Lars Bertram

Universität zu Lübeck

Background Studies on DNA methylation (DNAm) in Alzheimer’s disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression. Methods Here, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined thes...

Dysregulation of microRNA gene expression has been implicated in many neurodegenerative diseases, including Parkinson’s disease. However, the individual dysregulated microRNAs remain largely unknown. Previous meta-analyses have highlighted several microRNAs being differentially expressed in post-mortem Parkinson’s disease and Alzheimer's disease br...

Dysregulation of microRNAs (miRNAs) is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Hitherto, sample sizes from differential miRNA expression studies in AD are exceedingly small aggravating any biological inference. To overcome this limitation, we investigated six candidate miRNAs in a large collec...

Genome-wide association studies (GWAS) of Alzheimer′s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal component...

Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from...

Background: The immune system plays a crucial role in the pathogenesis of neurodegenerative diseases. Here, we explored whether blood immune cell profiles are already altered in healthy individuals with a genetic predisposition to amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD). Methods: Using multicolor flow cytometry, we analyzed...

The immune system likely plays a key role in Parkinson's disease (PD) pathophysiology. Thus, we investigated whether immune cell compositions are already altered in healthy individuals at high genetic risk for PD. We quantified 92 immune cell subtypes in the blood of 442 individuals using multicolor flow cytometry. Polygenic risk scores (PGS) for P...

Aging is a complex process influenced by mechanisms operating at numerous levels of functioning. Multiple biomarkers of age have been identified, yet we know little about how the different alternative age indicators are intertwined. In the Berlin Aging Study II (nmin= 328; nmax= 1,517, women = 51%; 14.27 years of education), we examined how levels...

INTRODUCTION The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood‐derived DNA methylation as a promising tool for early dementia risk detection. METHODS In conjunction with an extensive array of machine learning...

INTRODUCTION We investigated blood DNA methylation patterns associated with 15 well‐established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease...

INTRODUCTION We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phospho...

While numerous studies have confirmed a causal association between lipoprotein(a) [Lp(a)] and cardiovascular diseases, only a few studies have assessed the relationship between Lp(a) and pulmonary health, with inconsistent findings regarding this topic. This study’s aim was to examine whether levels of serum Lp(a) are associated with lung function...

INTRODUCTION: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal am...

INTRODUCTION Recent genome‐wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarker...

Idiopathic Parkinson’s disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinson’s disease reported on eight suggestive short-tandem repeat-based risk loci (α = 5.3 × 10−6), of which four were novel, i.e. they had not been implicated in Parkins...

Introduction Biological age reflects inter-individual differences in biological function and capacity beyond chronological age. Biological age can be estimated by DNA methylation age (DNAmA) and its deviation from chronological age, DNAmA acceleration (DNAmAA). Low levels of serum selenium, selenoprotein P (SELENOP), and the selenocysteine-containi...

The immune system plays a crucial role in many human diseases. In this context, genome-wide association studies (GWAS) offer valuable insights to elucidate the role of immunity in health and disease. The present multi-omics study aimed to identify genetic determinants of immune cell type distributions in the blood of healthy individuals and to asse...

Background The aim of this study was to identify DNA methylation signatures that were associated with 15 CSF biomarker measures of Alzheimer’s disease (AD) or neurodegeneration. Method We profiled DNA methylation in 886 blood samples from the EMIF‐AD study using the Illumina EPIC array, identifying differentially methylated loci, and regions consi...

DNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neu...

Aging is a complex process influenced by mechanisms operating at numerous levels of functioning. Multiple biomarkers of age have been identified, yet we know little about how the different alternative age indicators are intertwined. In the Berlin Aging Study II, we examined how levels and seven-year changes in indicators derived from blood assays,...

Across healthy adult life our brains undergo gradual structural change in a pattern of atrophy that resembles accelerated brain changes in Alzheimer's disease (AD). Here, using four polygenic risk scores for AD (PRS-AD) in a longitudinal adult lifespan sample aged 30 to 89 years (2-7 timepoints), we show that healthy individuals who lose brain volu...

Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-sha...

Background Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principa...

INTRODUCTION: Given the established association between DNA methylation and the pathophysiology of dementia and its plausible role as a molecular mediator of lifestyle and environment, blood-derived DNA methylation data could enable early detection of dementia risk. METHODS: In conjunction with an extensive array of machine learning techniques, we...

Background: Change in body weight during the COVID-19 pandemic as an unintended side effect of lockdown measures has been predominantly reported for younger and middle-aged adults. However, information on older adults for which weight loss is known to result in adverse outcomes, is scarce. Aims: Describe body weight change in older adults before, d...

Background Genome‐wide association studies (GWAS) on dementia have successfully identified variants conferring risk to disease. Still, how such variants impact exact biological mechanisms underlying disease remains largely unclear. Protein quantitative trait loci (pQTLs) measured in cerebrospinal fluid (CSF) may provide insight into these neurobiol...

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively...

Mild Cognitive Impairment (MCI) is a phase that can precede Alzheimer’s Disease (AD). To better understand the molecular mechanisms underlying conversion from MCI to AD, we utilized four algorithms to identify key pathways. Data consisted of metabolites (n=540) and proteins (n=3630) measured in plasma coupled to clinical data (n=26). The cohort com...

Introduction: This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration [AT(N)] framework, mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD. Methods: Using the European Medical Information Framework (EM...

Background Patients with Type 2 diabetes mellitus (T2D) are at risk for micro- and macrovascular complications. Implementable risk scores are needed to improve targeted prevention for patients that are particularly susceptible to complications. The epigenetic clock estimates an individual’s biological age using DNA methylation profiles. Methods In...

Genetic similarity matrices are commonly used to assess population substructure (PS) in genetic studies. Through simulation studies and by the application to whole-genome sequencing (WGS) data, we evaluate the performance of three genetic similarity matrices: the unweighted and weighted Jaccard similarity matrices and the genetic relationship matri...

Particularly older people are at risk for deficient vitamin D levels, as their capability for cutaneous synthetization is lower and they are often less exposed to sunlight. However, the resulting impact on one individual’s health is not fully understood. To examine potential consequences of low vitamin D levels for health of older people, we examin...

GWAS studies showed that cerebrospinal fluid (CSF) levels of total‐tau in Alzheimer’s disease (AD) are associated with genetic variations in GMNC (Cruchaga,2013). GMNC is involved in neural progenitor cell differentiation and regulates the generation of multiciliated ependymal cells (Kyrousi,2015), but the precise role of GMNC in AD pathophysiology...

Genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown and disease mechanisms are often unclear. Using CSF biomarkers of AD as outcome may aid in gene discovery and in elucidating disease processes. We previously demonstrated that six CSF biomarkers (β‐amyloid, total/phosphoryla...

High-quality biomarkers are needed to predict age-related phenotypes and evaluate health-related interventions. Telomere length has been known as a biomarker of aging for some time, however, its potential for clinical use is limited. Epigenetic age estimators and biological age (bioage) composites have been developed and refined over the past decad...

The diagnosis of metabolic syndrome (MetS) relies on cut-off values for five cardiovascular risk factors, three of which must be met to make the diagnosis. While this approach has certain advantages in the clinical setting, it only allows a binary classification relying on cut-off values. Thus, individuals receiving the same MetS diagnosis may diff...

Introduction: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. Methods: We performed whole-exome gene-based rare-variant association studies (RVASs) of...

Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau le...

APOE Ɛ4, the major genetic risk factor for sporadic Alzheimer’s disease (AD), has a dose‐dependent effect on the risk of development of AD. It remains unclear how APOE Ɛ4 dose affects different pathophysiological processes in AD, and therefore we studied APOE genotype effects on the CSF proteome of prodromal AD individuals. CSF proteomics was perfo...

Background and objective Blood-based biomarkers represent a promising approach to help identify early Alzheimer’s disease (AD). Previous research has applied traditional machine learning (ML) to analyze plasma omics data and search for potential biomarkers, but the most modern ML methods based on deep learning has however been scarcely explored. In...

Genetic variants in UMOD associate with kidney function and hypertension. These phenotypes are also linked to sex-related differences and impairment in cognitive and physical function in older age. Here we evaluate longitudinal associations between a common UMOD rs4293393-A>G variant and changes in estimated glomerular filtration rate (eGFR), blood...

The recently reported TNIP1 / GPX3 locus from AD GWAS studies was investigated. Using proteomics and other functional omics data, we identified evidence for a functional mechanism linking variants in this locus to decreased CSF GPX3 levels as AD progresses, suggesting a new potential target for intervention.

The decline in episodic memory (EM) performance is a hallmark of cognitive aging and an early clinical sign in Alzheimer’s disease (AD). In this study, we conducted an epigenome-wide association study (EWAS) using DNA methylation (DNAm) profiles from buccal and blood samples for cross-sectional (n = 1019) and longitudinal changes in EM performance...

Epigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal...

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal...

Adverse effects of psychological stress on physical and mental health, especially in older age, are well documented. How perceived stress relates to the epigenetic clock measure, DNA methylation age acceleration (DNAmAA), is less well understood and existing studies reported inconsistent results. DNAmAA was estimated from five epigenetic clocks (7-...

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, i...

Biomarkers defining biological age are typically laborious or expensive to assess. Instead, in the current study, we identified parameters based on standard laboratory blood tests across metabolic, cardiovascular, inflammatory, and kidney functioning that had been assessed in the Berlin Aging Study (BASE) (n = 384) and Berlin Aging Study II (BASE-I...

INTRODUCTION This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the Amyloid/Tau/Neurodegeneration [AT(N)] framework, MCI conversion to AD, and genetic risk for AD. METHODS Using the EMIF-AD MBD cohort, we measured 696 proteins in cerebrospinal fluid (n=371), 4001 proteins in pl...

Patients with diabetes mellitus are at risk for micro- and macrovascular complications that are responsible for a substantial part of the individual health burden and socio-economic costs. Therefore, implementable risk scores are needed to improve targeted prevention for patients that are particularly susceptible to complications. The “epigenetic c...

Background: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) prote...

Alzheimer’s disease (AD) is a complex neurodegenerative disorder. The relative contribution of the numerous underlying functional mechanisms is poorly understood. To comprehensively understand the context and distribution of pathways that contribute to AD, we performed text-mining to generate an exhaustive, systematic assessment of the breadth and...

Adverse effects of low vitamin D level on mortality and morbidity are controversially discussed. Especially older people are at risk for vitamin D deficiency and therefore exposed to its potentially harmful consequences. A way of measuring differences in the biological age is through DNA methylation age (DNAm age) and its deviation from chronologic...

Introduction: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E Ɛ4 genotype. Methods: We...

Cognitive performance is both heritable and sensitive to environmental inputs and sustained practice over time. However, it is currently unclear how genetic effects on cognitive performance change over the course of learning. We examine how polygenic scores (PGS) created from genome-wide association studies of educational attainment and cognitive p...

The original article [1] contained an error in co-author, Lars Bertram’s affiliation which has since been corrected.

A new genome-wide association study has identified 41 previously unknown loci associated with Alzheimer disease. However, these data provide limited insight into disease mechanisms or benefits for clinical prediction of Alzheimer disease.

Alzheimer’s disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with t...

Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent...

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk predi...

Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genomewide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinic...

The question of how much sleep is best for the brain attracts scientific and public interest, and there is concern that insuficient sleep leads to poorer brain health. However, it is unknown how much sleep is sufficient and how much is too much. We analyzed 51,295 brain magnetic resonnance images from 47,039 participants, and calculated the self-re...