Sequential associations of myelin dysfunction with Aβ and Tau pathology in Alzheimer's disease: a dynamic myelin perturbation.

Disruption of temporo-parietal network in Alzheimer’s disease and its association with memory impairment

Alzheimer’s disease (AD) is characterised by the accumulation of β-amyloid (Aβ) and tau proteins, resulting in neurodegeneration and cognitive decline. Although Aβ and tau disrupt synaptic function, the association linking these molecular pathologies to network-level dysfunction and memory impairment remains poorly understood. Here, we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity related to memory encoding, which may provide a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from 205 participants in the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) across the AD spectrum. Effective connectivity was assessed using Dynamic Causal Modelling (DCM) of task-fMRI data, focusing on the parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU)—regions central to memory encoding. Disruptions in connectivity between temporal and parietal lobes were associated with both memory impairment and indices of AD pathology. Specifically, reduced positive effective connectivity from the PCU to the PPA and from the HC to the PCU were linked to higher p-tau-181 levels, with an amplification effect observed in the presence of amyloid accumulation for the latter connectivity. The disruption from the PCU to the PPA was found to be associated with decreased memory performance. Together, these findings indicate that temporo-parietal connectivity is associated with both AD molecular pathology and, for a subset of connections, with memory performance.

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.

Disrupted myelin homeostasis in grey matter of 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.

White matter abnormalities in Alzheimer's disease: Implications for pathophysiology, diagnosis, and treatment.

White matter (WM) abnormalities have emerged as a critical element in Alzheimer's disease (AD) pathogenesis, shifting from their former status as a passive consequence to an active contributor to disease progression. Notably, microstructural WM alterations, detectable early via advanced neuroimaging techniques such as diffusion tensor imaging, frequently precede overt gray matter atrophy and cognitive decline, highlighting their potential as early contributors to AD pathogenesis. The origins of WM pathology are multifactorial, involving a complex interplay among β-amyloid (Aβ) and tau aggregation, energy dysmetabolism, neuroinflammation, vascular dysfunction, and cellular senescence. Importantly, we emphasize a paradigm-shifting perspective: WM degeneration acts not merely as a downstream outcome but as a key driver of AD pathogenesis, capable of accelerating protein aggregation, amplifying neuroinflammation, and compromising neural plasticity. Given its early manifestation and close association with symptom onset, WM integrity has emerged as a sensitive and reliable biomarker for early AD detection and progression monitoring. Moving beyond diagnostics, the growing understanding of WM pathophysiology has unveiled a new frontier of therapeutic interventions aimed at myelin regeneration and WM protection. Despite persisting translational challenges, targeting WM integrity represents a pivotal avenue for developing disease-modifying therapies capable of slowing disease progression and improving clinical outcomes in patients with AD.

Association Between Plasma Phosphorylated Tau-217 and Cognition in Parkinson's Disease.

BACKGROUND Alzheimer's disease (AD) co-pathology contributes to dementia in PD, but its role in earlier cognitive impairment remains uncertain. OBJECTIVE To determine if p-tau217, a biomarker of early AD, is associated with cognitive impairment in PD. METHODS Plasma p-tau217 levels in 167 PD patients without dementia and 63 controls were related to performance on standard neuropsychological testing, and to cognitive impairment as defined by a MoCA score <26 and by self-report. Plasma GFAP, NfL and APOE ε4 carrier status were also examined. RESULTS No significant differences in p-tau217, GFAP and NfL level were observed between groups (pFDR > 0.08). Higher p-tau217 was associated with worse visuospatial function and greater self-reported cognitive impairment, but these associations did not survive correction (pFDR > 0.08). There was no association with cognitive impairment (pFDR > 0.08). CONCLUSION These results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.