draw for proteomics measurement, sex, and education-adjusted), and elastic-net regression were used. Statistical significance was determined using an FDR threshold of 10%. Participants (62.3 to 99.4 years) were mostly women (80.68%) with 15.1 years of education. In multivariable linear mixed-effect models, we found that higher levels of osteoprotegerin (OPG) and chemokine (C-C motif) ligand 23 (CCL23) were cross-sectionally associated with poorer global cognition (beta=-0.205 and beta=-0.148), and higher CCL23 was associated with poorer semantic memory (beta=-0.206). Furthermore, protein × time interaction analyses indicated that higher OPG, Stem cell factor (SCF), and chemokine (C-X-C motif) ligand 9 (CXCL9) levels were associated with faster decline in global cognition (OPG × time term: beta=-0.042), semantic memory (SCF × time term: beta=-0.059, OPG × time term: beta=-0.043), episodic memory (SCF × time term: beta=-0.064; OPG × time term: beta=-0.044), and visuospatial ability (CXCL9×time term: beta=-0.012). In latent class mixed models, several significant protein × time interactions were observed for episodic memory in the subgroup with initial below-average performance and gradual decline. Using elastic net regression, we identified signatures of global cognitive level (26 proteins), but the prediction of cognitive decline was poor. In older Black adults, circulating inflammatory proteins were linked to cognition, reinforcing the role of systemic inflammation as a potential driver of neurodegeneration in this population.
Anat Yaskolka Meir, H. Adeola, S. Tasaki et al.· Brain : a journal of neurolo...· 0 citations
OBJECTIVE
Limited research has assessed prospective associations of systemic inflammatory (GlycA) and immune (complement factor 3 [C3] and 4 [C4]) biomarkers with future cognition in midlife women, who potentially experience worsening inflammation around the menopause transition. We aim to assess the associations of midlife serum GlycA, C3, and C4 with future cognitive performance in women.
METHODS
Serum GlycA, C3, and C4 were repeatedly measured over 6.1 ± 3.9 years in 503 midlife women (1,234 observations) from the Study of Women's Health Across the Nation high-density lipoprotein ancillary study. Longitudinal measures of working memory, processing speed, and episodic memory, immediate and delayed recall, were administered 1.46 ± 0.95 years later. We applied joint models to examine the associations of baseline biomarkers and their changes since baseline with subsequent cognition.
RESULTS
Higher levels of serum GlycA and complement factor 4 at baseline (50.17 ± 2.65 y) were significantly associated with worse working memory and better immediate recall, respectively, over the next decade. Higher baseline complement factor 4 and increases in C3 and C4 since baseline tended to associate with better future immediate and/or delayed recall.
CONCLUSIONS
Higher baseline GlycA, rather than its changes since baseline, was associated with lower future working memory, whereas higher baseline complement factor 4 and increases in C3 and C4 since baseline appeared cognitively protective. Targeting inflammation amelioration and immunity improvement over the menopause transition may provide an open avenue to preserve future cognitive health.
Meiyuzhen Qi, Carol A. Derby, Daniel J. Rader et al.· Menopause· 0 citations
INTRODUCTION
Alzheimer's Disease (AD) is a neurological condition that increases in severity from a gradual start. Previous studies have found an association between long sleep (LS) and AD. To slow its progression, it is important to recognize biomarkers associated with the early stages of both AD and LS.
METHODS
This study aimed to use two-sample Mendelian Randomization (MR) to identify blood and urine biomarkers associated with AD and LS. Thirty-five biomarkers from blood and urine were included as exposures in the MR analysis, while AD and LS were considered the outcomes. The AD dataset included 39,106 patients and 46,828 controls from Europe. Data on sleep duration were obtained from a GWAS in 34,184 cases and 305,742 controls of European ancestry. This study included 35 blood and urine biomarkers across 355,891 participants, including 318,953 white British, 23,582 non-white British, 6,019 African, and 7,338 South Asian participants from the UK Biobank.
RESULTS
Cystatin C, CRP, and Non-Albumin protein showed genetic association with AD and LS. The genetic association results after Bonferroni's correction are significant for Non-Albumin Protein in AD and LS.
DISCUSSION
This study provides further insight into the genetic associations and relationships among AD, LS, and other biomarkers; it also presents several potential candidates for AD and LS diagnosis and treatment. The opposing roles of C-reactive Protein, Cystatin C, and Non-Albumin protein in AD and LS warrant a greater exploration of their differential functions at various ages and in specific brain microenvironments in future studies.
CONCLUSION
This study provides a theoretical basis for the diagnosis and treatment of AD and LS. More experiments are needed in the future to verify this prediction.
Jian-Ran Ma, Zhen Wei, Chunshu Rong et al.· Current Alzheimer Research· 0 citations
Dementia poses a substantial global health burden, necessitating public health focus on modifiable risk factors. While sleep duration has been linked to dementia risk, studies specifically addressing middle-aged and older Chinese adults remain limited. Using cross-sectional (n=12,187) and longitudinal (n=9,030, 4-year follow-up) data from CHARLS, along with two-sample Mendelian randomization (MR), we examined associations between sleep duration and dementia, and causality between insomnia and dementia. We observed the strongest dementia risk among individuals reporting extreme sleep durations (<5h or >10h), both cross-sectional (OR=2.99, 95% CI: 2.47-3.62, P<0.001) and longitudinally (HR=1.55, 95% CI: 1.25-1.91, P<0.001). Restricted cubic spline analyses demonstrated a significant U-shaped dose-response association (P for nonlinearity <0.001). MR findings provided suggestive evidence for a potential causal effect of insomnia on dementia risk (OR=1.06, 95% CI: 1.01-1.13, P=0.029). Sensitivity analyses confirmed robustness. Optimizing sleep duration and managing insomnia may help reduce dementia risk in Chinese middle-aged and older adults.
Xiaoqing Tao, Shan Wang, Li He et al.· Neurosciences research· 0 citations
Obstructive sleep apnea (OSA) and insomnia are highly prevalent in older adults and both have been linked to cognitive decline. However, it remains unclear whether the physiological burden of OSA or the sleep fragmentation associated with insomnia more strongly predicts cognitive impairment. This study examined whether OSA risk or insomnia better was associated with memory problems and cognitive slowing among community-dwelling older Canadians. Given the cross-sectional design, the study evaluated associations rather than causal relationships.
Data were drawn from 946 participants in the Canadian Longitudinal Study on Aging (CLSA), including 473 individuals reporting a physician-diagnosed memory problem and 473 age- and sex-matched controls. OSA risk was assessed using the validated STOP-BA(N)G questionnaire. At the same time, insomnia was defined using operational research criteria based on sleep onset latency, wake after sleep onset, and duration. Cognitive processing speed was measured via Choice Reaction Time (CRT). General linear models, logistic regression, and discriminant analyses examined associations between sleep parameters and cognitive outcomes, controlling for age, sex, body mass index, income, and diabetes.
Participants with memory problems had significantly higher STOP-BA(N)G scores (
F
(1,931) = 7.10,
p
= 0.008) and slower CRTs (
p
= 0.05) compared to controls. Insomnia alone or comorbid with OSA (COMISA) was not associated with cognitive outcomes. In discriminant analysis, STOP-BA(N)G score (
r
= 0.45) and diabetes (
r
= 0.26) were the strongest predictors of memory problems, correctly classifying 66.6% of cases. Sex-stratified analyses demonstrated that the association between higher STOP-BA(N)G scores and memory problems remained significant in both men and women, although effect sizes were somewhat larger in men.
Higher OSA risk was associated with poorer memory and slower cognitive processing in older adults, whereas insomnia was not associated with these outcomes. Because of the cross-sectional design, causality cannot be inferred. Screening for OSA and metabolic comorbidities in patients with memory complaints may help identify individuals at increased risk of cognitive impairment.
D. Rizzo, M. Baltzan, Mohamed Abu-farha et al.· Frontiers in Psychology· 0 citations
Background: Sleep disorders are common in postmenopausal women and may contribute to cognitive decline. We investigated whether plasma biomarkers differentiate cognitive impairment (CI) in this population.Methods: In this cross-sectional exploratory study, we recruited 105 outpatients with insomnia disorder (79 women and 26 men) aged 45-60 years with insomnia symptoms (PSQI > 5, ISI > 7). Cognition was assessed using the Chinese Brief Cognitive Test (CBCT) and Auditory Verbal Learning Test. Postmenopausal women were classified as CI or non-CI based on CBCT criteria. Plasma glial fibrillary acidic protein (GFAP), neurofilament light chain, orexin A, total tau, and phosphorylated tau-181 (p-Tau) were measured using enzyme-linked immunosorbent assay. Associations with cognition and exploratory classification performance were examined using correlation and receiver operating characteristic analyses.Results: Postmenopausal women exhibited higher anxiety and poorer cognitive performance despite comparable insomnia severity. Among them (non-CI n=42; CI n=37), the CI group had higher plasma GFAP (14.82 vs. 12.42 ng/mL, P = .004) and p-Tau (1,002.18 vs. 918.27 pg/mL, P = .034). Biomarkercognition correlations were weak. GFAP showed the highest apparent performance among individual biomarkers (area under the curve, AUC = 0.672). The clinical information-adjusted model incorporating orexin A, GFAP, and p-Tau showed the highest apparent AUC among biomarker combinations (AUC = 0.755), although internally validated performance was more modest.Conclusions: Plasma GFAP and p-Tau, with potential incremental contribution from orexin A, may provide exploratory information for identifying cognitive vulnerability in postmenopausal women with insomnia disorder. These exploratory findings require validation in larger and independent cohorts.
Dan-Yun Wang, Bing Chen, K. Jin et al.· Psychiatry and Clinical Psyc...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
