Genetic insights in Alzheimer's disease

In the search for new genes in Alzheimer's disease, classic linkage-based and candidate-gene-based association studies have been supplanted by exome sequencing, genome-wide sequencing (for mendelian forms of Alzheimer's disease), and genome-wide association studies (for non-mendelian forms). The identification of new susceptibility genes has opened new avenues for exploration of the underlying disease mechanisms. In addition to detecting novel risk factors in large samples, next-generation sequencing approaches can deliver novel insights with even small numbers of patients. The shift in focus towards translational studies and sequencing of individual patients places each patient's biomaterials as the central unit of genetic studies. The notional shift needed to make the patient central to genetic studies will necessitate strong collaboration and input from clinical neurologists.

[1]  D. Hernandez,et al.  Alzheimer Risk Variant CLU and Brain Function During Aging , 2013, Biological Psychiatry.

[2]  A. Goate,et al.  Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe , 2003, Human mutation.

[3]  R. Tanzi,et al.  Role of common and rare APP DNA sequence variants in Alzheimer disease , 2012, Neurology.

[4]  Hilkka Soininen,et al.  Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations , 2011, Neurobiology of Aging.

[5]  Lesley Jones,et al.  Genetic evidence for the involvement of lipid metabolism in Alzheimer's disease. , 2010, Biochimica et biophysica acta.

[6]  Eric M Reiman,et al.  Functional Links Between Aβ Toxicity, Endocytic Trafficking, and Alzheimer’s Disease Risk Factors in Yeast , 2011, Science.

[7]  S. Hunt,et al.  Amphiphysin heterodimers: potential role in clathrin-mediated endocytosis. , 1997, Molecular biology of the cell.

[8]  K. Sleegers,et al.  SORL1 is genetically associated with increased risk for late‐onset Alzheimer disease in the Belgian population , 2008, Human mutation.

[9]  A. Singleton,et al.  Repeat expansion in C9ORF72 in Alzheimer's disease. , 2012, The New England journal of medicine.

[10]  K. Lunetta,et al.  Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. , 2010, Archives of neurology.

[11]  M. Daly,et al.  Common SNPs in HMGCR in Micronesians and Whites Associated With LDL-Cholesterol Levels Affect Alternative Splicing of Exon13 , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[12]  P. Bosco,et al.  Erratum: Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease (Molecular Psychiatry (2013) 18 (521) DOI: 10.1038/mp.2012.75)) , 2013 .

[13]  S. Langdon,et al.  Structural organization of the human MS4A gene cluster on Chromosome 11q12 , 2001, Immunogenetics.

[14]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[15]  Michael Weiner,et al.  Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort , 2010, NeuroImage.

[16]  F. Jessen,et al.  Association of the Alzheimer's disease clusterin risk allele with plasma clusterin concentration. , 2011, Journal of Alzheimer's disease : JAD.

[17]  D. Campion,et al.  APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy , 2006, Nature Genetics.

[18]  D A Bennett,et al.  Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory , 2012, Neurology.

[19]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[20]  Thomas W. Mühleisen,et al.  Hippocampal Function in Healthy Carriers of the CLU Alzheimer's Disease Risk Variant , 2011, The Journal of Neuroscience.

[21]  J. Wiszniewska,et al.  Olfactory copy number association with age at onset of Alzheimer disease , 2011, Neurology.

[22]  J. Ioannidis,et al.  Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case–control study , 2011, The Lancet Neurology.

[23]  Michelle K. Lupton,et al.  Deep Sequencing of the Nicastrin Gene in Pooled DNA, the Identification of Genetic Variants That Affect Risk of Alzheimer's Disease , 2011, PloS one.

[24]  S. Potkin,et al.  Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort , 2010, Neurology.

[25]  C. Ferri,et al.  World Alzheimer Report 2009 , 2009 .

[26]  I. Walker,et al.  SP‐40,40, a protein involved in the control of the complement pathway, possesses a unique array of disulphide bridges , 1992, FEBS letters.

[27]  Alzheimer's Disease Neuroimaging Initiative,et al.  Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease , 2011, Molecular Psychiatry.

[28]  L. Tan,et al.  Complement receptor 1 polymorphisms and risk of late-onset Alzheimer's disease , 2010, Brain Research.

[29]  W. Wakarchuk,et al.  Distinct Endocytic Mechanisms of CD22 (Siglec-2) and Siglec-F Reflect Roles in Cell Signaling and Innate Immunity , 2007, Molecular and Cellular Biology.

[30]  I. Lieberburg,et al.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. , 1990, Science.

[31]  S. Bohlander,et al.  Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. , 1999, Molecular biology of the cell.

[32]  Margaret A. Pericak-Vance,et al.  Novel late-onset Alzheimer disease loci variants associate with brain gene expression , 2012, Neurology.

[33]  Eileen Daly,et al.  Proteome-based identification of plasma proteins associated with hippocampal metabolism in early Alzheimer’s disease , 2008, Journal of Neurology.

[34]  L. Farrer,et al.  Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community. , 2003, Human molecular genetics.

[35]  M Mancuso,et al.  Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease , 2012, Molecular Psychiatry.

[36]  Kristopher L. Nazor,et al.  Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells , 2012, Nature.

[37]  J. Shulman,et al.  Functional screening of Alzheimer pathology genome-wide association signals in Drosophila. , 2011, American journal of human genetics.

[38]  M. J. Fresnadillo Martínez,et al.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions , 2010, Nature Genetics.

[39]  K. Blennow,et al.  Clusterin in cerebrospinal fluid: Analysis of carbohydrates and quantification of native and glycosylated forms , 2006, Neurochemistry International.

[40]  B. Maher Personal genomes: The case of the missing heritability , 2008, Nature.

[41]  Guillén Fernández,et al.  CR1 genotype is associated with entorhinal cortex volume in young healthy adults , 2011, Neurobiology of Aging.

[42]  David B Goldstein,et al.  Genome-wide scan of copy number variation in late-onset Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[43]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[44]  G. Corthals,et al.  A Cortactin-CD2-associated Protein (CD2AP) Complex Provides a Novel Link between Epidermal Growth Factor Receptor Endocytosis and the Actin Cytoskeleton* , 2003, Journal of Biological Chemistry.

[45]  E. Ingelsson,et al.  Genome‐wide and gene‐based association implicates FRMD6 in alzheimer disease , 2012, Human mutation.

[46]  L. Hazrati,et al.  Genetic association of CR1 with Alzheimer's disease: A tentative disease mechanism , 2012, Neurobiology of Aging.

[47]  James T Becker,et al.  The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease , 2011, Genome Medicine.

[48]  Susan M Resnick,et al.  Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. , 2010, Archives of general psychiatry.

[49]  E. Lander,et al.  The mystery of missing heritability: Genetic interactions create phantom heritability , 2012, Proceedings of the National Academy of Sciences.

[50]  V. Pankratz,et al.  Replication of CLU, CR1, and PICALM associations with alzheimer disease. , 2010, Archives of neurology.

[51]  Hans Lehrach,et al.  The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. , 2011, Archives of general psychiatry.

[52]  Kewei Chen,et al.  Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. , 2010, Human molecular genetics.

[53]  S. Johnston,et al.  Neural hyperactivation in carriers of the Alzheimer's risk variant on the clusterin gene , 2011, European Neuropsychopharmacology.

[54]  F. Pasquier,et al.  Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites , 2011, Molecular Psychiatry.

[55]  B. Strooper,et al.  Presenilin clinical mutations can affect γ‐secretase activity by different mechanisms , 2006, Journal of neurochemistry.

[56]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[57]  Y. Pawitan,et al.  Strategies and issues in the detection of pathway enrichment in genome-wide association studies , 2009, Human Genetics.

[58]  P. S. St George-Hyslop,et al.  The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample. , 2002, American journal of human genetics.

[59]  G. Rouleau,et al.  A Mutation that Creates a Pseudoexon in SOD1 Causes Familial ALS , 2009, Annals of human genetics.

[60]  Jason J. Corneveaux,et al.  A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline. , 2012, Human molecular genetics.

[61]  M. Carrasquillo,et al.  Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus , 2012, Neurobiology of Aging.

[62]  F. Jessen,et al.  A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats , 2012, Human mutation.

[63]  Sonja W. Scholz,et al.  Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease , 2009, Nature Genetics.

[64]  P. S. St George-Hyslop,et al.  Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. , 2011, Archives of neurology.

[65]  P. Bosco,et al.  APOE and Alzheimer disease: a major gene with semi-dominant inheritance , 2011, Molecular Psychiatry.

[66]  G. Schellenberg,et al.  Genome-wide association reveals genetic effects on human Aβ42 and τ protein levels in cerebrospinal fluids: a case control study , 2010, BMC neurology.

[67]  David B Goldstein,et al.  Screening the human exome: a comparison of whole genome and whole transcriptome sequencing , 2010, Genome Biology.

[68]  C. Weickert,et al.  Role of ATP‐binding cassette transporters in brain lipid transport and neurological disease , 2008, Journal of neurochemistry.

[69]  Margaret A. Pericak-Vance,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease , 1997 .

[70]  Nick C Fox,et al.  Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease , 2009 .

[71]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[72]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[73]  P. S. St George-Hyslop,et al.  Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk , 2012, Molecular Neurodegeneration.

[74]  P. Linsel-Nitschke,et al.  ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages , 2006, The Journal of cell biology.

[75]  K. Sleegers,et al.  Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. , 2007, Archives of neurology.

[76]  C. van Broeckhoven,et al.  A novel presenilin 1 mutation associated with Pick's disease but not β‐amyloid plaques , 2004, Annals of neurology.

[77]  G. Schellenberg,et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus , 1995, Science.

[78]  B. Dubois,et al.  Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. , 1999, American journal of human genetics.

[79]  Albert Hofman,et al.  Plasma clusterin and the risk of Alzheimer disease. , 2011, JAMA.

[80]  Jason J. Corneveaux,et al.  CR1 is associated with amyloid plaque burden and age‐related cognitive decline , 2011, Annals of neurology.

[81]  Claudia Manzoni,et al.  A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis , 2009, Science.

[82]  D. Campion,et al.  APP locus duplication in a Finnish family with dementia and intracerebral haemorrhage , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[83]  Miguel Ángel Martínez,et al.  Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex. , 1997, American journal of human genetics.

[84]  Nick C Fox,et al.  Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease , 2011, Nature Genetics.

[85]  Sudha Seshadri,et al.  Genome-wide analysis of genetic loci associated with Alzheimer disease. , 2010, JAMA.

[86]  S. DeKosky,et al.  Association of CLU and PICALM variants with Alzheimer's disease , 2012, Neurobiology of Aging.

[87]  M. Mattson,et al.  Evidence for CALM in Directing VAMP2 Trafficking , 2008, Traffic.

[88]  J. Rommens,et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene , 1995, Nature.

[89]  K. Sleegers,et al.  Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. , 2006, American journal of human genetics.

[90]  K. Sleegers,et al.  APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. , 2006, Brain : a journal of neurology.

[91]  Nick C Fox,et al.  Genetic Variability in CLU and Its Association with Alzheimer's Disease , 2010, PloS one.

[92]  Hugo Vanderstichele,et al.  Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein , 1998, Nature.

[93]  Yasuyoshi Watanabe,et al.  A new amyloid β variant favoring oligomerization in Alzheimer's‐type dementia , 2008, Annals of neurology.

[94]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[95]  J. Haines,et al.  Identification and Confirmation of an Exonic Splicing Enhancer Variation in Exon 5 of the Alzheimer Disease Associated PICALM Gene , 2012, Annals of human genetics.

[96]  Olle Melander,et al.  From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus , 2010, Nature.

[97]  Margaret A. Pericak-Vance,et al.  Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants , 2012, PLoS genetics.

[98]  M. Nalls,et al.  Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer’s disease , 2009, neurogenetics.

[99]  F. Marrosu,et al.  C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population , 2012, Neurobiology of Aging.

[100]  N. Jahanshad,et al.  Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults , 2011, The Journal of Neuroscience.

[101]  C. van Broeckhoven,et al.  Mean age‐of‐onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40 , 2006, Human mutation.

[102]  R. Khera,et al.  Complement Receptor 1: Disease associations and therapeutic implications , 2008, Molecular Immunology.

[103]  K. Sleegers,et al.  Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease , 2008, Neurology.

[104]  K. Lunetta,et al.  The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease , 2007, Nature Genetics.

[105]  E. Wijsman,et al.  Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE , 2011, PLoS genetics.

[106]  Nick C Fox,et al.  Clinical and biomarker changes in dominantly inherited Alzheimer's disease. , 2012, The New England journal of medicine.

[107]  A. Fagan,et al.  Fine Mapping of Genetic Variants in BIN1, CLU, CR1 and PICALM for Association with Cerebrospinal Fluid Biomarkers for Alzheimer's Disease , 2011, PloS one.

[108]  A. Singleton,et al.  Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease , 2012, Neurobiology of Aging.

[109]  Sandro Sorbi,et al.  Meta-analysis of the association between variants in SORL1 and Alzheimer disease. , 2011, Archives of neurology.

[110]  H. Okano,et al.  Modeling familial Alzheimer's disease with induced pluripotent stem cells. , 2011, Human molecular genetics.

[111]  S. Bassett,et al.  Alzheimer's risk variants in the clusterin gene are associated with alternative splicing , 2011, Translational Psychiatry.

[112]  Marisa O. Hollinshead,et al.  Identification of common variants associated with human hippocampal and intracranial volumes , 2012, Nature Genetics.

[113]  A. A. Romanovsky,et al.  Putative dual role of ephrin‐Eph receptor interactions in inflammation , 2006, IUBMB life.

[114]  D. G. Clark,et al.  Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease , 2011, Nature Genetics.

[115]  B Croisile,et al.  High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease , 2012, Molecular Psychiatry.

[116]  V. Pankratz,et al.  Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study , 2011, Molecular Neurodegeneration.

[117]  T. Suuronen,et al.  Clusterin: A forgotten player in Alzheimer's disease , 2009, Brain Research Reviews.

[118]  N. Matsumoto,et al.  Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[119]  Holly Soares,et al.  Meta-Analysis for Genome-Wide Association Study Identifies Multiple Variants at the BIN1 Locus Associated with Late-Onset Alzheimer's Disease , 2011, PloS one.

[120]  Ole A. Andreassen,et al.  A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline , 2012, Nature.

[121]  A. Hofman,et al.  Serum clusterin levels are not increased in presymptomatic Alzheimer's disease. , 2011, Journal of proteome research.

[122]  J. Haines,et al.  Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis , 1997 .

[123]  L. Kiemeney,et al.  Corrigendum: Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer , 2009, Nature Genetics.

[124]  Nick C Fox,et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes , 2009, Nature Genetics.

[125]  D. G. Ferguson,et al.  A 70-kDa apolipoprotein designated ApoJ is a marker for subclasses of human plasma high density lipoproteins. , 1990, The Journal of biological chemistry.

[126]  Mert Sabuncu,et al.  Genetic variation and neuroimaging measures in Alzheimer disease. , 2010, Archives of neurology.

[127]  D. Drachman,et al.  Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia , 2007, Clinical genetics.

[128]  Michelle K. Lupton,et al.  No evidence that extended tracts of homozygosity are associated with Alzheimer's disease , 2011, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[129]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[130]  Yusuke Nakamura,et al.  Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease , 2009, Nature Genetics.

[131]  Simon Heath,et al.  Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis. , 2010, Journal of Alzheimer's disease : JAD.

[132]  H. Haapasalo,et al.  CLU, CR1 and PICALM genes associate with Alzheimer's-related senile plaques , 2011, Alzheimer's Research & Therapy.

[133]  L. Fratiglioni,et al.  Role of genes and environments for explaining Alzheimer disease. , 2006, Archives of general psychiatry.