Author: Cindy Birck

“Accrual of Alzheimer’s disease pathology as a function of proximity to parental dementia onset”

Authors: Elina T. Ziukelis, Elijah Mak, Craig Ritchie, John T. O’Brien, Dag Aarsland, for the European Prevention of Alzheimer’s Disease (EPAD) Consortium

Abstract:

Introduction: Whether temporal proximity to parental onset of dementia (PPO) can be used to estimate timing of the preclinical stage of sporadic Alzheimer’s disease (AD) remains uncertain.

Methods: We investigated cross-sectionally adults aged > 50 without dementia included in the European Prevention of Alzheimer’s Dementia (EPAD) study. PPO was tested as a predictor of quantitative levels of cerebrospinal fluid (CSF) β-amyloid (1-42) (Aβ1-42) in those with a parental history of dementia (n = 688) and of phosphorylated tau (p-tau) and EPAD neuropsychological examination (ENE) subscores in an amyloid positive subgroup (n = 226). Possible interactions were explored.

Results: Shorter PPO predicted lower CSF Aβ1-42 level (β = 9.357; T = 4.161; p < 0.001), interacting with apolipoprotein E (APOE) -𝜀4 carriage in a dose-dependent manner. Concomitant APOE-𝜀2 carriage appeared to provide protection. PPO did not predict p-tau levels or cognitive performance.

Discussion: PPO may provide a valid method of stratifying risk of early AD pathologic change in APOE-𝜀4 carriers, with empirical and clinical applications.

Highlights:

• Proximity to age of parental dementia onset can predict amyloid accrual
• The effect is APOE-𝜀4 dose-dependent and APOE-𝜀2 appears to provide protection
• PPO does not appear to predict further advancement along the AD continuum
• In the era of anti-amyloid treatments, this may inform timing of amyloid screening
• Used as an empirical metric, PPO could help elucidate the natural history of LOAD

DOI: doi.org/10.1002/dad2.70092

Published online: 27 February 2025 in the journal Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring

“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