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

“Cerebral Microbleeds and Amyloid Pathology Estimates From the Amyloid Biomarker Study”

Authors: Julie E Oomens, Veerle van Gils, Stephanie J B Vos, Whitney M Freeze, Nancy N Maserejian, Gioacchino Curiale, Cai Gillis , Mercè Boada, Wiesje M van der Flier, Jakub Hort, Sterling C Johnson, Alberto Lleó, Inez H Ramakers, Karen M Rodrigue, Pascual Sánchez-Juan, Marie Sarazin , Nikolaos Scarmeas, Henrik Zetterberg, Daniel Alcolea, Frederik Barkhof, Kaj Blennow, Michel Bottlaender , Anouk den Braber, Jirí Cerman, Marta Drake-Perez, Juan Fortea, Ron Handels , Silvia Ingala, Julio F Jiménez-Bonilla, Stratos Karavasilis, Julien Lagarde, Nienke Legdeur, Luigi Lorenzini, Marta Marquié , Justine E F Moonen, Pauline Olivieri, Adelina Orellana, Rik Ossenkoppele, Leonardo A Rivera-Rivera, Eloy Rodríguez-Rodriguez, Agustín Ruiz Laza, Charlotte E Teunissen, Betty M Tijms, Giorgos Velonakis, Frans R J Verhey, Pieter Jelle Visser, Willemijn J Jansen ; European Prevention of Alzheimer’s Dementia (EPAD) Consortium; Fundació ACE Healthy Brain Initiative (FACEHBI) Study Group; BIOFACE Study Group

Abstract:

Importance: Baseline cerebral microbleeds (CMBs) and APOE ε4 allele copy number are important risk factors for amyloid-related imaging abnormalities in patients with Alzheimer disease (AD) receiving therapies to lower amyloid-β plaque levels.

Objective: To provide prevalence estimates of any, no more than 4, or fewer than 2 CMBs in association with amyloid status, APOE ε4 copy number, and age.

Design, setting, and participants: This cross-sectional study used data included in the Amyloid Biomarker Study data pooling initiative (January 1, 2012, to the present [data collection is ongoing]). Data from 15 research and memory clinic studies were pooled and harmonized. Participants included individuals for whom data on age, cognitive status, amyloid status, and presence of CMBs were available. Data were analyzed from October 22, 2023, to April 26, 2024.

Main outcomes and measures: The main outcomes were age, cognitive status, amyloid status and presence, location, and number of CMBs. Presence of amyloid pathology was determined based on 42 amino acid-long form of amyloid-β peptide (Aβ42) levels in cerebrospinal fluid or on amyloid-positron emission tomography. Presence and, in a subset, location (lobar vs deep) and number of CMBs were determined on magnetic resonance imaging (locally with visual rating).

Results: Among 4080 participants included in the analysis, the mean (SD) age was 66.5 (8.9) years, and 2241 (54.9%) were female. A total of 2973 participants had no cognitive impairment (cognitive unimpairment [CU]), and 1107 had mild cognitive impairment (MCI) or AD dementia (ADD). One thousand five hundred and thirteen participants (37.1%) had amyloid pathology, 1368 of 3599 (38.0%) with data available were APOE ε4 carriers, and 648 (15.9%) had CMBs. In the CU group, amyloid pathology and APOE ε4 copy number were not associated with presence of any, no more than 4, or fewer than 2 CMBs but were associated with increased odds of lobar CMBs (odds ratio [OR] for amyloid, 1.42 [95% CI, 1.20-1.69], P < .001; OR for 2 vs 0 alleles, 1.81 [95% CI, 1.19-2.74], P = .006; OR for 1 vs 0 alleles, 1.10 [95% CI, 0.83-1.46], P = .49; and OR for 2 vs 1 allele, 1.64 [95% CI, 0.90-2.97], P = .11; overall P = .02). In the MCI-ADD group, amyloid pathology was associated with presence of any CMBs (OR, 1.51 [95% CI, 1.17-1.96], P = .002), no more than 4 CMBs (OR, 1.44 [95% CI, 1.18-1.82], P = .002), and fewer than 2 CMBs (OR 1.34 [95% CI, 1.03-1.74], P = .03) but not lobar CMBs. APOE ε4 copy number was associated with presence of any (OR for 2 vs 0 alleles, 1.72 [95% CI, 0.88-3.35], P = .11; OR for 1 vs 0 alleles, 0.78 [95% CI, 0.59-1.04], P = .09; and OR for 2 vs 1 allele, 2.20 [95% CI, 1.32-3.67], P = .002; overall P < .001) and no more than 4 CMBs (OR for 2 vs 0 alleles, 1.31 [95% CI, 0.64-2.68], P = .45; OR for 1 vs 0 alleles, 0.75 [95% CI, 0.54-1.04], P = .08; and OR for 2 vs 1 allele, 1.76 [95% CI, 0.97-3.19], P = .06; overall P = .03) but not with fewer than 2 or lobar CMBs. Prevalence estimates of CMBs ranged from 6% at 50 years of age in a non-APOE ε4 allele carrier with no amyloid pathology and no cognitive impairment to 52% at 90 years of age in an APOE ε4 homozygote carrier with amyloid pathology and cognitive impairment.

Conclusions and relevance: In this cross-sectional study of 4080 participants, prevalence estimates of CMBs were associated with amyloid status, APOE ε4 copy number, and age. CMB prevalence estimates may help inform safety evaluations for antiamyloid clinical trials.

DOI: 10.1001/jamanetworkopen.2024.55571

Published online: 22 January 2025 in the journal JAMA Network Open

“Blood-brain barrier permeable β-blockers association with Alzheimer’s disease cerebrospinal fluid biomarkers levels in non-demented individuals”

Authors:  
Mariateresa Buongiorno, Gonzalo Sánchez-Benavides, Clara Marzal-Espí, Darly Milena Giraldo, Jerzy Krupinski, Natalia Cullell, Oriol Grau-Rivera, Marc Suárez-Calvet, Juan Domingo Gispert, Alex de la Sierra, and for the Alzheimer’s Disease Neuroimaging Initiative, and the European Prevention of Alzheimer’s Disease (EPAD) Consortium

Abstract:

β-blockers that easily cross the blood-brain barrier (BBB) seem to diminish the risk of Alzheimer’s disease (AD), hypothetically facilitating waste clearance. However, their effect on AD pathophysiological markers is unknown. We compared cerebrospinal fluid (CSF) AD biomarker levels among non-demented individuals taking low, intermediate, or high BBB permeable β-blockers in two samples (ADNI: n = 216; EPAD: n = 79). We found that CSF amyloid-β levels were higher in individuals taking highly permeable β-blockers in the ADNI sample. This result was not replicated in EPAD, in which diminished levels of pTau181 and tTau were observed. These data suggest that β-blockers may impact AD pathophysiology.

DOI: https://doi.org/10.1177/13872877241293812

Published online: 25 November 2024 in SAGEJournals

“Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer’s continuum: Evidence across two independent cohorts”

Authors: Raffaele Cacciaglia, Carles Falcón, Gonzalo Sánchez Benavides, Anna Brugulat-Serrat, Marta Milà Alomà, Marc Suárez Calvet, José Luis Molinuevo, Karine Fauria, Carolina Minguillón, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Kaj Blennow, Henrik Zetterberg, Luigi Lorenzini, Alle Meije Wink, Silvia Ingala, Frederik Barkhof, Craig W. Ritchie, Juan Domingo Gispert, for the ALFA study

Abstract:

Introduction: Identifying the link between early Alzheimer’s disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals.

Methods: We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (APOE) status, follow-up time, and years of education.

Results: In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau).

Discussion: Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade.

Highlights: Our results underscore the importance of undertaking Alzheimer’s preclinical trials. We assessed brain atrophy and cognitive decline in asymptomatic individuals. Aβ biomarkers predicted MTL atrophy independently of p-tau.

DOI: doi.org/10.1002/alz.14415

Published online: 3 February 2025 in the journal Alzheimer’s & Dementia: the journal of the Alzheimer’s Association

“Grey-Matter Structure Markers of Alzheimer’s Disease, Alzheimer’s Conversion, Functioning and Cognition: A Meta-Analysis Across 11 Cohorts”

Authors: Baptiste Couvy-Duchesne, Vincent Frouin, Vincent Bouteloup, Nikitas Koussis, Julia Sidorenko, Jiyang Jiang, Alle Meije Wink, Luigi Lorenzini, Frederik Barkhof, Julian N. Trollor, Jean-François Mangin, Perminder S. Sachdev, Henry Brodaty, Michelle K. Lupton, Michael Breakspear, Olivier Colliot, Peter M. Visscher, Naomi R. Wray, for the Alzheimer’s Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of ageing, the Alzheimer’s Disease Repository Without Borders Investigators, the MEMENTO cohort Study Group

Abstract:

Alzheimer’s disease (AD) brain markers are needed to select people with early-stage AD for clinical trials and as quantitative endpoint measures in trials. Using 10 clinical cohorts (N = 9140) and the community volunteer UK Biobank (N = 37,664) we performed region of interest (ROI) and vertex-wise analyses of grey-matter structure (thickness, surface area and volume). We identified 94 trait-ROI significant associations, and 307 distinct cluster of vertex-associations, which partly overlap the ROI associations. For AD versus controls, smaller hippocampus, amygdala and of the medial temporal lobe (fusiform and parahippocampal gyri) was confirmed and the vertex-wise results provided unprecedented localisation of some of the associated region. We replicated AD associated differences in several subcortical (putamen, accumbens) and cortical regions (inferior parietal, postcentral, middle temporal, transverse temporal, inferior temporal, paracentral, superior frontal). These grey-matter regions and their relative effect sizes can help refine our understanding of the brain regions that may drive or precede the widespread brain atrophy observed in AD. An AD grey-matter score evaluated in independent cohorts was significantly associated with cognition, MCI status, AD conversion (progression from cognitively normal or MCI to AD), genetic risk, and tau concentration in individuals with none or mild cognitive impairments (AUC in 0.54–0.70, p-value < 5e-4). In addition, some of the grey-matter regions associated with cognitive impairment, progression to AD (‘conversion’), and cognition/functional scores were also associated with AD, which sheds light on the grey-matter markers of disease stages, and their relationship with cognitive or functional impairment. Our multi-cohort approach provides robust and fine-grained maps the grey-matter structures associated with AD, symptoms, and progression, and calls for even larger initiatives to unveil the full complexity of grey-matter structure in AD.

DOI: doi.org/10.1002/hbm.70089

Published online: 3 February 2025 in the journal Human Brain Mapping