European Prevention Of Alzheimer's Dementia Research Articles

Validation of the brain health index in the European Prevention of Alzheimer's Dementia cohort

BackgroundBrain 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. AimAssess 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. MethodsBHI 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. ResultsData 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. ConclusionsBHI 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.

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

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. 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. 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. 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.

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

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.

Interactions between apolipoprotein E, sex, and amyloid-beta on cerebrospinal fluid p-tau levels in the European prevention of Alzheimer's dementia longitudinal cohort study (EPAD LCS).

SummaryBackgroundAlzheimer's Disease, the leading cause of dementia, is over-represented in females. The apolipoprotein E (APOE)ε4 allele is the strongest genetic risk factor for late-onset AD and is associated with aberrant cerebrospinal fluid levels (CSF) of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ). There is some evidence that sex may mediate the relationship between APOE status and CSF tau, however, evidence is mixed.MethodsWe aimed to examine the interaction between sex, APOE ε4 status, CSF Aβ on t-tau and p-tau in 1599 mid-to-late life individuals without a diagnosis of dementia in the European Prevention of Alzheimer's Dementia (EPAD) longitudinal cohort study.FindingsWe found a significant interaction between APOE status, sex, and CSF Aβ on CSF p-tau levels (β = 0·18, p = 0·04). Specifically, there was a stronger association between APOE status and CSF Aβ42 on CSF p-tau in males compared to females. Further, in females with high Aβ levels (reflecting less cortical deposition), ε4 carriers had significantly elevated p-tau levels relative to non-carriers (W = 39663, p = 0·01). However, there were no significant differences in p-tau between male ε4 carriers and non-carriers with high Aβ (W = 23523, p = 0·64).InterpretationAn interaction between sex and cerebrospinal fluid Aβ may mediate the relationship between APOE status and CSF p-tau. These data suggest tau accumulation may be independent of Aβ in females, but not males.FundingInnovative Medicines Initiative, Swedish Research Council, Alzheimer Drug Discovery Foundation, Swedish Alzheimer Foundation, the Swedish state under the agreement between the Swedish government and the County Councils: the ALF-agreement, and the Alzheimer's Association 2021 Zenith Award.

The Open-Access European Prevention of Alzheimer’s Dementia (EPAD) MRI dataset and processing workflow

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer’s Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences.Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features — i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia.The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features — Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) — were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.

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

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.

Neuroimaging‐derived phenotypes in the European Prevention of Alzheimer Dementia (EPAD) Cohort Study

AbstractBackgroundNeuroimaging biomarkers in large‐scale multimodal studies have proven effective for early diagnosis. Image‐derived phenotypes (IDPs) are summary features derived from modalities such as magnetic resonance imaging (MRI). We provide an overview of the IDPs computed from the European Prevention of Alzheimer Dementia (EPAD) cohort study, a multi‐center European study including multimodal brain MRI.MethodBaseline data from the first 1500 participants of the EPAD LCS were included. The imaging protocol consists of core (3D‐T1w, 3D‐FLAIR, 2D‐T2w, 2D‐T2*), and advanced (resting‐state fMRI, SWI, diffusion MRI, and ASL) sequences. 3D‐T1w IDPs consisted of regional volumes derived from FreeSurfer v6.0 and the Learn Embeddings for Atlas Propagation (LEAP) segmentation pipelines and 3D‐FLAIR IDPs were white matter hyperintensity (WMH) volumes measured by Bayesian Model Selection (BaMoS). Mean functional connectivity of rs‐fMRI networks was extracted with FSL MELODIC and dual‐regression analyses. For diffusion‐weighted imaging, we used FSL TBSS to quantify 48 regional fractional anisotropy (FA) values according to the JHU atlas of white matter tracts. ExploreASL was used to calculate mean Cerebral blood flow (CBF) and spatial coefficient‐of‐variation (sCoV) from ASL images. To evaluate the biological relevance of IDPs, we assessed their relationship with non‐imaging phenotypes.ResultA total of 358 core and 119 advanced IDPs were derived. GM volume was inversely correlated with age, with stronger effects in medio‐temporal areas (Figure 1). Regional WMH volumetrics showed mostly frontal and parietal WM lesions that were associated with aging (Figure 2). Heterogeneous changes in within‐network functional connectivity were observed with older age, with mild differences between CDR 0 and 0.5 contrasts, mostly related to the default‐mode and frontoparietal networks (Figure 3). Age was also associated inversely with skeletonised FA values. Stronger reductions appeared in amyloid positive participants (Figure 4).ConclusionWe show the relevance of IDPs from the EPAD neuroimaging dataset. The observed relationships with non‐imaging phenotypes confirm their biological relevance and are in agreement with previous studies. The proposed IDP framework may constitute a valuable resource for researchers using EPAD data, promoting reproducibility of results and easily adaptable for other studies and cohorts.

Differential gray matter connectivity correlates of CSF biomarkers: Results from the EPAD Cohort

AbstractBackgroundGray matter network (GMN) disruptions correlate with amyloid burden in the earliest stages of Alzheimer’s Disease (AD) pathology in cognitively unimpaired individuals. However, it remains unknown if and how hyperphosphorylated tau (p‐tau) influences GMNs. Here, we investigated the relation between GMNs and cerebrospinal fluid (CSF) p‐tau181 levels in non‐demented individuals from the European Prevention of Alzheimer Dementia (EPAD) cohort and evaluated whether this relationship is mediated by amyloid and Clinical Dementia Rating (CDR) status.MethodWe included 1198 participants from the EPAD v1500.0 release, who had both CSF biomarkers and structural MRI available. The cut‐off for amyloid‐β positivity (A+) was defined at &lt;1000 pg/mL. Single‐subject network properties were extracted from 3D‐T1w MRI (Figure 1). Regional values were computed for 117 AAL atlas regions. Linear models were used to investigate main effects and interactions between amyloid status and p‐tau181 levels on global GMN measures. A three‐way interaction with CDR was modeled. Age, sex, site, total intracranial volume, and network size were included as covariates. Analyses were repeated for local network properties across AAL regions and FDR‐adjusted.ResultSample characteristics are provided in Table 1. A+ individuals had lower degree, clustering, gamma, and small world coefficients, and higher betweenness centrality (Figure 2). Higher p‐tau181 levels were associated with lower values of degree, betweenness centrality, lambda, and path length (Figure 3). Lambda, path length, and clustering showed an interaction effect of amyloid status and CDR on their relationship with p‐tau181 levels: A‐ individuals with CDR 0 had lower path length and lambda in association with tau, while A+ CDR 0.5 individuals with lower clustering coefficient values showed higher p‐tau181 (Figure 4). No associations were found for other GMN measures. Regional analysis showed a relationship of p‐tau181 with local path length in the precuneus (Figure 5).ConclusionGMN alterations show distinct associations with p‐tau181 levels, partially affected by amyloid and CDR status. Non‐amyloid related alterations of path length might be linked to axonal tau‐related changes. Clustering alterations seem instead to be linked to amyloid deposition and resulting local synaptic disconnectivity.

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.

BackgroundWe classified non‐demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.Materials and methodsFrom 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut‐offs of 1000 pg/mL for amyloid beta (Aß)1‐42 and 27 pg/mL for p‐tau181 were validated using Gaussian mixture models. Given strong correlation of p‐tau and t‐tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age‐adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.ResultsAge was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A–T–N–, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non‐Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T–N– compared to A–T–N– (P < 0.001).DiscussionIn non‐demented individuals along the AD continuum, p‐tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.

Cognitive Functions as Predictors of Alzheimer's Disease Biomarker Status in the European Prevention of Alzheimer's Dementia Cohort.

Alterations in Alzheimer's disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer's Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study showed that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-β (Aβ) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aβ. While previous research has focused on the relationship between cognition and levels of Aβ, our findings suggest that p-tau may potentially be a more significant correlate.

Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings

BackgroundRecruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings.MethodsWe monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status.ResultsA total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95–0.99]), high education (OR = 1.64 [1.23–2.17]), male sex (OR = 1.56 [1.19–2.04]), and positive family history of dementia (OR = 1.66 [1.19–2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02–1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81–4.94]). These results were similar across prescreen settings.ConclusionsNumbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD.

Associations Between Multimorbidity and Cerebrospinal Fluid Amyloid: A Cross-Sectional Analysis of the European Prevention of Alzheimer's Dementia (EPAD) V500.0 Cohort.

Multimorbidity (the co-occurrence of multiple chronic conditions) is increasingly common, especially among people with dementia. Few neuroimaging studies have explored amyloid biomarkers in people with multimorbidity. We aimed to conduct the first study of the association between multimorbidity and cerebrospinal fluid amyloid-β42 (CSF Aβ). The European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study V500.0 dataset includes volunteers aged ≥50 years from 12 sites. Participants undergo detailed phenotyping, including CSF measures and a self-reported medical history. Using logistic and linear regression analyses, we explored the association between multimorbidity and continuous chronic condition count with CSF Aβ positivity (Aβ42 <1000pg/ml) and continuous CSF Aβ concentration. All models were adjusted for age, sex, APOE status, education, and family history of dementia. Among 447 eligible participants without dementia, the mean (SD) age was 66.6 (6.6) years, 234 (52.3%) were women, and 157 (35.1%) were amyloid positive. With chronic conditions regarded as pseudo-continuous, each additional condition carried a decreased likelihood of amyloid positivity (OR = 0.82, 95% CI: 0.68-0.97; p = 0.026). With CSF Aβ as a continuous variable, each additional condition was associated with an increase of 54.2 pg/ml (95% CI: 9.9-98.5, p = 0.017). Having ≥2 conditions was inversely associated with amyloid positivity (OR 0.59, 95% CI: 0.37-0.95, p = 0.030) compared to one or none. Our findings suggest that the established association between multimorbidity and dementia may be due to a pathway other than amyloid. However, this cross-sectional study does not allow us to make causal inferences. Longitudinal work is required to confirm the inverse association found.

Dispelling myths and legends about dementia.

Dispelling myths and legends about dementia.

Systems Biology Methods for Alzheimer's Disease Research Toward Molecular Signatures, Subtypes, and Stages and Precision Medicine: Application in Cohort Studies and Trials.

Alzheimer's disease (AD) is a complex multifactorial disease, involving a combination of genomic, interactome, and environmental factors, with essential participation of (a) intrinsic genomic susceptibility and (b) a constant dynamic interplay between impaired pathways and central homeostatic networks of nerve cells. The proper investigation of the complexity of AD requires new holistic systems-level approaches, at both the experimental and computational level. Systems biology methods offer the potential to unveil new fundamental insights, basic mechanisms, and networks and their interplay. These may lead to the characterization of mechanism-based molecular signatures, and AD hallmarks at the earliest molecular and cellular levels (and beyond), for characterization of AD subtypes and stages, toward targeted interventions according to the evolving precision medicine paradigm. In this work, an update on advanced systems biology methods and strategies for holistic studies of multifactorial diseases-particularly AD-is presented. This includes next-generation genomics, neuroimaging and multi-omics methods, experimental and computational approaches, relevant disease models, and latest genome editing and single-cell technologies. Their progressive incorporation into basic research, cohort studies, and trials is beginning to provide novel insights into AD essential mechanisms, molecular signatures, and markers toward mechanism-based classification and staging, and tailored interventions. Selected methods which can be applied in cohort studies and trials, with the European Prevention of Alzheimer's Dementia (EPAD) project as a reference example, are presented and discussed.

AN ADAPTED STAGED CONSENT MODEL FOR RECRUITMENT AND INFORMED CONSENT IN READINESS COHORTS: THE PERSPECTIVE OF THE EUROPEAN PREVENTION OF ALZHEIMER’S DEMENTIA CONSORTIUM (EPAD)

To facilitate screening and recruitment of research participants and to reduce time and costs associated with traditional trials in Alzheimer's disease, researchers are setting up ‘readiness cohorts’. These cohorts are well-characterized populations of potential participants for recruitment into prevention or early treatment trials. In setting up such cohorts, researchers must make ethically challenging design decisions. Therefore, within the interdisciplinary Ethical, Legal and Social implications (ELSI) work package of the European Prevention of Alzheimer's Dementia (EPAD) project, we developed ethics guidelines for responsible development of a readiness cohort (the EPAD longitudinal cohort study), including guidance on recruitment and informed consent. We used a mixed methods approach. First, we performed a literature review. Second, we held several meetings in person and by teleconference during 2015/2016 to discuss associated ethical dilemmas. Third, we organized multi-disciplinary group discussions within EPAD to create concrete broad-based ethics guidance for recruitment and informed consent. The longitudinal and transitional nature of a readiness cohort creates the risk of the cohort and its concatenated trials becoming a ‘fish trap’ for its participants. With every step further into such a research project, it becomes more difficult for a participant to go back or retract from participation. Therefore, we recommend an adapted staged-consent model for concatenated projects like EPAD, which are extended over time and multi-staged, and in which participants and data move from one stage to the next. This consent model feeds relevant information, bit by bit, along research participants’ journey, and asks informed consent at every moment in which important decisions need to be made by participants. Although informed consent is always given for a specific stage of the research project, information about the ‘totality of the project’ must always and explicitly be part of the informed consent process. It is critical to the success of readiness cohorts to carefully align ethical guidance for recruitment and informed consent. The ELSI work package of EPAD recommends an adapted staged-consent model. This model may also be of value to other research collaborations in the process of developing and using readiness cohorts in Alzheimer's disease research.

METHODOLOGICAL AND LOGISTIC STRATEGIES FOR A LARGE MULTI-CENTER β-AMYLOID PET EUROPEAN PROJECT: AMYLOID IMAGING TO PREVENT ALZHEIMER’S DISEASE (AMYPAD)

‘Amyloid imaging to prevent Alzheimer's disease’ (AMYPAD; www.amypad.org) is a 5-year programme within the Innovative Medicines Initiative (IMI), a joint undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). AMYPAD will study the impact of β-amyloid PET imaging on the diagnosis and management of AD, the natural history of amyloid accumulation in the pre-symptomatic stage of AD and the selection of individuals for secondary prevention trials. To this end, a network of ∼20 European PET centres aims to conduct a total of 6000 scans. AMYPAD's work package 2 (WP2) will support these goals by developing an efficient tracer supply strategy, setting-up a clinical imaging network, developing image acquisition, quality control and quantification protocols, and deploying a centralized platform for image transfer, analysis and sharing. Since both NeuraCeq (Piramal Imaging) and Vizamyl (GE Healthcare) will be used in AMYPAD, standardization of β-amyloid load measurements across tracers will be crucial to ensure full comparability of the quantitative outcomes of the project. On top of this, specific sub-studies in WP2 will focus on: 1) accurate determination of amyloid change rates though dynamic PET scanning, 2) further development of the role of PET/MR for β-amyloid imaging, 3) refinement of amyloid quantification methods, and 4) identification of lifestyle and environmental factors affecting amyloid accumulation. Quantitative outcomes in AMYPAD will be expressed in the Centiloid scale (Klunk et al. Alzheimers Dement. 2015) in order to ensure the full comparability across tracers and to enable generalization the project's results. At present, WP2 has designed the tracer distribution strategy, set-up the clinical imaging network, and deployed the platform for image transfer and quantification. AMYPAD will improve our understanding of the utility of β-amyloid PET imaging in both clinical and research contexts and will generate a large amount of image data of high value for research purposes. Through WP2, AMYPAD will apply methodologies for quantitative β-amyloid imaging and will leverage with EPAD (European Prevention of Alzheimer's Dementia) to reconcile the datasets gathered in the context of these two IMI projects and share them with the general scientific community.

Setting the scene: The evidence for pre-clinical change, projections of the impact of intervention, and implications for public health

Alzheimer's disease has long been considered a neurodegenerative disorder of late life for which there is currently no disease-modifying treatment. This view is now being revised as increasing evidence suggests a long pre-clinical phase extending back into mid-life during which there is exposure to multiple potentially reversible risk factors. Further thought is now being given to the possibility of both early life intervention programs and development of new drug treatments focusing on the pre-dementia period. But how can the impact of such treatments be measured at this early stage since overt dementia may not be diagnosed for decades? In the four talks in this symposium, we will discuss evidence for pre-clinical change, theoretical models which have been used to project the possible impact of risk factor modification in mid-life and their integration into a future public health strategies. The development of new statistical risk models to determine the impact of such prevention measures will be outlined. We will consider the possibilities for drug development targeting the pre-clinical period before presenting the PREVENT Project and EPAD (http://ep-ad.org/), a multi-million euro IMI-Horizon 2020 funded project for the development of pre-clinical proof of concept trials. Titles of the four presentations: 1. Setting the scene: the evidence for pre-clinical change, projections of the impact of intervention, and implications for public health (TCR) 2. New statistical risk models for determining the impact of prevention measures in the pre-dementia period (GMT) 3. The PREVENT Study: a prospective cohort study to identify mid-life biomarkers of late-onset Alzheimer's disease (KR) 4. The European Prevention of Alzheimer's Dementia (EPAD) Project: developing interventions for the secondary prevention of Alzheimer's dementia (CWR)Disclosure of interestThe authors have not supplied their declaration of competing interest.

Ethical Issues in the Development of Readiness Cohorts in Alzheimer's Disease Research.

There is growing interest in the development of novel approaches to secondary prevention trials in Alzheimer's disease to facilitate screening and recruitment of research participants and to reduce the time and costs associated with clinical trials. Several international research collaborations are setting up research infrastructures that link existing research cohorts, studies or patient registries to establish 'trial-ready' or 'readiness' cohorts. From these cohorts, individuals are recruited into clinical trial platforms. In setting up such research infrastructures, researchers must make ethically challenging design decisions in at least three areas: re-contacting participants in existing research studies, obtaining informed consent for participation in a readiness cohort, and disclosure of Alzheimer's disease-related biomarkers. These ethical considerations have been examined by a dedicated workgroup within the European Prevention of Alzheimer's Dementia (EPAD) project, a trans-European longitudinal cohort and adaptive proof-of-concept clinical trial platform. This paper offers recommendations for the ethical management of re-contact, informed consent and risk disclosure which may be of value to other research collaborations in the process of developing readiness cohorts for prevention trials in Alzheimer's disease and other disease areas.

Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project

The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease.