​ALZHEIMER’S OR LATE ?
Alzheimer's disease (AD), the leading cause of dementia worldwide, clinically manifests in its typical form as an amnestic syndrome and is characterized by the aggregation and accumulation of abnormal amyloid-β and tau proteins. However, AD is not the only cause of progressive amnesia. The latter can also result from a related pathology, limbic-predominant age-related TDP-43 encephalopathy (LATE), which initially presents with a clinical picture similar to AD. LATE is associated with another proteinopathy (TDP-43) and follows a distinct clinical progression. Currently, it is impossible to definitively diagnose LATE in living patients.

WHITE MATTER: A DISCRIMINATING BIOMARKER ?
In a recent groundbreaking study, the authors tested the hypothesis that white matter analysis could differentiate Alzheimer’s disease (AD) from LATE, pathologies primarily considered to affect gray matter. Their approach was based on the fixel-based method, an advanced diffusion MRI technique that characterizes fiber orientations within a voxel, enabling detailed investigation of the brain’s white matter bundles. The results underscored the value of this approach for studying early nerve fiber alterations in both diseases.
In this new study, the researchers present the results of a longitudinal analysis tracking the evolution of white matter alterations over two years in two patient groups, early-stage AD and presumed LATE, at inclusion and during follow-up. They assessed i) cognitive and functional decline in both groups, and ii) amyloid and tau burden measured via PET imaging at inclusion in AD patients. In both AD and presumed LATE, the authors observed a progression of white matter bundle alterations in the temporo-parietal and temporo-frontal tracts, most of which were already present at inclusion, as well as, to a lesser extent, in Arnold’s temporopulvinar tract. They also identified differential progression patterns depending on the pathology: in AD, alterations primarily affected temporal fasciculi, limbic pathways, and the cingulum, whereas in presumed LATE, they mainly involved the bilateral superior longitudinal fasciculi. Alterations in these fiber tracts at inclusion were associated with faster cognitive decline. However, there were only weak associations between white matter tract alterations and amyloid or tau burden measured by PET at inclusion in AD.
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This study demonstrates that fixel-based analysis of diffusion MRI images can precisely reveal distinct white matter alterations in patients with similar cognitive impairments, suggesting that these changes could serve as a potential predictive biomarker for cognitive decline, differentiating Alzheimer’s disease from LATE.

Legend: Fixel whole-brain analyses in patients with AD © Lebrun et al., Geroscience, 2026
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Contacts : Aurélie Lebrun (aurelie.lebrun98@gmail.com) ; Yann Leprince (yann.leprince@cea.fr) ; Michel Bottla​ender​ (michel.bottlaender@cea.fr)