Category: Publications

“Facilitating clinical use of the Amsterdam Instrumental Activities of Daily Living Questionnaire: Normative data and a diagnostic cutoff value”

Authors: Merel C. Postema, Mark A. Dubbelman, Jürgen Claesen, Craig Ritchie, Merike Verrijp, Leonie Visser, Pieter-Jelle Visser, Marissa D. Zwan, Wiesje M. van der Flier and Sietske A.M. Sikkes

Abstract:

Objective:The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is well validated and commonly used to assess difficulties in everyday functioning regarding dementia. To facilitate interpretation and clinical implementation across different European countries, we aim to provide normative data and a diagnostic cutoff for dementia.

Methods: Cross-sectional data from Dutch Brain Research Registry (N = 1,064; mean (M) age = 62 ± 11 year; 69.5% female), European Medial Information Framework-Alzheimer’s Disease 90 + (N = 63; Mage = 92 ± 2 year; 52.4% female), and European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (N = 247; Mage = 63 ± 7 year; 72.1% female) were used. The generalized additive models for location, scale, and shape framework were used to obtain normative values (Z-scores). The beta distribution was applied, and combinations of age, sex, and educational attainment were modeled. The optimal cutoff for dementia was calculated using area under receiver operating curves (AUC-ROC) and Youden Index, using data from Amsterdam Dementia Cohort (N = 2,511, Mage = 64 ± 8 year, 44.4% female).

Results: The best normative model accounted for a cubic-like decrease of IADL performance with age that was more pronounced in low compared to medium/high educational attainment. The cutoff for dementia was 1.85 standard deviation below the population mean (AUC = 0.97; 95% CI [0.97–0.98]).

Conclusion:We provide regression-based norms for A-IADL-Q and a diagnostic cutoff for dementia, which help improve clinical assessment of IADL performance across European countries.

DOI: https://doi.org/10.1017/S1355617724000031

Published online: 8 March 2024 in the Journal of the International Neuropsychological Society

“Validation of the brain health index in the European Prevention of Alzheimer’s Dementia cohort”

Authors: Jodi K. Watt, David Alexander Dickie, Frederick K. Ho, Donald M. Lyall, Jesse Dawson, Terence J. Quinn, European Prevention of Alzheimer’s Disease (EPAD) Consortium

Abstract:

Background: Brain Health Index (BHI) assimilates various MRI sequences, giving a quantitative measure of brain health. To date, BHI validation has been cross-sectional and limited to selected populations. Further large-scale validation and assessment of temporal change is required to understand its clinical utility.

Aim: Assess 1) relationships between variables associated with cognitive decline and BHI 2) associations between BHI and measures of cognition and 3) longitudinal changes in BHI and relationship with cognitive function.

Methods: BHI computation involved Gaussian mixture-model cluster analysis of T1, T2, T2*, and T2 FLAIR MRI data from participants within the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Group differences (gender- and health-based) were evaluated using independent samples Welch’s t-tests. Relationships between BHI, age and cognitive tests used linear regression. Longitudinal analysis (12/24 months) utilised mixed linear regression models to examine BHI changes, and paired BHI/cognition associations.

Results: Data from N = 1496 predominantly Caucasian participants (50–88 years old, 43.32% male) were used. BHI scores were lower in those with diabetes (p < 0.001, d = 0.419), hypertension (p < 0.001, d = 0.375), hypercholesterolemia (p < 0.001, d = 0.193) and stroke (p < 0.05, d = 0.512). APOE was not significantly related to BHI scores. After correction for age, cross-sectional BHI scores were significantly associated with all measures of cognitive function in males, but only the Four Mountains Test (4MT) in females. Longitudinal change in BHI and cognition were not consistently related.

Conclusions: BHI is a valid marker of cognitive decline and relatively stable over 1-2 year follow-up periods. Further work should assess temporal changes over a longer duration and determine relationships between BHI and cognition in more diverse populations.

DOI: https://doi.org/10.1016/j.cccb.2024.100214

Published online: 5 April 2024 in the Journal Cerebral Circulation – Cognition and Behavior

“Modifiable dementia risk factors and AT(N) biomarkers: findings from the EPAD cohort”

Authors: Eddy Roccati, Aidan David Bindoff, Jessica Marie Collins, Joshua Eastgate, Jay Borchard, Jane Alty, Anna Elizabeth King, James Clement Vickers, Margherita Carboni, Chad Logan, EPAD Consortium

Abstract:

Introduction: Modifiable risk factors account for a substantial proportion of Alzheimer’s disease (AD) cases and we currently have a discrete AT(N) biomarker profile for AD biomarkers: amyloid (A), p-tau (T), and neurodegeneration (N). Here, we investigated how modifiable risk factors relate to the three hallmark AT(N) biomarkers of AD.

Methods: Participants from the European Prevention of Alzheimer’s Dementia (EPAD) study underwent clinical assessments, brain magnetic resonance imaging, and cerebrospinal fluid collection and analysis. Generalized additive models (GAMs) with penalized regression splines were modeled in the AD Workbench on the NTKApp.

Results: A total of 1,434 participants were included (56% women, 39% APOE ε4+) with an average age of 65.5 (± 7.2) years. We found that modifiable risk factors of less education (t = 3.9, p < 0.001), less exercise (t = 2.1, p = 0.034), traumatic brain injury (t = −2.1, p = 0.036), and higher body mass index (t = −4.5, p < 0.001) were all significantly associated with higher AD biomarker burden.

Discussion: This cross-sectional study provides further support for modifiable risk factors displaying neuroprotective associations with the characteristic AT(N) biomarkers of AD.

DOI: https://doi.org/10.3389/fnagi.2024.1346214

Published online: 7 February 2024 in the Journal Frontiers in Aging Neuroscience

“The European Prevention of Alzheimer’s Dementia Programme: An Innovative Medicines Initiative-funded partnership to facilitate secondary prevention of Alzheimer’s disease dementia”

Authors: Stina Saunders, Sarah Gregory, Matthew H S Clement, Cindy Birck, Serge van der Geyten, Craig W Ritchie

Abstract:

Introduction: Tens of millions of people worldwide will develop Alzheimer’s disease (AD), and only by intervening early in the preclinical disease can we make a fundamental difference to the rates of late-stage disease where clinical symptoms and societal burden manifest. However, collectively utilizing data, samples, and knowledge amassed by large-scale projects such as the Innovative Medicines Initiative (IMI)-funded European Prevention of Alzheimer’s Dementia (EPAD) program will enable the research community to learn, adapt, and implement change.

Method: In the current article, we define and discuss the substantial assets of the EPAD project for the scientific community, patient population, and industry, describe the EPAD structure with a focus on how the public and private sector interacted and collaborated within the project, reflect how IMI specifically supported the achievements of the above, and conclude with a view for future.

Results: The EPAD project was a €64-million investment to facilitate secondary prevention of AD dementia research. The project recruited over 2,000 research participants into the EPAD longitudinal cohort study (LCS) and included over 400 researchers from 39 partners. The EPAD LCS data and biobank are freely available and easily accessible via the Alzheimer’s Disease Data Initiative’s (ADDI) AD Workbench platform and the University of Edinburgh’s Sample Access Committee. The trial delivery network established within the EPAD program is being incorporated into the truly global offering from the Global Alzheimer’s Platform (GAP) for trial delivery, and the almost 100 early-career researchers who were part of the EPAD Academy will take forward their experience and learning from EPAD to the next stage of their careers.

Discussion: Through GAP, IMI-Neuronet, and follow-on funding from the Alzheimer’s Association for the data and sample access systems, the EPAD assets will be maintained and, as and when sponsors seek a new platform trial to be established, the learnings from EPAD will ensure that this can be developed to be even more successful than this first pan-European attempt.

DOI: 10.3389/fneur.2022.1051543

Published online: 22 November 2022 in the Journal Frontiers in Neurology

“Spatial cognition is associated with levels of phosphorylated-tau and β-amyloid in clinically normal older adults”

Authors: Gillian Coughlan, Brennan DeSouza, Peter Zhukovsky, Michael Hornberger, Cheryl Grady, Rachel F Buckley; European Prevention of Alzheimer’s Disease (EPAD) Consortium

Abstract:

Spatial cognition is associated with Alzheimer’s disease (AD) biomarkers in the symptomatic stages of the disease. We investigated whether cerebrospinal fluid (CSF) biomarkers (phosphorylated-tau [p-tau] and β-amyloid) are associated with poorer spatial cognition in clinically normal older adults. Participants were 1875 clinically normal adults (age 67.8 [8.5] years) from the European Prevention of Alzheimer’s Dementia Consortium. Mixed effect models assessed the cross-sectional association between p-tau₁₈₁, β-amyloid_1-42 (Aβ_1-42) and p-tau₁₈₁/Aβ_1-42 ratio and spatial cognition measured using semi-automated Supermarket Task and the 4 Mountains Task. Levels of p-tau₁₈₁, Aβ_1-42, and p-tau₁₈₁/Aβ_1-42 ratio were significantly associated with spatial cognition scores on both tasks. The p-tau₁₈₁/Aβ_1-42 ratio showed the largest effect sizes (β = -0.04/0.05, p < 0.001). Lower entorhinal cortical volume was associated with poorer outcomes on both tasks (β = 0.06, p < 0.002) and accounted for 18%-22% of the direct association between p-tau₁₈₁ and spatial cognition scores. In conclusion, degeneration of the entorhinal cortex mediates a significant proportion of the association between p-tau₁₈₁ and spatial assessments in cognitively normal adults. Future studies should focus on increasing the sensitivity of digital spatial assessments.

DOI: 10.1016/j.neurobiolaging.2023.06.016

Published online: 29 June 2023 in the Journal Neurobiology of Aging

“Alzheimer’s Disease and Small Vessel Disease Differentially Affect White Matter Microstructure”

Authors: Mario Tranfa, Luigi Lorenzini, Lyduine E. Collij, David Vállez García, Silvia Ingala, Giuseppe Pontillo, Leonard Pieperhoff, Alessio Maranzano, Robin Wolz, Sven Haller, Kaj Blennow, Giovanni Frisoni, Carole H. Sudre, Gael Chételat, Michael Ewers, Pierre Payoux, Adam Waldman, Pablo Martinez-Lage, Adam J. Schwarz, Craig W. Ritchie, Joanna M. Wardlaw, Juan Domingo Gispert, Arturo Brunetti, Henk J. M. M. Mutsaerts, Alle Meije Wink, Frederik Barkhof

Abstract:

Objective: Alzheimer’s disease (AD) and cerebral small vessel disease (cSVD), the two most common causes of dementia, are characterized by white matter (WM) alterations diverging from the physiological changes occurring in healthy aging. Diffusion tensor imaging (DTI) is a valuable tool to quantify WM integrity non-invasively and identify the determinants of such alterations. Here, we investigated main effects and interactions of AD pathology, APOE-ε4, cSVD, and cardiovascular risk on spatial patterns of WM alterations in non-demented older adults.

Methods: Within the prospective European Prevention of Alzheimer’s Dementia study, we selected 606 participants (64.9 ± 7.2 years, 376 females) with baseline cerebrospinal fluid samples of amyloid β_1-42 and p-Tau₁₈₁ and MRI scans, including DTI scans. Longitudinal scans (mean follow-up time = 1.3 ± 0.5 years) were obtained in a subset (n = 223). WM integrity was assessed by extracting fractional anisotropy and mean diffusivity in relevant tracts. To identify the determinants of WM disruption, we performed a multimodel inference to identify the best linear mixed-effects model for each tract.

Results: AD pathology, APOE-ε4, cSVD burden, and cardiovascular risk were all associated with WM integrity within several tracts. While limbic tracts were mainly impacted by AD pathology and APOE-ε4, commissural, associative, and projection tract integrity was more related to cSVD burden and cardiovascular risk. AD pathology and cSVD did not show any significant interaction effect.

Interpretation: Our results suggest that AD pathology and cSVD exert independent and spatially different effects on WM microstructure, supporting the role of DTI in disease monitoring and suggesting independent targets for preventive medicine approaches.

DOI: doi.org/10.1002/acn3.52071

Published online: 16 May 2024 in the Journal Annals of Clinical and Translational Neurology

“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