Category: Publications

Ethical Arguments Concerning the Use of Alzheimer’s Disease
Biomarkers in Individuals with No or Mild Cognitive
Impairment: A Systematic Review and Framework for
Discussion

Ethical challenges in preclinical Alzheimer’s disease
observational studies and trials: Results of the
Barcelona summit

“Ethical Frameworks for Disclosure of Alzheimer Disease Biomarkers to Research Participants: Conflicting Norms and a Nuanced Policy”

Authors: Eline M. Bunnik, Marthe Smedinga, Richard Milne, Jean Georges, Edo Richard, Maartje H. N. Schermer

Abstract: More and more frequently, clinical trials for Alzheimer disease (AD) are targeting cognitively unimpaired individuals who are at increased risk of developing the disease. It is not always clear whether AD biomarker information should be disclosed to research participants: on the one hand, research participants may be interested in learning this information because of its perceived utility, but on the other hand, learning this information may be harmful, as there are very few effective preventive or therapeutic options available for AD. In this article, we bring together three separate sets of ethical guidance literature: on the return of individual research results, on an individual’s right to access personal data, and on transparent enrollment into clinical trials. Based on these literatures, we suggest policies for the disclosure of AD biomarker test results in longitudinal observational cohort studies, clinical trials, and hybrid research projects, such as the European Prevention of Alzheimer’s Dementia (EPAD) project, in which we served as an ethics team. We also present and critically discuss recommendations for disclosure of AD biomarkers in practice. We underscore that, as long as the clinical validity of AD biomarkers remains limited, there are good reasons to avoid actively disclosing them to cognitively unimpaired research participants.

DOI: 10.1002/eahr.500146

Published online: 31 October 2022 in the Journal Ethics & Human Research

Ethical issues in the development of readiness
cohorts in Alzheimer’s disease research

European Prevention of Alzheimer’s Dementia Registry:
Recruitment and prescreening approach for a longitudinal
cohort and prevention trials

European Prevention of Alzheimer’s Dementia
Longitudinal Cohort Study (EPAD LCS): study
protocol

Evaluating the Alzheimer’s disease data landscape

Evolution and future directions for the concept of mild
cognitive impairment

“Gray matter network properties show distinct associations with CSF p-tau 181 levels and amyloid status in individuals without dementia”

Authors: Lorenzini Luigi, Ingala Silvia, Wottschel Viktor, Alle Meije WinkHenk JMM Mutsaerts, Haller Sven, Blennow Kaj, John T. O’Brien, Frisoni B. Giovanni, Chételat Gael, Payoux Pierre, Martinez-Lage Pablo, Waldman Adam, Wardlaw Joanna, Ritchie Craig, Juan Domingo Gispert, Pieter Jelle Visser, Scheltens Philip, Barkhof Frederik, Betty M. Tijms

Abstract: Gray matter networks are altered with amyloid accumulation in the earliest stage of AD, and are associated with decline throughout the AD spectrum. It remains unclear to what extent gray matter network abnormalities are associated with hyperphosphorylated-tau (p-tau). We studied the relationship of cerebrospinal fluid (CSF) p-tau181 with gray matter networks in non-demented participants from the European Prevention of Alzheimer’s Dementia (EPAD) cohort, and studied dependencies on amyloid and cognitive status. Gray matter networks were extracted from baseline structural 3D T1w MRI. P-tau181 and abeta were measured with the Roche cobas Elecsys System. We studied the associations of CSF biomarkers levels with several network’s graph properties. We further studied whether the relationships of p-tau 181 and network measures were dependent on amyloid status and cognitive stage (CDR). We repeated these analyses for network properties at a regional level, where we averaged local network values across cubes within each of 116 areas as defined by the automated anatomical labeling (AAL) atlas. Amyloid positivity was associated with higher network size and betweenness centrality, and lower gamma, clustering and small-world coefficients. Higher CSF p-tau 181 levels were related to lower betweenness centrality, path length and lambda coefficients (all p < 0.01). Three-way interactions between p-tau181, amyloid status and CDR were found for path length, lambda and clustering (all p < 0.05): Cognitively unimpaired amyloid-negative participants showed lower path length and lambda values with higher CSF p-tau181 levels. Amyloid-positive participants with impaired cognition demonstrated lower clustering coefficients in association to higher CSF p-tau181 levels. Our results suggest that alterations in gray matter network clustering coefficient is an early and specific event in AD.

DOI: 10.1016/j.nbas.2022.100054

Published online: 23 October 2022 in the Journal Aging Brain

“Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort”

Authors: Rasha N. M. Saleh, Michael Hornberger, Craig W. Ritchie and Anne Marie Minihan

Abstract:

Background: The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.

Methods: The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.

Results: APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.

Conclusion: HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

DOI: 10.1186/s13195-022-01121-5

Published online: 9 January 2023 in the Journal Alzheimer’s Research Therapy