Jun 2026· Journal of Alzheimer's Disease· Vol 112, pp. 1362 - 1376· 0 citations· 43 references
Medicine
TL;DR
Elevated IL-6 is independently linked to cerebrovascular injury and poorer cognition beyond classical AD biomarkers, supporting a vascular–inflammatory pathway distinct from amyloid and tau pathology.
Abstract
Background Chronic inflammation contributes to neurodegeneration and cerebrovascular injury, yet it remains unclear whether inflammatory biomarkers influence white matter hyperintensity (WMH) volume and cognition independent of Alzheimer's disease (AD) plasma biomarkers. Objective This study examined whether inflammatory biomarkers were associated with WMH volume and multidomain cognitive performance independent of AD plasma biomarkers, and whether WMH volume mediated associations between IL-6 and cognition. Methods Using data from 1806 participants in the Health and Aging Brain Study–Health Disparities (HABS-HD), we examined associations between log transformed plasma inflammatory biomarkers (IL-10, TNF-α, IL-6, and IL-5) and WMH volume and cognitive performance (memory, executive function, processing speed, language). Multivariable linear regression models adjusted for demographic and vascular risk factors were repeated with additional adjustment for AD biomarkers (p-Tau181, NfL, total tau, Aβ42/40). Mediation analyses were included to test whether WMH meditated the association between IL-6 and cognitive domains. Results Higher IL-6 levels were consistently associated with increased WMH volume in base and AD-adjusted regression models. Increased levels of IL-6 were also associated with poorer performance in all cognitive domains, but these associations did not survive multiple comparisons correction. WMH partially mediated the association between IL-6 and memory (23%) and processing speed (19%). Conclusions Elevated IL-6 is independently linked to cerebrovascular injury and poorer cognition beyond classical AD biomarkers, supporting a vascular–inflammatory pathway distinct from amyloid and tau pathology. These findings underscore the importance of integrating inflammatory and neurodegenerative markers to elucidate heterogeneous mechanisms of brain aging across diverse populations.
Serum NfL was associated with anatomically specific WM microstructural changes, with differing patterns across clinical groups, and no significant associations were observed between serum or CSF GFAP concentrations and diffusion tensor imaging metrics.
T. Magalhães, R. Casseb, A. Moraes et al.· Journal of Alzheimer's Disea...· 0 citations
The findings identify a group of peripheral inflammatory markers associated with AD pathology and suggest that some of these relationships may vary by sex, warranting larger studies to clarify the role of sex in AD pathobiology.
R. Coig, L. Jain, M. Khrestian et al.· medRxiv· 0 citations
Abstract INTRODUCTION Upstream neuroinflammation plays an important role in Alzheimer's disease (AD) but remains poorly understood. We tested whether two distinct neuroinflammatory markers are associated with cerebrovascular burden and amyloid beta (Aβ), and downstream, with plasma phosphorylated tau (p‐tau217), medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits. METHODS Cognitively unimpaired older adults without dementia or mild cognitive impairment were recruited from a community sample (Biomarker Exploration in Aging, Cognition, and Neurodegeneration; [BEACoN]; N = 126). We used structural equation modeling to test whether plasma chitinase‐3‐like protein 1 (YKL‐40) and glial fibrillary acidic protein (GFAP) contribute to distinct pathways. RESULTS Higher plasma YKL‐40 was associated with greater white matter hyperintensity (WMH), whereas higher plasma GFAP was related to increased 18F‐florbetapir (FBP) standardized uptake value ratio (SUVR). Higher plasma GFAP, WMH, and FBP SUVR were independently associated with increased p‐tau217. Plasma p‐tau217 was associated with reduced MTL cortical thickness and hippocampal volume. Reduced hippocampal volume was related to worse memory. DISCUSSION Future work can further investigate these neuroinflammatory pathways as potential therapeutic targets for AD.
Batool Rizvi, Jenna N. Adams, Alison R. Bamford et al.· Alzheimer's & Dementia· 1 citation
A stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Keun You Kim, Hyunsun Ham, E. Yoon et al.· The journal of prevention of...· 0 citations
BackgroundVascular risk factors contribute substantially to late-life cognitive impairment and interact with neurodegenerative processes underlying dementia. Blood-brain barrier (BBB) dysfunction has emerged as a key mechanism linking vascular pathology to cognitive decline; however, circulating biomarkers reflecting BBB remodeling remain incompletely characterized.ObjectiveTo explore the association between circulating markers of BBB remodeling, amyloid-β (Aβ)1-40 and longitudinal cognitive decline in individuals with vascular risk factors.MethodsIn this prospective cohort study, 101 individuals (mean age 71 ± 5 years; 59.4% women) with long-standing hypertension and/or type 2 diabetes mellitus underwent serial assessment of serum BBB-related biomarkers (matrix metalloproteinases [MMPs], TIMP-1 and soluble tumor necrosis factor-like weak inducer of apoptosis [sTWEAK]), Aβ1-40, brain MRI, and standardized cognitive testing (Mini-Mental State Examination and Addenbrooke's Cognitive Examination Version V) over a mean follow-up of 24 ± 4.9 months. Cognitive decline was defined as a clinically meaningful reduction in global cognitive scores.ResultsTwelve participants (11.9%) developed cognitive decline. Higher serum MMP-7 levels at 12 months were independently associated with subsequent cognitive decline after adjustment for age, sex and baseline cognition (adjusted OR 2.13; 95% CI 1.09-4.13; p = 0.026). Baseline levels of Aβ1-40, MMP-9, and sTWEAK were associated with lower cognitive performance.ConclusionsElevated circulating MMP-7 at 12 months was associated with cognitive decline suggesting a potential role for BBB remodeling in vascular contributions to cognitive impairment. These findings should be considered exploratory and require validation in larger studies.
I. López-Dequidt, Y. Leira, S. Cinza-Sanjurjo et al.· Journal of Alzheimer's Disea...· 0 citations
In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation.
Martina Valletta, D. L. Vetrano, E. Laukka et al.· Annals of Neurology· 0 citations