John Hardy

University College London | UCL · Institute of Neurology

Alzheimer’s disease (AD) is a spatially dynamic pathology that implicates a growing volume of multiscale data spanning genetic, cellular, tissue, and organ levels of the organization. These data and bioinformatics analyses provide clear evidence for the interactions within and between these levels. The resulting heterarchy precludes a linear neuron...

Alzheimer’s disease is the most common neurological disease worldwide. Unfortunately, there are currently no effective treatment methods nor early detection methods. Furthermore, the disease underlying molecular mechanisms are poorly understood. Global bulk gene expression profiling suggested that the disease is governed by diverse transcriptional...

Recently, our lab identified bi-allelic mutations in the NKX6.2 gene that cause autosomal recessive spastic ataxia and hypomyelinating leukodystrophy. In addition to this we have identified a number of genetic causes of other leukodystrophies. Since these genes were identified we have extended our analysis of the clinical phenotypes in a large numb...

Background: Genome wide association studies (GWAS) have helped identify large numbers of genetic loci that significantly associate with increased risk of developing diseases. However, translating genetic knowledge into understanding of the molecular mechanisms underpinning disease (i.e. disease-specific impacted biological processes) has to date p...

The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer's disease, in order to demonstrate if the BDR sample also display...

Objective The basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype. Methods Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richards...

The neuronal microtubule-associated protein tau (MAPT) is central to the pathogenesis of many dementias, including Alzheimer's disease. Autosomal dominant mutations in MAPT cause inherited frontotemporal dementia (FTD), but the underlying pathogenic mechanisms are unclear. Using human stem cell models of FTD due to MAPT mutations, we find that tau...

Objective Individuals with Down syndrome (DS) have an extremely high genetic risk for Alzheimer's disease (AD), however, the course of cognitive decline associated with progression to dementia is ill‐defined. Data‐driven methods can estimate long‐term trends from cross‐sectional data while adjusting for variability in baseline ability, which compli...

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 ca...

Background: Down syndrome (DS) may be considered a genetic form of Alzheimer's disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative co...

Importance Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. Objectives To examine whether there are com...

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential ge...

The derivation of microglia from human stem cells provides systems for understanding microglial biology and enables functional studies of disease-causing mutations. We describe a robust method for the derivation of human microglia from stem cells, which are phenotypically and functionally comparable to primary microglia. We used stem cell-derived m...

Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to r...

A correction has been published and is linked to the HTML and PDF versions of this paper. The error has not been fixed in the paper.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin f...

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHM...

Over the last few years, as more and more sequencing studies have been performed, it has become apparent that the identification of pathogenic mutations is, more often than not, a complex issue. Here, with a focus on neurodegenerative diseases, we have performed a survey of coding genetic variability that is unlikely to be pathogenic. We have perfo...

Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. Th...

[This corrects the article DOI: 10.1371/journal.pmed.1002487.].

Objectives To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson’s disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive fun...

Correction: The original version of this article [1] unfortunately contained a typographical error. The 'Alzheimer's Disease Neuroimaging Initiative' was erroneously included as 'Alzheimer's Disease Neuroimaging Initative' in the author list of the article.

Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum...

Fold enrichment plots of enrichment versus nominal −log10(p)-values (corrected for inflation) in amyotrophic lateral sclerosis (ALS) below the standard genome-wide association study threshold of p < 5 × 10−8 as a function of significance of association with 6 immune-mediated diseases. The 6 immune-mediated diseases are Crohn disease (CD), ulcerativ...

“Conjunction” Manhattan plot of conjunction and conditional −log10(FDR) values for amyotrophic lateral sclerosis (ALS) given 6 immune-mediated diseases. The 6 immune-mediated diseases are Crohn disease (CD; ALS|CD, red), ulcerative colitis (UC, ALS|UC, orange), type 1 diabetes (T1D, ALS|T1D, teal), rheumatoid arthritis (RA, ALS|RA, green), celiac d...

Individual bar plots showing cell-type-specific expression for LRRK2. (TIFF)

Individual bar plots showing cell-type-specific expression for PGBD5. (TIFF)

Summary-data-based Mendelian randomization results. (DOCX)

Fold enrichment plots of enrichment versus nominal −log10(p)-values (corrected for inflation) in progressive supranuclear palsy (PSP) below the standard genome-wide association study threshold of p < 5 × 10−8 as a function of significance of association with 6 immune-mediated diseases. The 6 immune-mediated diseases are Crohn disease (CD), ulcerati...

“Conjunction” Manhattan plot of conjunction and conditional −log10(FDR) values for progressive supranuclear palsy (PSP) given 6 immune-mediated diseases. The 6 immune-mediated diseases are Crohn disease (CD; PSP|CD, red), ulcerative colitis (UC, PSP|UC, orange), type 1 diabetes (T1D, PSP|T1D, teal), rheumatoid arthritis (RA, PSP|RA, green), celiac...

Individual bar plots showing cell-type-specific expression for TBKBP1. (TIFF)

Overlapping loci between CBD and immune-mediated diseases at a conjunction FDR < 0.05. (DOCX)

Fold enrichment plots of enrichment versus nominal −log10(p)-values (corrected for inflation) in corticobasal degeneration (CBD) below the standard genome-wide association study threshold of p < 5 × 10−8 as a function of significance of association with 6 immune-mediated diseases. The 6 immune-mediated diseases are Crohn disease (CD), ulcerative co...

“Conjunction” Manhattan plot of conjunction and conditional −log10(FDR) values for corticobasal degeneration (CBD) given 6 immune-mediated diseases. The 6 immune-mediated diseases are Crohn disease (CD; CBD|CD, red), ulcerative colitis (UC, CBD|UC, orange), type 1 diabetes (T1D, CBD|T1D, teal), rheumatoid arthritis (RA, CBD|RA, green), celiac disea...

Overlapping loci between PSP and immune-mediated diseases at a conjunction FDR < 0.05. (DOCX)

Physical interaction and gene co-expression networks for the pleiotropic genes with significant cis-eQTLs. (DOCX)

Overlapping loci between ALS and immune-mediated diseases at a conjunction FDR < 0.05. (DOCX)

cis-eQTLs between FTD and immune-mediated disease shared risk SNPs and associated genes across a variety of tissues. (DOCX)

Background: Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has b...

Alzheimer disease (AD), a progressive and neurodegenerative disease, is the most common form of dementia with high incidence in elderly people. Neuropathologically the disease is defined by the combined presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of phosphorylated tau protein. Genetically, the first...

Background Weighted Gene Co-expression Network Analysis (WGCNA) is a widely used R software package for the generation of gene co-expression networks (GCN). WGCNA generates both a GCN and a derived partitioning of clusters of genes (modules). We propose k-means clustering as an additional processing step to conventional WGCNA, which we have impleme...

Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was...

Chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments in individuals with past exposure to repetitive head impacts. From 1980 to 2010, 2014 retired football (soccer) players with dementia were followed up regularly until death. All were skilled headers of the ball; 13 were professional and 1...

Background Parkinson’s disease (PD) is associated with motor and non-motor symptoms, including cognitive impairment. Genetic features may influence clinical symptoms. Objective Familial PD patients have been recruited through the ABN British Neurological Surveillance Unit (BNSU) to the Parkinson’s Families Project. A primary aim of this study is t...

Background While age and the APOE ε4 allele are major risk factors for Alzheimer’s disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. Methods We used over 200 “AD resilient” individuals and an innovative, pedigree-ba...

Aim: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent GWAS have uncovered 20 new loci for AD risk, however these...

Sporadic early onset Alzheimer’s disease (sEOAD) exhibits the symptoms of late onset Alzheimer’s disease (LOAD) but lacks the familial aspect of the early onset familial form. The genetics of Alzheimer’s disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and mult...

Neurodegenerative diseases present an enormous challenge to medicine and the need for biomarker discovery and novel drug-directed strategies are thus of high priority. A common disease feature is the accumulation of misfolded proteins, which leads to cellular stress responses, including raised calcium levels, and results in neuronal death. Peptidyl...

Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (...

HPLC analysis of the CoA to acetyl-CoA ratio, comparing iPSCs and neurons. This change in ratio represents a change in respiration dependency on glycolysis and oxidative phosphorylation. Numbers in histograms represent experimental replicates. (TIFF)

Characterisation of patient-derived iPSC lines. Karyographs to show karyotype stability in the patient-derived reprogrammed iPSCs. All patient-derived iPSCs displayed normal karyotype and g-banding. Confirmation of heterozygous mutations in differentiated iPSC-derived neurons (at least 100 days), mutations depicted within red boxes. gDNA–genomic DN...

Background Recent evidence suggests that glucosidase beta acid (GBA) mutations predispose Parkinson’s disease (PD) patients to a greater burden of cognitive impairment and non-motor symptoms. This emerging knowledge has not yet been considered in patients who have undergone deep brain stimulation (DBS); a surgery that is generally contraindicated i...

Many common genetic factors have been identified to contribute to PD susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci have been poorly studied. Using International Parkinson’s Disease Genomics Consortium datasets, we performed a comprehensive study to determ...

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first-generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant...

Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer's disease have given Area Under the Curve estimates of <80%. However, these have been based on the genetic analysis of clinical case control series. Here we apply the same analytic approaches to a pathological case control series and show a predictive...

Background Systems biology approaches to Alzheimer’s disease (AD) are comparatively rare and reductionist concepts still prevail. We challenge the idea that either tau or Aß are the causal agents in the pathology of AD, and instead consider the role systemic factors play in its neurodegenerative spread through the brain. Method In a new systems pat...

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we...

Genome wide association studies (GWAS) for Parkinson’s disease (PD) have previously revealed a significant association with a locus on chromosome 7p15.3, initially designated as the glycoprotein non-metastatic melanoma protein B (GPNMB) locus. In this study, the functional consequences of this association on expression were explored in depth by int...

Background: Systems biology approaches to Alzheimer’s disease(AD) are comparatively rare and reductionist concepts still prevail. We challenge the idea that either tau or A-beta the causal agents in the pathology of AD, and instead consider the role systemic factors play in its neurodegenerative spread through the brain. Methods: In a new systems...

Background Both positive and negative associations between higher body mass index (BMI) and Parkinson disease (PD) have been reported in observational studies, but it has been difficult to establish causality because of the possibility of residual confounding or reverse causation. To our knowledge, Mendelian randomisation (MR)—the use of genetic in...

Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and novel ways for man...