Category: Publications

“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