Jul 2026· Journal of Alzheimer's Disease· Vol 113, pp. 158 - 168· 0 citations· 68 references
Medicine
TL;DR
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.
Abstract
Background Alzheimer's disease (AD) is increasingly prevalent in Latin America. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising biomarkers of neurodegeneration, but their relationship with white matter (WM) integrity remains unclear. Objective To investigate associations between fluid neurodegeneration biomarkers and WM microstructure in a Brazilian cohort of individuals across the AD continuum and cognitively healthy controls. Methods Ninety-one participants were included: 27 cognitively healthy controls (mean age = 68.3 ± 5.2 years) and 64 amyloid-positive individuals with mild cognitive impairment or AD dementia (mean age = 70.6 ± 6.9 years). AD participants were characterized by low cerebrospinal fluid (CSF) Aβ42 concentrations (<540 pg/mL) and altered Aβ42/p-Tau and Aβ42/t-Tau ratios. Serum and CSF concentrations of NfL and GFAP were measured using single-molecule array technology and examined in relation to diffusion tensor imaging metrics, including fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity (AxD). Results Within the clinical AD group, higher serum NfL levels were associated with lower AxD in the left cingulum tract (r = -0.372, p = 0.007). In cognitively healthy controls, serum NfL showed positive correlations with AxD and mean diffusivity in the right cingulum (r = 0.650, p = 0.001 and r = 0.607, p = 0.003, respectively). No significant associations were observed between serum or CSF GFAP concentrations and diffusion tensor imaging metrics. Conclusions Serum NfL was associated with anatomically specific WM microstructural changes, with differing patterns across clinical groups.
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
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
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
Structural brain changes during the earliest asymptomatic stages of Alzheimer’s disease (AD) remain poorly understood. Previous research in preclinical AD shows heterogeneous findings, reporting both subtle neuronal loss and paradoxical increases in grey matter (GM) volume. This study applies an extensive cerebrospinal fluid (CSF) biomarker panel to better understand the biological processes underlying longitudinal GM changes in cognitively unimpaired (CU) adults, spanning the amyloid/tau (AT) continuum.
We analysed data from 627 CU individuals from three longitudinal cohorts (ALFA+, Wisconsin ADRC, WRAP), with repeated MRI (3.5 ± 0.9 years) and baseline CSF biomarkers from the NeuroToolKit panel (Roche Diagnostics). Using non-negative matrix factorization, we decomposed the CSF biomarker levels into six latent components, reflecting amyloid-β (Aβ) pathology, tau-related pathophysiology with synaptic injury, neuroaxonal injury, microglial reactivity, astrocytic reactivity, and cytokine signalling. We tested associations between component weights and voxel-wise longitudinal GM volume changes using single-component and a joint-all components model. Analyses were performed across the full sample and stratified by AT status. Associations with longitudinal cognitive performance (PACC) were assessed using linear mixed-effects models.
The Aβ pathology component was the strongest and most widespread predictor of longitudinal GM atrophy, predominantly in temporal and frontal regions, also when controlling for tau pathophysiology, neuroaxonal injury, or neuroinflammatory components. Higher Aβ pathology scores were also associated with cognitive decline. The component capturing tau-related pathophysiology and synaptic injury initially associated with GM loss but lost significance after accounting for other biomarker components. In contrast, components reflecting microglial reactivity, astrocytic reactivity, and cytokine signalling were associated with longitudinal GM volume increases, with effects varying by AT stage.
In this large longitudinal sample of asymptomatic individuals, the Aβ-dominant biomarker component showed the strongest association with longitudinal GM atrophy and cognitive decline, beyond the effects of tau pathophysiology and neuroaxonal injury. While glial and inflammatory processes may contribute to transient GM increases in preclinical AD. A better understanding of these dynamic relationships between structural brain changes and various biological pathways at the earliest stages of AD is crucial to inform the development of interventions before irreversible neurodegeneration occurs.
W. Pelkmans, R. Cacciaglia, Michalis Kassinopoulos et al.· Molecular Neurodegeneration· 0 citations
BACKGROUND AND OBJECTIVES
Plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, is elevated across multiple neurodegenerative conditions, including Alzheimer disease. However, its role in neurodegeneration and cognitive decline driven by cerebrovascular pathology, independent of β-amyloid (Aβ) copathology, remains poorly characterized. We investigated whether plasma GFAP is associated with medial temporal atrophy and cognition across a spectrum of cerebrovascular burden in Aβ-negative cognitively impaired individuals.
METHODS
In this cross-sectional multicenter study, Aβ PET-negative cognitively impaired participants were recruited from South Korean memory clinics. Plasma GFAP was measured using ultrasensitive Simoa assays. White matter hyperintensity burden was graded using the Fazekas scale and stratified into low (LVP: Fazekas 1) and high (HVP: Fazekas 2-3) cerebrovascular burden groups. Medial temporal gray matter density was assessed using voxel-based morphometry, and hippocampal and amygdalar volumes were derived from T1-weighted MRI adjusted for intracranial volume. Linear regression, interaction, and bootstrap mediation models were used to assess associations among GFAP, brain structure, and cognition.
RESULTS
A total of 324 participants were included (LVP n = 203; HVP n = 121; median age 73 years [interquartile range 66-78]; 67.9% female). Compared with LVP, HVP participants were older (75 vs 71 years; p < 0.0001), had lower Mini-Mental State Examination (MMSE) scores (22.7 vs 24.5; p = 0.005), and higher plasma GFAP (136.7 vs 112.1 pg/mL; p = 0.001). Higher GFAP was associated with lower medial temporal gray matter density in HVP (β = -0.311; p = 0.001) but not LVP (β = -0.012; p = 0.858), with a significant GFAP-vascular burden interaction (β = -0.309; p = 0.008). In HVP, higher GFAP was associated with smaller hippocampal (β = -0.179; p = 0.044) and amygdalar volumes (β = -0.169; p = 0.049) and lower MMSE (β = -0.194; p = 0.039). Medial temporal atrophy statistically explained the GFAP-MMSE association (indirect β = -0.071, 95% CI -0.140 to -0.010; p = 0.016). Vascular comorbidities (diabetes, dyslipidemia, hypertension) did not modify the GFAP-cognition association.
DISCUSSION
In Aβ-negative cognitively impaired individuals with high cerebrovascular burden, elevated plasma GFAP is associated with medial temporal atrophy and cognitive decline, suggesting GFAP may capture astrocyte-reactivity relevant to vascular cognitive impairment beyond amyloid pathology. These cross-sectional findings require confirmation in longitudinal and ethnically diverse cohorts.
M. S. Oliveira-Junior, M. Rodrigues, Livia Amaral et al.· Neurology· 0 citations
Grey matter network topology is altered in Alzheimer’s disease and these alterations are related to cognitive decline, which suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to tau.
Diederick M. de Leeuw, F. Duits, E. Dicks et al.· Brain Communications· 0 citations