Category: Publications

“Early detection of Alzheimer’s disease using small RNAs. Results from the EPAD cohort”

Authors: Tobias Sikosek , Marco Heuvelman, Jagoda Mika, Mustafa Kahraman, Julia Jehn, Maurice Frank, Alberto Daniel-Moreno, Jessika Ceiler, Jasmin Skottke, Marta Sanchez-Delgado, Patrick Neubert, Christina Rudolf , Kaja Tikk, Rastislav Horos, Jeffrey L Cummings, Josie Butchart, Craig Ritchie, Jean Manson, Bruno R Steinkraus; EPAD consortium

Abstract:

Background: Alzheimer’s disease (AD) is the most common form of dementia, and early diagnosis is crucial to enable effective interventions. Currently, Alzheimer’s disease is diagnosed through cognitive assessments, brain imaging and fluid biomarkers focused on determining amyloid (A) and, tau (T) protein levels as well as neurodegeneration (N) in the AT(N) framework. Prognostic biomarkers for predicting cognitive decline within the amyloid positive (Aβ+) individuals would further strengthen the framework.

Objectives: This study evaluated small RNAs as novel auxiliary biomarkers, independent of the AT(N) framework, either alone or in combination with established protein markers, for detecting the earliest cognitive decline in AD.

Design: The European Prevention of Alzheimer’s Disease (EPAD) clinical trial platform is a prospective, multi-center study designed to investigate biomarkers for preclinical and prodromal AD.

Setting: Peripheral whole blood RNA sequencing was performed on participants across Europe with no cognitive impairment or very mild cognitive impairment (MCI), stratified by cerebrospinal fluid amyloid levels.

Participants: 1,913 participants, 50 years or older and free of dementia diagnosis at enrollment, were analyzed.

Intervention: (if any) Not applicable.

Measurements: Ultra-deep small RNA sequencing was performed on whole blood samples using a refined blocking protocol to eliminate highly abundant erythroid small RNAs, and thereby to open sequencing bandwidth for the discovery of less abundant biomarker RNAs. Biomarker RNAs were deconvolved into plasma or blood cell origin and analyzed for functional relevance. We define high and low amyloid groups based on a cutoff on the p-tau₁₈₁/Aβ_1-42 ratio as determined from cerebrospinal fluid.

Results: We identified a combination of small RNAs that predicted early cognitive decline (Clinical Dementia Rating of 0.5) with an area under the receiver-operator curve of ∼0.7. Notably, when focusing on individuals with cognitive decline and high amyloid burden (Aβ+), the predictive accuracy improved to an AUC of 0.77. This performance could be extended to the entire cohort when combining blood RNA and CSF amyloid markers (AUC 0.76). We conducted bioinformatic analyses to interrogate the likely functional relevance of these small RNAs, uncovering several links to dementia-relevant pathways, including neuronal, cardiovascular, and inflammatory activities. Our findings also suggest that small nucleolar RNAs warrant further investigation as potential disease-relevant markers, in addition to microRNAs.

Conclusions: Integrating small RNA biomarkers with protein-based assays offers preliminary evidence for stratifying MCI, particularly within the amyloid positive continuum. Small nucleolar RNAs and microRNAs warrant further exploration as complementary diagnostic tools, and their use may enable more precise and effective interventions.

DOI:https://doi.org/10.1016/j.tjpad.2025.100257

Published online: September 2025 in the journal of Prevention of Alzheimer’s disease

“Brain MRI signatures across sex and CSF Alzheimer’s disease biomarkers”

Authors: You Cheng, Yingnan He Karthik Gopinath, Benjamin Billot, Juan Eugenio Iglesias, Chao-Yi Wu, Hiroko Dodge, Anne-Marie Will, Becky Carlyle, Pia Kivisäkk, Bradley T Hyman, Steven E Arnold, Sudeshna Das; for the Alzheimer’s Disease Neuroimaging Initiative and for the European Prevention of Alzheimer’s Disease (EPAD) Consortium

Abstract:

The relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease and neurodegenerative effects is not fully understood. This study investigates neurodegeneration patterns across CSF Alzheimer’s disease biomarker groups, the association of brain volumes with CSF amyloid and tau status and sex differences in these relationships in a clinical neurology sample. MRI and CSF Alzheimer’s disease biomarkers data were analysed in 306 patients of the Mass General Brigham healthcare system aged 50+ (mean age = 68.4 ± 8.8 years; 43.1% female), who had lumbar punctures within 1 year of clinical MRI scans. We first analysed neurodegeneration patterns across four biomarker groups: 60 controls (A−T−&CU; amyloid negative, tau negative, cognitively unimpaired), 25 A+T− (amyloid positive, tau negative), 121 A+T+ (amyloid positive, tau positive) and 100 other dementia (A−T−&CI; amyloid negative, tau negative, cognitively impaired). Second, we examined volumetric associations with amyloid (amyloid positive, tau negative versus control) and tau in the presence of amyloid (amyloid positive, tau positive versus amyloid positive, tau negative) across 52 brain areas. Third, we examined sex differences in these relationships. Finally, we validated core analyses across three independent datasets—NACC (National Alzheimer’s Coordinating Center), ADNI (Alzheimer’s Disease Neuroimaging Initiative) and EPAD (European Prevention of Alzheimer’s Dementia)—totalling 3137 participants, and performed meta-analyses to obtain more robust estimates. We observed distinct neurodegeneration patterns across biomarker groups, with disrupted connectivity (brain volume covariance networks) in amyloid positive and other dementia groups, while amyloid and tau negative, cognitively unimpaired controls exhibited the most connected network. Amyloid was associated with subcortical, cerebellar and brainstem atrophy, with consistent association observations in the thalamus and amygdala across all four datasets. Tau in the presence of amyloid demonstrated general brain shrinkage through enlargement of extracerebral CSF, alongside unexpected ventricle shrinkages. Sex-based analyses revealed that A+T+ (amyloid positive, tau positive) had lower sex differences in connectivity patterns compared with other groups. Sex differences were also noted in amyloid-related ventricular volume changes. This study reveals how amyloid and tau affect brain connectivity and volume across sex and CSF biomarker groups, emphasizing global brain changes and sex differences. By leveraging automated pipelines and advanced MRI and biomarker analyses, we extracted meaningful and replicable findings from heterogeneous clinical samples from real-world data. The meta-analyses across four datasets enhance the generalizability of our results.

DOI: 10.1093/braincomms/fcaf210

Published online: 30 May 2025 in the journal Brain Communications

“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: 10.1002/dad2.70092

Published online: 30 May 2025 in the journal Alzheimer’s & Dementia

“ADataViewer: exploring semantically harmonized Alzheimer’s disease cohort datasets”

Authors: Yasamin Salimi, Daniel Domingo-Fernández, Carlos Bobis-Álvarez, Martin Hofmann-Apitius & Colin Birkenbihl for the Alzheimer’s Disease Neuroimaging Initiative, the Japanese Alzheimer’s Disease Neuroimaging Initiative, for the Aging Brain: Vasculature, Ischemia, and Behavior Study, the Alzheimer’s Disease Repository Without Borders Investigators, for the European Prevention of Alzheimer’s Disease (EPAD) Consortium

Abstract:

Background: Currently, Alzheimer’s disease (AD) cohort datasets are difficult to find and lack across-cohort interoperability, and the actual content of publicly available datasets often only becomes clear to third-party researchers once data access has been granted. These aspects severely hinder the advancement of AD research through emerging data-driven approaches such as machine learning and artificial intelligence and bias current data-driven findings towards the few commonly used, well-explored AD cohorts. To achieve robust and generalizable results, validation across multiple datasets is crucial.

Methods: We accessed and systematically investigated the content of 20 major AD cohort datasets at the data level. Both, a medical professional and a data specialist, manually curated and semantically harmonized the acquired datasets. Finally, we developed a platform that displays vital information about the available datasets.

Results: Here, we present ADataViewer, an interactive platform that facilitates the exploration of 20 cohort datasets with respect to longitudinal follow-up, demographics, ethnoracial diversity, measured modalities, and statistical properties of individual variables. It allows researchers to quickly identify AD cohorts that meet user-specified requirements for discovery and validation studies regarding available variables, sample sizes, and longitudinal follow-up. Additionally, we publish the underlying variable mapping catalog that harmonizes 1196 unique variables across the 20 cohorts and paves the way for interoperable AD datasets.

Conclusions: In conclusion, ADataViewer facilitates fast, robust data-driven research by transparently displaying cohort dataset content and supporting researchers in selecting datasets that are suited for their envisioned study. The platform is available at https://adata.scai.fraunhofer.de/.

DOI: doi.org/10.1186/s13195-022-01009-4

Published online: 21 May 2022 in the journal Alzheimer’s Research & Therapy

“Age differences in the association between sleep and Alzheimer’s disease biomarkers in the EPAD cohort”

Authors: Sharon L. Naismith, Yue Leng, Jake R. Palmer, Brendan P. Lucey

Abstract:

Introduction: We aimed to determine the independent association between sleep quality and Alzheimer’s disease (AD) biomarkers, and whether the associations differ with age.

Methods: We included 1240 individuals aged ≥50, without dementia from the European Prevention of Alzheimer’s Disease v1500.0 dataset. Linear regression was used to examine Pittsburgh Sleep Quality Index (PSQI) scores against cerebrospinal fluid (CSF) phosphorylated tau/β-amyloid ratio (p-tau/Aβ42) for the entire sample and via age tertiles. Models controlled for demographic, clinical, genetic, vascular, and neuroimaging variables.

Results: For the youngest age tertile, shorter sleep duration and higher sleep efficiency were associated with greater p-tau/Aβ42 ratio. For the oldest tertile, longer sleep latency was associated with greater p-tau/Aβ42.

Discussion: Differential relationships between sleep and AD pathology depend on age. Short sleep duration and sleep efficiency are relevant in middle age whereas time taken to fall asleep is more closely linked to AD biomarkers in later life.

Highlights: This study shows age differences in the link between sleep and AD biomarkers.Shorter sleep was associated with greater p-tau/Aβ42 ratio in middle age.The association was independent of genetic, vascular, and neuroimaging markers of AD.

DOI: 10.1002/dad2.12380

Published online: 25 November 2022 in the Journal Alzheimer’s & Dementia

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

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

At, with and beyond risk: expectations of living with
the possibility of future dementia

Brain Amyloid Pathology and Cognitive Function
Alzheimer Disease Without Dementia?

Cognitive Dispersion is not Associated with Cerebrospinal Fluid
Biomarkers of Alzheimer’s Disease: Results from the European
Prevention of Alzheimer’s Dementia (EPAD) v500.0 Cohort