Neuroplasticity and immune system are related to altered grey matter networks: a cohort study in sporadic Alzheimer’s disease

Relation of fluid neurodegeneration biomarkers with white matter integrity in Alzheimer's disease patients in Latin America

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.

Parallel neuroinflammatory pathways to cerebrovascular burden and amyloid beta in Alzheimer's disease

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.

Neurobiological correlates of longitudinal grey matter volume changes in preclinical Alzheimer’s disease

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.

Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer’s disease

Identification of gene expression changes in post-mortem brain tissue of Alzheimer’s disease donors compared to controls have implicated numerous biological pathways for Alzheimer’s disease pathophysiology. Nonetheless, there is still limited understanding of how gene expression dysregulation underpins specific proteinopathies core to Alzheimer’s disease. Here we investigate brain transcriptomic changes in a well characterized cohort of Alzheimer’s disease donors to identify genes and networks that associate with Alzheimer’s disease endophenotypes including neuropathology measures (Braak stage, Thal phase and cerebral amyloid angiopathy score) and Alzheimer’s disease-related brain protein levels (Apolipoprotein E, Amyloid-β 40, Amyloid-β 42, tau, and phospho-Tau). Bulk transcriptome measures were collected from the temporal cortex tissue of 477 Alzheimer’s disease donors. Following quality control, transcriptome-wide association studies were performed for each endophenotype. We used weighted gene co-expression network analysis to build co-expression networks and integrated transcriptome with epigenetic and genetic data from the same donors. We detected a total of 5,740 Bonferroni significant temporal cortex gene associations with Alzheimer’s disease endophenotypes, most of which were with brain tau levels. We discovered tau-associated co-expression modules enriched in known and novel Alzheimer’s disease pathways. We found that a beneficial (or neutral) brain biochemical state of higher total tau and lower phospho-Tau are associated with increased levels of synaptic, DNA damage/repair, nucleic acid metabolism and myelin processes. In contrast, in a detrimental state of lower total and higher phospho-Tau, there is upregulation of vascular and immune, and downregulation of mitochondrial and myelin pathways. There are brain gene expression perturbations that are associated with Alzheimer’s disease endophenotypes. While some of these associations are common across multiple endophenotypes, many are distinct for different Alzheimer’s disease-related proteins. Based on these findings, we propose a hypothetical model of dynamic brain gene expression changes that track with progressive Alzheimer’s disease proteostasis. These expression changes hold potential to serve as dynamic, precision biomarkers of brain Alzheimer’s disease progression. This study demonstrates the potential of integrative multiomics and deep Alzheimer’s disease endophenotype analyses in well-characterized brain tissues to uncover with precision the complex biology of Alzheimer’s disease.

A cerebrospinal fluid blood–brain barrier dysfunction score is associated with progression from mild cognitive impairment to Alzheimer's disease

MRI-derived brain aging trajectories across the Alzheimer's continuum: links to cognition, pathology and lifestyle risk factors

BAG is a reliable non-invasive marker of structural brain health sensitive to AD pathology and to modifiable AD risk and supports its relevance for early risk stratification and prevention-oriented research.