Aug 2026· Journal of Alzheimer's Disease· pp.
13872877261474103
· 0 citations· 22 references
Medicine
TL;DR
Elevated circulating MMP-7 at 12 months was associated with cognitive decline suggesting a potential role for BBB remodeling in vascular contributions to cognitive impairment, and should be considered exploratory and require validation in larger studies.
Abstract
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.
Dementia reflects vascular and neurodegenerative processes in late life, yet studies often examine risks and outcomes individually. This study tested whether the cumulative burden of risks relate to vascular brain injury and cognitive performance and whether brain markers are associated with part of these associations through cross-sectional indirect pathways. Cross-sectional data were drawn from 38,414 older adults in the National Alzheimer's Coordinating Center database. A composite index summed ten binary risk factors: hypertension, diabetes, hypercholesterolemia, alcohol misuse, smoking, depression, obesity, hearing loss, vision loss, and low education. Outcomes included white matter hyperintensities (WMHs), infarcts, hippocampal atrophy, global cognition, cognitive status, delayed recall, and semantic fluency. Higher cumulative risk burden was associated with poorer cognitive outcomes and greater structural brain injury. Each additional risk factor was linked to worse global cognitive status, greater clinical severity, lower delayed recall, lower semantic fluency, and higher odds of WMHs, cerebral infarcts, and hippocampal atrophy. Hippocampal atrophy demonstrated the largest indirect pathway among the evaluated MRI markers, whereas WMHs and infarcts showed smaller indirect pathways. The findings suggest that cumulative modifiable risk burden is associated with poorer brain health and cognitive functioning in later life. Examining risk factors collectively provides a clearer understanding of brain health vulnerability and supports multidomain prevention strategies that target clustered modifiable risks.
T. Khudair, S. Raeesi, Yashar Zeighami et al.· GeroScience· 0 citations
Abstract Introduction Chronic heart failure (HF) is associated with mild cognitive impairment (MCI), vascular dementia, and Alzheimer’s disease. Blood-based neurodegenerative biomarkers may support early risk stratification and outcome prediction in HF. Methods In the prospective Cognition.Matters-HF cohort study, serum neurofilament light chain (NfL), glial fibrillary acidic protein, and phosphorylated tau protein-181, as well as plasma amyloid-β peptides (Aβ38, Aβ40, Aβ42) and β-synuclein, were quantified longitudinally over 36 months using ultrasensitive immunoassays and immunoprecipitation mass spectrometry. Cerebral magnetic resonance imaging and standardized domain-specific cognitive testing were performed. Multivariable logistic regression was used to assess associations with future MCI, brain structural changes, and 5-year all-cause mortality. Results Among 104 patients with chronic HF (10% female, age 64 ± 10 years), all biomarkers except NfL increased significantly over 3 years (P < .05). Median annual percentage changes were 36.6% for phosphorylated tau protein-181, 4.6% for glial fibrillary acidic protein, 2.6% for β-synuclein, 0.6% for Aβ38, 0.5% for Aβ40, and 0.3% for Aβ42. After adjusting for clinical confounders, increases in Aβ38 and Aβ42 independently associated with future MCI, pathological white matter hyperintensity progression (>5% per year), and 5-year mortality (all P < .05). Glial fibrillary acidic protein levels and phosphorylated tau protein-181 trajectories were independently associated with pathological brain atrophy (>0.3% per year). Conclusion In clinically stable patients with chronic HF, longitudinal increases in circulating amyloid-β peptides associated with cognitive decline, structural brain changes, and mortality. Serial biomarker assessment provided stronger prognostic information than baseline measurements alone. Replication in larger cohorts is required.
J. Traub, Anna Frey, G. Homola et al.· ESC Heart Failure· 0 citations
Aging is accompanied by an increasing prevalence of frailty and age-related cognitive decline (CD). Cognitive frailty (CF), characterized by physical frailty and cognitive impairment, has been associated with oxidative stress, neuroinflammation, mitochondrial dysfunction, and cardiovascular impairment. However, its biological foundations remain only partially understood. This review synthesizes evidence on biomarkers associated with the blood-brain barrier (BBB) and neurovascular unit (NVU) in CD and CF. These biomarkers are associated with endothelial injury, pericyte damage, BBB permeability, tight junction disruption, glial activation, and extracellular vesicles (EVs). They are assessed by analyzing cerebrospinal fluid (CSF), blood, neuroimaging (including DCE-MRI), and histology. The most frequently evaluated markers were CSF sPDGFRβ, the CSF/serum albumin ratio (QAlb), DCE-MRI permeability, and the adhesion molecules ICAM-1 and VCAM-1. Key convergent findings suggest that BBB breakdown (particularly pericyte injury, as indicated by elevated CSF sPDGFRβ) can precede or occur independently of classical amyloid-β and tau pathology, predict CD in APOE4 carriers over up to 4.5 years, and be associated with disrupted default mode network connectivity. Elevated QAlb demonstrated dose-response prognostic value for clinical deterioration, while DCE-MRI permeability was associated with poorer episodic memory and predicted white-matter injury, which mediated cognitive impairment. Endothelial activation markers were elevated early and predicted progression, whereas vWF exhibited a stage-dependent, potentially biphasic association. Overall, BBB/NVU biomarkers support vascular and neuroinflammatory mechanisms as early, partially Alzheimer's disease-independent contributors to CD and CF, with significant modification by APOE4 and metabolic comorbidities, and with distinct signatures across Alzheimer's disease and vascular cognitive impairment.
Juan de Dios Rodríguez-Callejas, A. Mimenza-Alvarado, C. Lomas-Soria et al.· Revista de investigacion cli...· 0 citations
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
Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, synaptic plasticity, and cognitive function. Age-related decline in BDNF signaling has been implicated in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and mild cognitive impairment. However, the prognostic value of circulating BDNF and its genetic variants remains controversial due to inconsistent findings across studies. This review synthesizes current evidence on peripheral BDNF levels and the Val66Met polymorphism as potential biomarkers of age-related cognitive decline and neurodegeneration. We critically analyze biological mechanisms linking BDNF to neurodegeneration, including its interaction with amyloid-beta and tau pathology. We further examine factors underlying discrepant results: demographic characteristics, comorbidities, lifestyle factors, pharmacological interventions, and methodological variability. Despite these challenges, BDNF remains a promising diagnostic factor. Nevertheless, standardizing preanalytical protocols and accounting for patient heterogeneity are essential to unlock its diagnostic potential.
Tatiana V. Tulupova, M. Vedunova, E. Mitroshina· Frontiers in Aging Neuroscie...· 0 citations
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) and higher plasma p‐tau217 was associated with reduced MTL cortical thickness and hippocampal volume.
Batool Rizvi, Jenna N. Adams, Alison R. Bamford et al.· Alzheimer's & Dementia· 1 citation