Ahmad Al Khleifat

• MB BCh., M.Sc., PhD.
• Medical Professional at King's College London

Background: Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To addre...

Background Next Generation Sequencing (NGS) is a commonly used technology for studying the genetic basis of biological processes and it underpins the aspirations of precision medicine. However, there are significant challenges when dealing with NGS data. Firstly, a huge number of bioinformatics tools for a wide range of uses exist, therefore it is...

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College Lon...

There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwi...

Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more...

Background Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case–control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of o...

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigen...

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related dise...

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the gradual death of motor neurons in the brain and spinal cord, leading to fatal paralysis. Socioeconomic status (SES) is a measure of an individual's shared economic and social status, which has been shown to have an association with health outcomes. Understanding...

Time-to-event prediction is a key task for biological discovery, experimental medicine, and clinical care. This is particularly true for neurological diseases where development of reliable biomarkers is often limited by difficulty visualising and sampling relevant cell and molecular pathobiology. To date, much work has relied on Cox regression beca...

Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates common genetic association results from the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing...

Significantly more men develop amyotrophic lateral sclerosis (ALS) than women, and heritability is not uniform between male and female transmissions, together suggesting a role for sex in the genetic aetiology of the disease. We therefore performed sex-stratified genome-wide and transcriptome-wide analyses of ALS risk, identifying six novel sex-spe...

Objective Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods Genetic data of 11,1...

Recently, large-scale case-control analyses have been prioritized in the study of ALS. Yet the same effort has not been put forward to investigate additive moderate phenotypic effects of genetic variants in genes driving ALS risk, despite case-level evidence suggesting a potential oligogenic risk model. Considering its direct clinical and therapeut...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including geneti...

Background and Objectives A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete dis...

Amyotrophic lateral sclerosis (ALS) displays considerable clinical and genetic heterogeneity. Machine learning approaches have previously been utilised for patient stratification in ALS as they can disentangle complex disease landscapes. However, lack of independent validation in different populations and tissue samples have greatly limited their u...

Objective: We investigated non-motor symptoms in ALS using sequential questionnaires; here we report the findings of the second questionnaire. Methods: A social media platform (Twitter, now known as X) was used to publicize the questionnaires. Data were downloaded from SurveyMonkey and analyzed by descriptive statistics, comparison of means, and...

Motivation: For a number of neurological diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and many others, certain genes are known to be involved in the disease mechanism. A common question is whether a structural variant in any such gene may be related to drug response in clinical trials and how this relationship can contribut...

Objective: While motor symptoms are well-known in ALS, non-motor symptoms are often under-reported and may have a significant impact on quality of life. In this study, we aimed to examine the nature and extent of non-motor symptoms in ALS. Methods: A 20-item questionnaire was developed covering the domains of autonomic function, sleep, pain, gas...

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, ‘wild-type like’ (WTL) and ‘metal binding region’ (MBR) variants, b...

With the increase in large multimodal cohorts and high‐throughput technologies, the potential for discovering novel biomarkers is no longer limited by data set size. Artificial intelligence (AI) and machine learning approaches have been developed to detect novel biomarkers and interactions in complex data sets. We discuss exemplar uses and evaluate...

Artificial intelligence (AI) and machine learning (ML) approaches are increasingly being used in dementia research. However, several methodological challenges exist that may limit the insights we can obtain from high‐dimensional data and our ability to translate these findings into improved patient outcomes. To improve reproducibility and replicabi...

Drug discovery and clinical trial design for dementia have historically been challenging. In part these challenges have arisen from patient heterogeneity, length of disease course, and the tractability of a target for the brain. Applying big data analytics and machine learning tools for drug discovery and utilizing them to inform successful clinica...

Objective: Variants in the superoxide dismutase (SOD1) gene are among the most common genetic causes of amyotrophic lateral sclerosis. Reflecting the wide spectrum of putatively deleterious variants that have been reported to date, it has become clear that SOD1-linked ALS presents a highly variable age at symptom onset and disease duration.Methods:...

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in progressive weakness of skeletal muscles including respiratory muscles. Epidemiological and clinical aspects of ALS are derived from a few world regions with very little representation of low- and middle-income countries. We therefore set out to det...

Primary lateral sclerosis (PLS) is the rarest form of motor neurone disease (MND). It is characterized by upper motor neuron degeneration, leading to progressive weakness, spasticity and functional disability. Although PLS does not typically shorten life substantially, it gradually impacts quality of life as the diseases progresses. There is no est...

Amyotrophic lateral sclerosis and Parkinson's disease are neurodegenerative diseases of the motor system which are now recognized also to affect non-motor pathways. Non-motor symptoms have been acknowledged as important determinants of quality of life in Parkinson's disease, and there is increasing interest in understanding the extent and role of n...

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a highly variable clinical presentation and multifaceted genetic and biological bases that translate into great patient heterogeneity. The identification of homogeneous subgroups of patients in terms of both clinical presentation and biological cau...

Background: Amyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that typically leads to death from respiratory failure within two to five years. Despite the identification of several genetic risk factors, the biological processes involved in ALS pathogenesis remain poorly understood. The motor cortex is an ideal r...

Background: Amyotrophic lateral sclerosis (ALS) displays considerable clinical, genetic and molecular heterogeneity. Machine learning approaches have shown potential to disentangle complex disease landscapes and they have been utilised for patient stratification in ALS. However, lack of independent validation in different populations and in pre-mor...

The current widespread adoption of next-generation sequencing (NGS) in all branches of basic research and clinical genetics fields means that users with highly variable informatics skills, computing facilities and application purposes need to process, analyse, and interpret NGS data. In this landscape, versatility, scalability, and user-friendlines...

Objective Variants in the superoxide dismutase ( SOD1 ) gene are among the most common genetic causes of amyotrophic lateral sclerosis. Reflecting the wide spectrum of putatively deleterious variants that have been reported to date, it has become clear that SOD1 -linked ALS presents a highly variable age at symptom onset and disease duration. Meth...

Introduction: Machine learning (ML) has been extremely successful in identifying key features from high-dimensional datasets and executing complicated tasks with human expert levels of accuracy or greater. Methods: We summarize and critically evaluate current applications of ML in dementia research and highlight directions for future research. Resu...

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead...

Progress in dementia research has been limited, with substantial gaps in our knowledge of targets for prevention, mechanisms for disease progression, and disease-modifying treatments. The growing availability of multimodal data sets opens possibilities for the application of machine learning and artificial intelligence (AI) to help answer key quest...

There is a growing interest in the study of human endogenous retroviruses (HERVs) given the substantial body of evidence that implicates them in many human diseases. Although their genomic characterization presents numerous technical challenges, next-generation sequencing (NGS) has shown potential to detect HERV insertions and their polymorphisms i...

Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction...

Background: The increasing availability of large high-dimensional data from experimental medicine, population-based and clinical cohorts, clinical trials, and electronic health records has the potential to transform dementia research. Our ability to make best use of this rich data will depend on utilisation of advanced machine learning and artific...

The increasing availability of large high‐dimensional data from experimental medicine, population‐based and clinical cohorts, clinical trials, and electronic health records has the potential to transform dementia research. Our ability to make best use of this rich data will depend on utilisation of advanced machine learning and artificial intellige...

Objectives: The use of synthetic data to supplement clinical trial placebo groups or for trial planning is rapidly gaining interest. However, there is not yet an established framework for generating synthetic data for these purposes. In this work we test two approaches to generating synthetic placebo arms for ALS trials with survival being the prim...

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. Investigating how different SOD1 variants affect the protein dynamics might help in understanding their pathogenic mechanism and explaining their het...

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with...

Objective Genetic variation in the neurofilament heavy chain gene ( NEFH ) has been convincingly linked to the pathogenesis of multiple neurodegenerative diseases, however, the relationship between NEFH mutations and ALS susceptibility has not been robustly explored. We therefore wanted to determine if genetic variants in NEFH modify ALS risk. Met...

Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in ALS. Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Using...

Dementia is caused by an acquired, sustained decline in brain function, leading to difficulty with everyday activities. With multiple aetiologies, clinical presentation varies, typically including problems with memory, cognition, and communication. Dementia research aims to identify risk factors, disease mechanisms and treatments. However, progress...

Human Endogenous Retroviruses (HERVs) integrated into the genome of vertebrates as a result of ancient exogenous infections and currently comprise ∼8% of our genome. The members of the most recently acquired HERV family, HERV-Ks, still retain potential to produce viral molecules and have been linked to a wide range of diseases including cancer and...

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, a family history is observed. Although Mendelian disease gene variants are found in apparently sporadic ALS, genetic testing is usually restricted to those with a family history or younger patients with sporadic disease. With the advent of ther...

The genetics of an individual is a crucial factor in understanding the risk of developing the neurodegenerative disease amyotrophic lateral sclerosis (ALS). There is still a large proportion of the heritability of ALS, particularly in sporadic cases, to be understood. Among others, active transposable elements drive inter-individual variability, an...

Background: Amyotrophic lateral sclerosis (ALS) shows considerable clinical heterogeneity, which affects clinical trials. A clinical staging system has been proposed for ALS with potential applications in patient care, research, trial design and health economic analyses. The King's system consists of five stages. We have previously shown that progr...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Selective vulnerability of energy-intensive motor neurons (MNs) has fostered speculation that mitochondrial function is a determinant of ALS. Previously, the position of mitochondrial function in the pathogenic cascade leading to neurotoxicity has been unclear. We separated u...

In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects...

The current widespread adoption of next-generation sequencing (NGS) in all branches of basic and clinical genetics fields means that users with highly variable informatics skills, computing facilities and application purposes need to process, analyse, and interpret NGS data. In this landscape, versatility, scalability, and user-friendliness are key...

The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS c...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide a...

There is a growing interest in the study of human endogenous retroviruses (HERVs) given the substantial body of evidence that implicates them in many human diseases. Although their genomic characterization presents numerous technical challenges, next-generation sequencing (NGS) has shown potential to detect HERV insertions and their polymorphisms i...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 indi...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 indi...

Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via expression Quantitative Trait Loci. Using multiple genome-wide methods we examined if Single Nucleotide Polymorphisms increase risk of Amyotrophic Lateral Sclerosis through expression Quantitative Trait Loci, and whe...

Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing was...

In October 2020, 62 scientists from nine nations worked together remotely in the Second Baylor College of Medicine & DNAnexus hackathon, focusing on different related topics on Structural Variation, Pan-genomes, and SARS-CoV-2 related research. The overarching focus was to assess the current status of the field and identify the remaining challenges...

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We...

Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing w...

With the increasing availability of next-generation sequencing (NGS), patients and non-specialist health care professionals are obtaining their genomic information without sufficient bioinformatics skills to analyze and interpret the data. In January 2021, four teams of scientists,clinicians, and developers from around the world worked collaborativ...

The non-coding genome is substantially larger than the protein-coding genome, but the lack of appropriate methodologies for identifying functional variants limits genetic association studies. Here, we developed analytical tools to identify rare variants in pre-miRNAs, miRNA recognition elements in 3’UTRs, and miRNA-target networks. Region-based bur...

Alexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published...

Background: Clinical stage in amyotrophic lateral sclerosis (ALS) can be assigned using King's staging with a simple protocol based on the number of CNS regions involved and the presence of significant nutritional or respiratory failure. It is important that the assigned clinical stage matches expectations, and generally corresponds with how a heal...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide ass...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced indivi...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced indivi...

In October 2020, 62 scientists from nine nations worked together remotely in the Second Baylor College of Medicine & DNAnexus hackathon, focusing on different related topics on Structural Variation, Pan-genomes, and SARS-CoV-2 related research. The overarching focus was to assess the current status of the field and identify the remaining challenges...

Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple r...

Graphical Abstract Highlights d Cross-ethnic meta-analysis finds an association between the ACSL5-ZDHHC6 locus and ALS d The ACSL5-ZDHHC6 association is replicated in an independent Australian cohort d ACSL5-ZDHHC6 lead SNP is in ACSL5 and is an eQTL of ZDHHC6 in brain tissues d ACSL5 SNPs might have an effect on fat-free mass in ALS patients Corre...

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We presen...

Increased cerebrospinal uid neuro lament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in fteen neurodegenerative diseases from two multicenter cohorts: King's College London (n = 847) and the Swedish BioFINDER study (n = 1464). Plasma...

Objective Smoking has been widely studied as a susceptibility factor for amyotrophic lateral sclerosis (ALS), but results are conflicting and at risk of confounding bias. We used the results of recently published large genome-wide association studies and Mendelian randomisation methods to reduce confounding to assess the relationship between smokin...

Introduction: Susceptibility to amyotrophic lateral sclerosis (ALS) is associated with smoking in some studies, but it is not clear which aspect of smoking behavior is related. Using detailed records of lifetime smoking we investigated the relationship between smoking and ALS in a UK population. Methods: In this retrospective case-control study, sm...

In the version of this article initially published, the affiliations of three authors were incorrect. Liam E. Abbott should have been associated with Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institut...

To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes...