Posts in Category ‘News

Back online with new LIGA paper on DNAm clocks

Welcome back to the LIGA newsfeed! You might have noticed a prolonged period of radio silence on our website since November 2023. The truth is, our team has been completely immersed in extensive data analysis and several large-scale multi-omics projects, leaving us with little time to update our “digital business card” (i.e. this website). We are excited to break this silence by sharing our latest scientific milestone. A new study led by former LIGA MSc student Anna M. Weissenburg was recently posted as a preprint on medRxiv. By evaluating 14 different DNA methylation clocks with respect to their ability to predict cognitive performance and decline, the study reveals that the third-generation DunedinPACE clock shows the strongest and most consistent associations with cognition in older adults. These results highlight DunedinPACE as representing a potential epigenetic biomarker for the early detection of cognitive decline. Anna prepared these analyses as part of her MSc thesis in our group (which she successfully defended in 2025). For this publication, several analyses and parts of the text were updated by co-first author and LIGA PhD student Marit Junge. The full text of this study can be found at https://doi.org/10.64898/2026.03.23.26349074v1.

• • •

DunedinPACE is best clock for many aging traits

Delving into the mechanisms of biological aging, our team has actively contributed to a trio of recent publications based on the Berlin Aging Study II (BASE-II) cohort. The first two studies, led by V.M. Vetter, offer a comprehensive cross-sectional and longitudinal comparison of various biological aging markers. By evaluating up to sixteen measures—including epigenetic clocks, proteomics, and composite laboratory markers—against age-associated phenotypes, we found that the epigenetic pace of aging, a DNA-methylation based “biological clock” called DunedinPACE shows the strongest consistency. In addition, DunedinPACE also emerged as the most robust predictor of mortality among fourteen consensus biomarkers for this trait. Adding to this, was an earlier report showing that DunedinPACE is also the most powerful epigenetic clock to predict the onset of metabolic syndrome, a combination of aging-relevant symptoms such as high blood pressure, elevated blood sugar, and increased abdominal fat. Besides Dr. Bertram, these collaborative efforts involved key analytical contributions from several current and former LIGA members, namely Marit P. Junge, J. Homann, L. Deecke, and C.M. Lill. You can access the full texts following these links: Vetter et al. 2026 Commun Med, Vetter et al. 2026 Biomark Res, and Demuth et al. 2025.

• • •

Three AGP papers shed new light on AD genetics

Within the framework of the Alzheimer’s Genome Project (AGP; led by long-standing LIGA collaborator Prof. Rudolph E. Tanzi at Harvard Medical School), our group has co-authored three new papers that significantly expand the genetic landscape of Alzheimer’s disease (AD). The first study by Willet et al., published in Alzheimers and Dementia, utilized an innovative analytical framework—matching heterogeneous cohorts via projected principal components—to mitigate genomic inflation, leading to the discovery of two novel AD-associated genes specifically within the Hispanic population. The second paper by Castanho et al., published in Molecular Neurodegeneration, investigates the molecular hallmarks of excitatory and inhibitory neuronal resilience to AD pathology, providing fresh insights into how specific cell types withstand neurodegeneration. Finally, the third study led by Gauron et al., published in Science Signaling, identifies a specific PKCη missense mutation that enhances Golgi-localized signaling, revealing its robust association with recessively inherited familial AD. The AGP is an international collaborative project running since 2005 and generously funded by the Cure Alzheimers Fund. AGP seeks to identify and characterize novel Alzheimer’s disease (AD) genes using extensive genetic databases based on genome-wide association studies (GWAS), whole genome sequencing (WGS), and whole exome sequencing (WES) data. Since 2024, LIGA is an active contributing site to the AGP with an extension to the STaR-AD project.

• • •

New proteome-based studies predict ALS and PD

Shifting the focus to the ultra-early detection of neurodegenerative diseases, the EPIC4ND collaboration, which is co-led by LIGA head Dr. Lars Bertram, has recently yielded two highly noteworthy manuscripts. Both originate from EPIC4ND PI and long-standing LIGA collaborator Prof. Christina M. Lill from University of Münster. The first paper describes a massive proteomic profiling effort that fundamentally redefines the timeline of Amyotrophic Lateral Sclerosis (ALS). By analyzing pre-diagnostic plasma samples up to two decades before clinical onset, the data revealed a prolonged pre-diagnostic phase characterized by significant immune, muscular, and metabolic involvement. The second paper applies a similar high-throughput plasma proteomics approach to uncover preclinical molecular signatures of Parkinson’s disease, crucially mapping out the molecular overlap with other neurodegenerative disorders to identify shared early pathological cascades. Both of these groundbreaking projects were spearheaded by Münster-based PhD student (and former LIGA member) Jan Homann and supervised Prof. Lill. From our end, LIGA’s current and former members Drs. Dobricic, Deecke and Bertram contributed heavily to the complex data processing. Both manuscripts are currently under-review and available as full-text preprints on the medRxiv server: Homann et al. 2025a and Homann et al. 2025b.

• • •

New EMIF-AD proteome and methylome studies

Advancing the frontier of minimally invasive diagnostics, our ongoing collaborative efforts within the EMIF-AD consortium have produced three compelling publications all published in Alzheimers & Dementia, the journal of the American Alzheimer’s Association, focusing on molecular biomarkers. The first paper by Vromen et al. (2025) details how cerebrospinal fluid (CSF) proteomic associations of different APOE genotypes reveal distinct protective and risk mechanisms. The analysis showed that the rare APOE ε2 variant may confer protection through improved neuronal plasticity, while ε4 carriers exhibit increased blood-brain barrier dysfunction. The second paper, by Koetsier et al. (2024), covers the development of a highly robust, blood-based multivariate DNA methylation risk score designed to predict cognitive impairment and dementia. Complementing this, the third study, by Smith et al. (2024), maps out specific blood DNA methylomic signatures that are tightly associated with established CSF biomarkers of AD. LIGA was instrumental in all three of these epigenetic and proteomic advancements; specifically, Drs. V. Dobricic, J. Homann, and L. Bertram contributed the EMIF-AD DNAm and GWAS data and performed some of the computational analyses underlying these studies.

• • •

Trajectories of brain health

In or collaborative efforts to explore the long-term trajectories of brain health, we have contributed to two recent high-impact papers emerging from the Lifebrain Consortium. The first publication, by Roe et al. in Nature Communications, describes how structural brain change trajectories in healthy adults correlate over the lifespan with Alzheimer’s-related genetic variation and concurrent memory decline. This longitudinal perspective helps pinpoint exactly when and how genetic risk begins to manifest physically in the brain. The second study, spearheaded by long-standing LIGA collaborator Prof. Anders Fjell at University of Oslo and published in Nature Human Behavior, rigorously examines the often-debated relationship between sleep and neurodegeneration. Surprisingly, after extensive analysis across multiple large European cohorts, the research team found absolutely no phenotypic or genotypic evidence for a link between sleep duration and brain atrophy, redirecting scientific focus towards more causative biological pathways. The LIGA team contributed valuable genome-wide SNP genotyping data and analytic insights to both of these studies.

• • •

New genomics studies from LIGA and Münster

Since the publication of the Genome Medicine GWAS, three independent projects co-led by LIGA have recently been completed and published, spanning complex genomics to immunological investigations. All three were spearheaded by members of the Translational Molecular Epidemiology Group at University of Münster, led by former LIGA member Prof. Christina M. Lill. The first paper, spearheaded by former LIGA PhD student Dr. Olena Ohlei, published in Brain Communications, features a comprehensive genome-wide meta-analysis of short-tandem repeats (STRs), utilizing advanced genotype imputation to identify novel genetic risk factors for Parkinson’s disease. The second study, spearheaded by former LIGA MSc student Dr. Laura Deecke, published in Alzheimers & Dementia, pivots to immunology in the context of neurodegeneration, demonstrating that there is no significant increase of CD8+ TEMRA cells in the blood of healthy adults who carry a high genetic risk for Alzheimer’s disease. This finding helps to refine our understanding of peripheral immune signatures prior to disease onset. The third publication, also first-authored by Dr. Deecke and published in the Journal of Investigative Dermatology, explores dermatological genetics, revealing how specific variants in the TERT gene increase the occurrence of solar lentigines by modifying telomerase expression exclusively in the skin. In addition to former LIGA members Drs. Ohlei, Deecke and Lill, current LIGA investigators Drs. Dobricic, Gmelin and Bertram contributed data, analyses, and expertise to various aspects of these studies.

• • •

New GWAS paper on Alzheimer’s biomarkers

In collaboration with our long-standing collaborators at VIB Center for Molecular Neurology in Antwerp, Belgium, the LIGA team published a new paper on the role of genetics on Alzheimer’s disease (AD) biomarker levels. Here, the data for six different CSF biomarkers ascertained in the EMIF-AD and ADNI datasets (n~1000) were combined using a novel multivariate approach to derive components that were deemed more informative than analyzing biomarkers individually. Using a genome-wide association study (GWAS) approach, we then searched for genetic determinants of biomarker component variation and identified five loci to show very strong (i.e. genome-wide significant) association, including two novel signals. One of the novel loci highlighted the gene GRIN2D, which is part of an important neurotransmitter receptor and plays an important role in learning and memory. A wide range of additional analyses suggested that the novel computational approach developed by our group can improve our understanding of AD genetics and may contribute to precision medicine. The study was published in the renowned journal “Genome Medicine” in October 2023. See also the press release of University of Lübeck on this paper.

• • •

New EWAS in Alzheimer’s brains published

This month a new epigenome-wide association study (EWAS) led by the LIGA team was published in the journal Alzheimer’s Research & Therapy. The study was based on generating genome-wide DNA methylation profiles in nearly 200 brain samples from patients with Alzheimer’s disease (AD) and controls with the aim to identify novel genomic regions showing differential methylation. By combining our novel DNAm data with those from two previous studies we identified 12 loci showing epigenome-wide significant association with AD. Four of these loci, near the genes CNFN/LIPE, TENT5A, PALD1/PRF1, and DIRAS1, represent novel findings. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. Our study represents the hitherto most comprehensive EWAS in AD using tissue from the entorhinal cortex and highlights several novel differentially methylated loci with potential effects on gene expression. The study was conducted with collaborators in Oxford and Kiel and represents the third publication of the doctoral thesis work of first author Yasmine Sommerer from the LIGA team.

• • •
1 2 3 5