Author: Cindy Birck

“Semantic Harmonization of Alzheimer’s Disease Datasets Using AD-Mapper”

Authors: Philipp Wegner, Helena Balabin,Mehmet Can Ay, Sarah Bauermeister, Lewis Killin, John Gallacher, Martin Hofmann-Apitius, Yasamin Salimi, for the Alzheimer’s Disease Neuroimaging Initiative, the Japanese Alzheimer’s Disease Neuroimaging Initiative, the Aging Brain: Vasculature, Ischemia, and Behavior Study, the Alzheimer’s Disease Repository Without Borders Investigators, and the European Prevention of Alzheimer’s Disease (EPAD) Consortium

Abstract:

Background:Despite numerous past endeavors for the semantic harmonization of Alzheimer’s disease (AD) cohort studies, an automatic tool has yet to be developed.

Objective: As cohort studies form the basis of data-driven analysis, harmonizing them is crucial for cross-cohort analysis. We aimed to accelerate this task by constructing an automatic harmonization tool.

Methods: We created a common data model (CDM) through cross-mapping data from 20 cohorts, three CDMs, and ontology terms, which was then used to fine-tune a BioBERT model. Finally, we evaluated the model using three previously unseen cohorts and compared its performance to a string-matching baseline model.

Results: Here, we present our AD-Mapper interface for automatic harmonization of AD cohort studies, which outperformed a string-matching baseline on previously unseen cohort studies. We showcase our CDM comprising 1218 unique variables.

Conclusion: AD-Mapper leverages semantic similarities in naming conventions across cohorts to improve mapping performance.

DOI: 10.3233/JAD-240116

Published online on 11 June 2024 in the Journal of Alzheimer’s Disease

“Alzheimer’s disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals”

Authors: Luigi Lorenzini, Lyduine E. Collij, Niccoló Tesi, Natàlia Vilor-Tejedor, Silvia Ingala, Kaj Blennow, Christopher Foley, Giovanni B. Frisoni, Sven Haller, Henne Holstege, Sven van der van der Lee, Pablo Martinez-Lage, Riccardo E. Marioni, Daniel L. McCartney, John O’ Brien, Tiago Gil Oliveira, Pierre Payoux, Marcel Reinders, Craig Ritchie, Philip Scheltens, Adam J. Schwarz, Carole H. Sudre, Adam D. Waldman, Robin Wolz, Gael Chatelat, Michael Ewers, Alle Meije Wink, Henk J. M. M. Mutsaerts, Juan Domingo Gispert, Pieter Jelle Visser, Betty M. Tijms, Andre Altmann, Frederik Barkhof

Abstract:

Introduction: Unraveling how Alzheimer’s disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine.

Methods: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity.

Results: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication.

Discussion: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies.

Highlights

• Polygenic risk for Alzheimer’s disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers.
• Inflammatory pathways are mostly related to cerebrovascular burden.
• White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

DOI: https://doi.org/10.1002/alz.14096

Published online: 29 July 2024 in the journal Alzheimer’s & Dementia

“Association of Vascular Risk Factors and Cerebrovascular Pathology With Alzheimer Disease Pathologic Changes in Individuals Without Dementia”

Authors: Luigi Lorenzini, Alessio Maranzano, Silvia Ingala, Lyduine E. Collij, Mario Tranfa, Kaj Blennow, Carol Di Perri, Christopher Foley, Nick C. Fox, Giovanni B. Frisoni, Sven Haller, Pablo Martinez-Lage, John O’Brien, Pierre Payoux, Craig Ritchie, Philip Scheltens, Adam J. Schwarz, Carole H. Sudre, Betty M. Tijms, Federico Verde, Nicola Ticozzi, Vincenzo Silani, Pieter Jelle Visser, Adam Waldman, Robin Wolz, Gael Chételat, Michael Ewers, Alle Meije Wink, Henk Mutsaerts, Juan Domingo Gispert, Joanna M. Wardlaw and Frederik Barkhof

Abstract:
Background and Objectives: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ_1-42) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau₁₈₁), atrophy, and cognition.

Methods: This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a “cSVD severity” latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aβ_1-42, P-tau₁₈₁, gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal).

Results: A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aβ_1-42 (β = −0.04 ± 0.01). All cSVD features were negatively associated with CSF Aβ_1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aβ_1-42 (indirect effect: β = −0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau₁₈₁ (indirect effect: β = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: β = −0.10 ± 0.03; β = −0.12 ± 0.05), and baseline cognitive performance (indirect effect: β = −0.16 ± 0.03) through CSF Aβ_1-42.

Discussion: In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aβ_1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

DOI: https://doi.org/10.1212/WNL.0000000000209801

Published online: 17 September 2024 in the journal Neurology