Journal Article

FZJ-2025-05730

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Detecting limbic predominant neurodegenerative co-pathologies in vivo in Alzheimer’s disease: magnetic resonance imaging markers, cognitive correlates, and prognosis

Richter, N. (Corresponding author)FZJ* ; Onur, O. A. ; Fink, G. R.FZJ*

2025
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s13195-025-01885-6  doi:10.34734/FZJ-2025-05730

Abstract: In Alzheimer's disease (AD), limbic non-AD co-pathologies are common and contribute to memory impairment and accelerated clinical progression. To date, in vivo biomarkers of these co-pathologies are lacking. Here, we examined whether specific regional gray matter (GM) atrophy patterns on magnetic resonance imaging (MRI) allow distinguishing between patients with 'pure' AD pathology and those with AD pathology and limbic non-AD co-pathologies (AD+).Methods: Atrophy patterns based on ante-mortem MRI scans of histopathologically confirmed 'pure' AD (n = 36) and AD+, i.e., AD pathology with concomitant limbic TDP-43 pathology and argyrophilic grain disease (n = 39), were applied to classify an independent cohort of clinically diagnosed patients with mild cognitive impairment (MCI, n = 224) and dementia (n = 221). Furthermore, we examined the degree to which an MRI marker of cortical degeneration reflecting tau pathology could improve the estimation of clinical progression.Results: Histopathologically confirmed AD+ pathology was associated with more substantial hippocampal atrophy but less cortical degeneration in intermediate Braak stage regions than 'pure' AD pathology. Clinically diagnosed AD patients with an AD+-classified ratio of cortical-to-hippocampal GM exhibited significantly more memory impairment. At the stage of MCI, AD+-classified atrophy was also associated with speeded clinical decline. Furthermore, tau-associated cortical degeneration emerged as the primary predictor of clinical progression across groups and disease stages.Conclusions: The data suggest that in MCI due to AD, additional non-AD limbic co-pathologies are associated with greater hippocampal but less cortical atrophy and more rapid clinical decline. In contrast, in mild dementia due to AD, hippocampal GM was not associated with prognosis. Instead, cortical degeneration appeared to drive clinical progression.Keywords: Argyrophilic grain disease; Braak stages; Dementia; Limbic predominant age-related TDP-43 encephalopathy (LATE); Mild cognitive impairment; Tau-protein; Voxel-based morphometry.

Note: Open Access funding enabled and organized by Projekt DEAL. Datacollection and sharing for this project was funded by the Alzheimer'sDisease Neuroimaging Initiative (ADNI) (National Institutes of Health GrantU01 AG024904) and DOD ADNI (Department of Defense award numberW81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, theNational Institute of Biomedical Imaging and Bioengineering, and throughgenerous contributions from the following: AbbVie, Alzheimer’s Association;Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.;Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.;Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-LaRoche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare;IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development,LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.;Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRxResearch; Neurotrack Technologies; Novartis Pharmaceuticals Corporation;Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company;and Transition Therapeutics. The Canadian Institutes of Health Researchis providing funds to support ADNI clinical sites in Canada. Private sectorcontributions are facilitated by the Foundation for the National Institutes ofHealth (www.fnih.org). The grantee organization is the Northern CaliforniaInstitute for Research and Education, and the study is coordinated by theAlzheimer’s Therapeutic Research Institute at the University of SouthernCalifornia. ADNI data are disseminated by the Laboratory for Neuro Imagingat the University of Southern California.This work was supported by agrant from the Marga and Walter Boll Foundation (Nr. 210–08-13), Kerpen,Germany, to GRF and OO.Open access publication funded by the DeutscheForschungsgemeinschaft (DFG, German Research Foundation) – 491111487.

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Contributing Institute(s):

1. Kognitive Neurowissenschaften (INM-3)

Research Program(s):

1. 5251 - Multilevel Brain Organization and Variability (POF4-525) (POF4-525)
2. DFG project G:(GEPRIS)491111487 - Open-Access-Publikationskosten / 2025 - 2027 / Forschungszentrum Jülich (OAPKFZJ) (491111487) (491111487)

Appears in the scientific report 2025

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