Peter St George-Hyslop

University of Cambridge, Cambridge, England, United Kingdom

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Publications (432)3765.94 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To detect rare coding variants underlying loci detected by genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD). We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A and PICALM in three independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 NIA-LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least two datasets were genotyped in independent groups of ancestry matched controls. Additionally, the Exome Aggregation Consortium (ExAC) was used as a reference dataset for population-based allele frequencies. Overall we detected a statistically significant 3.1-fold enrichment of the non-synonymous mutations in the Caucasian LOAD cases compared with controls (p=0.002) and no difference in synonymous variants. A stopgain mutation in ABCA7 (E1769X) and missense mutation in CD2AP (T374A) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in two of the six Caribbean Hispanic families where the mutations were discovered. Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease related mechanisms and potential therapies. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    Annals of Neurology 06/2015; DOI:10.1002/ana.24466 · 11.91 Impact Factor
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    ABSTRACT: The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
    Scientific Reports 06/2015; 5:10934. DOI:10.1038/srep10934 · 5.58 Impact Factor
  • Brain 03/2015; DOI:10.1093/brain/awv082 · 10.23 Impact Factor
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    ABSTRACT: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.
    Molecular Psychiatry 03/2015; DOI:10.1038/mp.2015.23 · 15.15 Impact Factor
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    ABSTRACT: Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid β-peptide (Aβ). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aβ produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aβ. We also briefly outline how the emerging knowledge about the pathways involved in Aβ generation and clearance can be potentially targeted therapeutically. Copyright © 2015. Published by Elsevier Inc.
    Molecular and Cellular Neuroscience 03/2015; 301. DOI:10.1016/j.mcn.2015.02.016 · 3.73 Impact Factor
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    ABSTRACT: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.
    JAMA Neurology 12/2014; DOI:10.1001/jamaneurol.2014.2157 · 7.01 Impact Factor
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    ABSTRACT: The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function.
    Molecular Neurodegeneration 12/2014; 9(1):59. DOI:10.1186/1750-1326-9-59 · 5.29 Impact Factor
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    ABSTRACT: Background:Inbreeding can be associated with a modification of disease risk due to excess homozygosity of recessive alleles affecting a wide range of phenotypes. We estimated the inbreeding coefficient in Caribbean Hispanics and examined its effects on risk of late-onset Alzheimer disease.Methods:The inbreeding coefficient was calculated in 3,392 subjects (1,451 late-onset Alzheimer disease patients and 1,941 age-matched healthy controls) of Caribbean Hispanic ancestry using 177,997 nearly independent single-nucleotide polymorphisms from genome-wide array. The inbreeding coefficient was estimated using the excess homozygosity method with and without adjusting for admixture.Results:The average inbreeding coefficient in Caribbean Hispanics without accounting for admixture was F = 0.018 (±0.048), suggesting a mating equivalent to that of second cousins or second cousins once removed. Adjusting for admixture from three parent populations, the average inbreeding coefficient was found to be 0.0034 (±0.019) or close to third-cousin mating. Inbreeding coefficient was a significant predictor of Alzheimer disease when age, sex, and APOE genotype were used as adjusting covariates (P = 0.03).Conclusion:The average inbreeding coefficient of this population is significantly higher than that of the general Caucasian populations in North America. The high rate of inbreeding resulting in increased frequency of recessive variants is advantageous for the identification of rare variants associated with late-onset Alzheimer disease.Genet Med advance online publication 13 November 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.161.
    Genetics in medicine: official journal of the American College of Medical Genetics 11/2014; DOI:10.1038/gim.2014.161 · 6.44 Impact Factor
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    ABSTRACT: The pathogenesis of Alzheimer disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.
    Journal of Alzheimer's disease: JAD 10/2014; 44(2). DOI:10.3233/JAD-141902 · 3.61 Impact Factor
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    ABSTRACT: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.
    JAMA Neurology 09/2014; DOI:10.1001/jamaneurol.2014.1491 · 7.01 Impact Factor
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    ABSTRACT: Genetic analyses of patients with neurodegenerative disorders have identified multiple genes that need to be investigated for the presence of damaging variants. However, mutation analysis by Sanger sequencing is costly and time consuming. We tested the utility of a recently designed semi-custom genome-wide array (NeuroX; Illumina, Inc) tailored to study neurodegenerative diseases (e.g., mutation screening). We investigated 192 patients with 4 different neurodegenerative disorders for the presence of rare damaging variations in 77 genes implicated in these diseases. Several causative mutations were identified and confirmed by Sanger sequencing, including PSEN1 p.M233T responsible for Alzheimer's disease in a large Italian family, as well as SOD1 p.A4V and p.I113T in patients with amyotrophic lateral sclerosis. In total, we identified 78 potentially damaging rare variants (frequency <1%), including ABCA7 p.L400V in a family with Alzheimer's disease and LRRK2 p.R1514Q in 6 of 98 patients with Parkinson's disease (6.1%). In conclusion, NeuroX appears to be helpful for rapid and accurate mutation screening, although further development may be still required to improve some current caveats.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.038 · 4.85 Impact Factor
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    Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2014; 10(4):P324. DOI:10.1016/j.jalz.2014.05.293 · 17.47 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P134. DOI:10.1016/j.jalz.2014.04.074 · 17.47 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here, we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wild-type littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid-β protein, may underlie the observed neuronal loss. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 07/2014; 522(10). DOI:10.1002/cne.23536 · 3.51 Impact Factor
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    ABSTRACT: Clinical and neuropathological similarities between Dementia with Lewy Bodies (DLB), ParkinsonÕs and AlzheimerÕs diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). Results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared to the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
    Human Molecular Genetics 06/2014; 23(23). DOI:10.1093/hmg/ddu334 · 6.68 Impact Factor
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    ABSTRACT: The G4C2-repeat expansion in C9orf72 is a common cause of Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of the CpG-island (5'of the repeat) in DNA samples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation level was significantly higher in FTLD expansion carriers than non-carriers (p=7.8E-13). Our results were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n=26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (p=0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5'of the G4C2-repeat is expansion-specific, but not syndrome-specific (ALS vs. FTLD).
    Human Molecular Genetics 06/2014; DOI:10.1093/hmg/ddu279 · 6.68 Impact Factor
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    ABSTRACT: Oligomers of the amyloid-β (Aβ) peptide have been implicated in the neurotoxicity associated with Alzheimer's disease. We have used single-molecule techniques to examine quantitatively the cellular effects of adding well characterized Aβ oligomers to primary hippocampal cells and hence determine the initial pathway of damage. We found that even picomolar concentrations of Aβ (1-40) and Aβ (1-42) oligomers can, within minutes of addition, increase the levels of intracellular calcium in astrocytes but not in neurons, and this effect is saturated at a concentration of about 10 nM of oligomers. Both Aβ (1-40) and Aβ (1-42) oligomers have comparable effects. The rise in intracellular calcium is followed by an increase in the rate of ROS production by NADPH oxidase in both neurons and astrocytes. The increase in ROS production then triggers caspase-3 activation resulting in the inhibition of long-term potentiation. Our quantitative approach also reveals that only a small fraction of the oligomers are damaging and that an individual rare oligomer binding to an astrocyte can initiate the aforementioned cascade of responses, making it unlikely to be due to any specific interaction. Preincubating the Aβ oligomers with an extracellular chaperone, clusterin, sequesters the oligomers in long-lived complexes and inhibits all of the physiological damage, even at a ratio of 100:1, total Aβ to clusterin. To explain how Aβ oligomers are so damaging but that it takes decades to develop Alzheimer's disease, we suggest a model for disease progression where small amounts of neuronal damage from individual unsequestered oligomers can accumulate over time leading to widespread tissue-level dysfunction.
    Biochemistry 04/2014; DOI:10.1021/bi401606f · 3.19 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.
    Nature 01/2014; 505(7484-7484):550-554. DOI:10.1038/nature12825 · 42.35 Impact Factor
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    ABSTRACT: The amyloid precursor protein (APP) and amyloid-β (Aβ) peptide play central roles in the pathology and etiology of Alzheimer's disease. Amyloid-induced impairments in neurogenesis have been investigated in several transgenic mouse models but the mechanism of action remains to be conclusively demonstrated. The changes in neurogenesis during this transition of increasing Aβ levels and plaque formation was investigated in the present study. We found that the proliferation of newborn cell in the dentate gyrus was enhanced prior to elevations in soluble Aβ production as well as amyloid deposition in 5 week-old TgCRND8 mice, which are well-established Alzheimer's disease models, compared to non-transgenic (Non-Tg) mice. The number of BrdU-positive cells remained higher in TgCRND8 vs Non-Tg mice for a period of 8 weeks. The numbers of BrdU/NeuN-positive cells were not significantly different in TgCRND8 compared to non-transgenic mice. A significant decrease in BrdU/GFAP but not in BrdU/S100β was found in Tg vs Non-Tg at 6 week-old age. In addition, a unique observation was made using isolated neuroprogenitor cells from TgCRND8 mice which were found to be less viable in culture and produced substantial amounts of secreted Aβ peptides. This suggests that the proliferation of neural progenitors in vivo may be modulated by high levels of APP expression and the resulting Aβ generated directly by the progenitor cells. These findings indicate that cell proliferation is increased prior to Aβ deposition and that cell viability is decreased in TgCRND8 mice over time.
    Neuroscience 12/2013; 261. DOI:10.1016/j.neuroscience.2013.12.021 · 3.33 Impact Factor

Publication Stats

26k Citations
3,765.94 Total Impact Points

Institutions

  • 2009–2015
    • University of Cambridge
      • Department of Clinical Neurosciences
      Cambridge, England, United Kingdom
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 1991–2015
    • University of Toronto
      • • Department of Medical Biophysics
      • • Tanz Centre for Research in Neurodegenerative Diseases
      • • Department of Medicine
      • • Hospital for Sick Children
      • • Division of Neurology
      Toronto, Ontario, Canada
  • 2013
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
  • 2012
    • University of Alberta
      • Centre for Prions and Protein Folding Diseases
      Edmonton, Alberta, Canada
  • 2002–2011
    • Toronto Western Hospital
      Toronto, Ontario, Canada
    • SickKids
      • Program in Genetics and Genome Biology
      Toronto, Ontario, Canada
    • University of Antwerp
      • VIB Department of Molecular Genetics
      Antwerpen, VLG, Belgium
    • Foundation Santa Lucia
      Roma, Latium, Italy
  • 2000–2011
    • Columbia University
      • • College of Physicians and Surgeons
      • • Taub Institute for Research on Alzheimer's Disease and the Aging Brain
      New York City, NY, United States
    • Hollywood Private Hospital
      Perth City, Western Australia, Australia
  • 2007
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1987–2007
    • University of Florence
      Florens, Tuscany, Italy
    • Massachusetts General Hospital
      • Neuroepigenetics Laboratory
      Boston, MA, United States
  • 2006
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2004–2006
    • French National Centre for Scientific Research
      • Institut de Pharmacologie Moléculaire et Cellulaire (IPMC)
      Paris, Ile-de-France, France
    • University of Texas at Dallas
      Richardson, Texas, United States
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2005
    • University of Ottawa
      Ottawa, Ontario, Canada
  • 2003
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2001
    • CUNY Graduate Center
      New York, New York, United States
    • University Health Network
      • Department of Medicine
      Toronto, Ontario, Canada
  • 1990
    • Medical Neurogenetics
      Atlanta, Georgia, United States
  • 1989
    • Boston University
      Boston, Massachusetts, United States
  • 1988
    • Harvard Medical School
      • Department of Genetics
      Boston, Massachusetts, United States