The genetics of Alzheimer’s disease

Alzheimer’s disease (AD) is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age), or late onset (over 65 years of age). Three main genes are involved in early onset AD: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). The apolipoprotein E (APOE) E4 allele has been found to be a main risk factor for late-onset Alzheimer’s disease. Additionally, genome-wide association studies (GWASs) have identified several genes that might be potential risk factors for AD, including clusterin (CLU), complement receptor 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM), and sortilin-related receptor (SORL1). Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2) and cluster of differentiation 33 (CD33). Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.

[1]  B. Crain,et al.  Ectopic White Matter Neurons, a Developmental Abnormality That May Be Caused by the PSEN1 S169L Mutation in a Case of Familial AD with Myoclonus and Seizures , 2001, Journal of neuropathology and experimental neurology.

[2]  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.

[3]  J. Aharon-Peretz,et al.  Germline mutational analysis of presenilin 1 and APP genes in Jewish-Israeli individuals with familial or early-onset Alzheimer disease using denaturing gradient gel electrophoresis (DGGE) , 1998, European Journal of Human Genetics.

[4]  R. Nitsch,et al.  High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. , 2000, American journal of human genetics.

[5]  A. Myers,et al.  Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease , 2007, Proceedings of the National Academy of Sciences.

[6]  M. Marra,et al.  Applications of next-generation sequencing technologies in functional genomics. , 2008, Genomics.

[7]  G. Schellenberg,et al.  A pedigree with a novel presenilin 1 mutation at a residue that is not conserved in presenilin 2. , 1999, Archives of neurology.

[8]  P. Aisen,et al.  Moving towards early clinical trials for amyloid-targeted therapy in Alzheimer's disease , 2013, Nature Reviews Drug Discovery.

[9]  K. Sleegers,et al.  Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. , 2004, Brain : a journal of neurology.

[10]  D. Selkoe,et al.  Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity , 1999, Nature.

[11]  P. S. St George-Hyslop,et al.  A presenilin‐1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI , 1997, Neurology.

[12]  E. Storey,et al.  Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene. , 1999, Neuroreport.

[13]  S. Sorbi,et al.  Genetic risk factors in familial Alzheimer's disease , 2001, Mechanisms of Ageing and Development.

[14]  J. Hardy,et al.  Two novel (M233T and ρ278T) presenilin‐1 mutations in early‐onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin‐1 mutations with a novel phenotype , 1997, Neuroreport.

[15]  L. Thal,et al.  Early‐onset Alzheimer's disease with a presenilin‐1 mutation at the site corresponding to the volga German presenilin‐2 mutation , 1997, Annals of neurology.

[16]  J. Hardy,et al.  Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene , 1991, Nature.

[17]  D. Mann.  Alzheimer's disease and Down's syndrome , 1988, Histopathology.

[18]  Francesco Vallania,et al.  High-throughput discovery of rare insertions and deletions in large cohorts. , 2010, Genome research.

[19]  Oscar L Lopez,et al.  Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. , 2013, JAMA.

[20]  D. Na,et al.  Identification of PSEN1 and APP Gene Mutations in Korean Patients with Early-Onset Alzheimer's Disease , 2008, Journal of Korean medical science.

[21]  L. Lannfelt,et al.  Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin-1 gene. , 1998, Archives of Neurology.

[22]  Clinical and genetic analysis of a pedigree of a thirty-six-year-old Familial Alzheimer's disease patient , 1997, Biological Psychiatry.

[23]  Nick C Fox,et al.  Early onset familial Alzheimer’s disease: Mutation frequency in 31 families , 2002 .

[24]  G. Schellenberg,et al.  APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease. , 1991, American journal of human genetics.

[25]  P. J. Caballero,et al.  A novel presenilin 1 mutation (V261L) associated with presenile Alzheimer's disease and spastic paraparesis. , 2008 .

[26]  Mark T. W. Ebbert,et al.  Genetics of Alzheimer's Disease , 2013, BioMed research international.

[27]  P. Scheltens.  Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer’s disease , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[28]  B. Tang,et al.  A novel presenilin 1 mutation (Ser169del) in a Chinese family with early-onset Alzheimer's disease , 2010, Neuroscience Letters.

[29]  V. La Bella,et al.  A novel mutation (Thr116Ile) in the presenilin 1 gene in a patient with early‐onset Alzheimer's disease , 2004, European journal of neurology.

[30]  Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer’s disease , 2007 .

[31]  J. Hardy,et al.  A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[32]  T. Ogihara,et al.  Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families , 1996, Neuroscience Letters.

[33]  A. Robles,et al.  Clinical Picture of a Patient With a Novel PSEN1 Mutation (L424V) , 2009, American Journal of Alzheimers Disease & Other Dementias.

[34]  J. Buxbaum,et al.  A novel Polish presenilin‐1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years , 1998, NeuroReport.

[35]  Richard J. Caselli,et al.  Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers , 2011, NeuroImage.

[36]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[37]  F. Tagliavini,et al.  A novel PSEN2 mutation associated with a peculiar phenotype , 2008, Neurology.

[38]  P. S. St George-Hyslop,et al.  Novel PS1 Mutation in a Bavarian Kindred With Familial Alzheimer Disease , 2004, Alzheimer disease and associated disorders.

[39]  M. Colonna,et al.  The TREM receptor family and signal integration , 2006, Nature Immunology.

[40]  Miguel Ángel Martínez,et al.  De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. , 1998, Journal of medical genetics.

[41]  J. Molinuevo,et al.  A novel PSEN1 mutation (K239N) associated with Alzheimer’s disease with wide range age of onset and slow progression , 2010, European journal of neurology.

[42]  B. Winblad,et al.  A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid , 1992, Nature Genetics.

[43]  C. van Broeckhoven,et al.  Novel PSEN1 Mutation in a Bulgarian Patient With Very Early-Onset Alzheimer’s Disease, Spastic Paraparesis, and Extrapyramidal Signs , 2009, American journal of Alzheimer's disease and other dementias.

[44]  A. Singleton,et al.  Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP , 2010, Neurobiology of Aging.

[45]  T. Tabira,et al.  Alzheimer's disease with spastic paresis and cotton wool type plaques , 2002, Journal of neuroscience research.

[46]  C. Duyckaerts,et al.  Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques , 2006, Human mutation.

[47]  M. Cruts,et al.  Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. , 1995, Human molecular genetics.

[48]  Jun Wang,et al.  Recent Patents and Advances in the Next-Generation Sequencing Technologies. , 2008, Recent patents on biomedical engineering.

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

[50]  Huaxi Xu,et al.  Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy , 2013, Nature Reviews Neurology.

[51]  Sandro Sorbi,et al.  Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. , 2003, Archives of neurology.

[52]  K. Kohara,et al.  Molecular evidence of presenilin 1 mutation in familial early onset dementia. , 2002, American journal of medical genetics.

[53]  S V Faraone,et al.  Genetics of Alzheimer's disease. , 1996, Journal of the Formosan Medical Association = Taiwan yi zhi.

[54]  James B Leverenz,et al.  Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. , 2010, Brain : a journal of neurology.

[55]  J. Aharon-Peretz,et al.  A novel mutation of presenilin 1 in familial Alzheimer’s disease in Israel detected by denaturing gradient gel electrophoresis , 1996, Human Genetics.

[56]  P. S. St George-Hyslop,et al.  Association between SORL1 and Alzheimer's disease in a genome-wide study , 2007, Neuroreport.

[57]  J. Durocher,et al.  Mutation detection using Surveyor nuclease. , 2004, BioTechniques.

[58]  J. Wegiel,et al.  A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117 (Pro117Ser): Comparison of clinical, neuropathological and cell culture phenotypes of Pro117Leu and Pro117Ser mutations. , 2004, Journal of Alzheimer's disease : JAD.

[59]  J. Collinge,et al.  Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. , 2004, Human molecular genetics.

[60]  A Hofman,et al.  Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. , 1998, Human molecular genetics.

[61]  F. Mottaghy,et al.  A novel presenilin1 mutation (Q223R) associated with early onset Alzheimer’s disease, dysarthria and spastic paraparesis and decreased Abeta levels in CSF , 2010, European journal of neurology.

[62]  J. Kira,et al.  A novel mutation (L250V) in the presenilin 1 gene in a Japanese familial Alzheimer's disease with myoclonus and generalized convulsion , 2003, Journal of the Neurological Sciences.

[63]  J. Haines,et al.  Assessment of amyloid beta-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases. , 1992, American journal of human genetics.

[64]  B. Rihn,et al.  APOE genotyping: comparison of three methods , 2009, Clinical and Experimental Medicine.

[65]  S. Yokoyama,et al.  Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. , 2011, Journal of atherosclerosis and thrombosis.

[66]  D. Campion,et al.  Ataxic variant of Alzheimer’s disease caused by Pro117Ala PSEN1 mutation , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[67]  L. Bertram,et al.  Towards unveiling the genetics of neurodegenerative diseases. , 2011, Seminars in neurology.

[68]  A. Tamaoka,et al.  Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy , 2000, Journal of neurology, neurosurgery, and psychiatry.

[69]  David M Holtzman,et al.  Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. , 2011, Archives of neurology.

[70]  J. Molinuevo,et al.  A novel mutation in the PSEN1 gene (L286P) associated with familial early‐onset dementia of Alzheimer type and lobar haematomas , 2007, European journal of neurology.

[71]  Akihiko Takashima,et al.  Presenilin-1 Mutation L271V Results in Altered Exon 8 Splicing and Alzheimer's Disease with Non-cored Plaques and No Neuritic Dystrophy* , 2003, The Journal of Biological Chemistry.

[72]  Jason J. Corneveaux,et al.  Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci , 2013, Annals of human genetics.

[73]  Lars Lannfelt,et al.  A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease , 1997, Neuroscience Letters.

[74]  D. Campion,et al.  Molecular diagnosis of autosomal dominant early onset Alzheimer’s disease: an update , 2005, Journal of Medical Genetics.

[75]  Thomas W. Mühleisen,et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease , 2013, Nature Genetics.

[76]  J. Hardy,et al.  An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala). , 2002, Neurology.

[77]  Su Jeong Park,et al.  Apolipoprotein E genotyping by multiplex tetra-primer amplification refractory mutation system PCR in single reaction tube. , 2007, Journal of biotechnology.

[78]  E. Wijsman,et al.  Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. , 1992, American journal of human genetics.

[79]  Xia Lin,et al.  A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer’s disease and spastic paraparesis , 2007, Journal of the Neurological Sciences.

[80]  P. Deyn,et al.  DNMBP is genetically associated with Alzheimer dementia in the Belgian population , 2009, Neurobiology of Aging.

[81]  Sheng-Di Chen 陈生弟,et al.  The Gab2 in signal transduction and its potential role in the pathogenesis of Alzheimer’s disease , 2010, Neuroscience Bulletin.

[82]  H. Mori,et al.  A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis. , 2004, Archives of neurology.

[83]  Jennifer Williamson,et al.  Genetic Aspects of Alzheimer Disease , 2009, The neurologist.

[84]  J. Jia,et al.  Chinese Presenilin-1 V97L mutation enhanced Aβ42 levels in SH-SY5Y neuroblastoma cells , 2006, Neuroscience Letters.

[85]  Nick C Fox,et al.  Early onset familial Alzheimer’s disease , 2002, Neurology.

[86]  R. Nitsch,et al.  Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I , 2000, Neurology.

[87]  B. Reed,et al.  Very early‐onset familial Alzheimer's disease: a novel presenilin 1 mutation , 2002, International journal of geriatric psychiatry.

[88]  A. Crump.  Alzheimer’s Disease in the UK , 1999 .

[89]  M. Daly,et al.  Variant TREM2 as risk factor for Alzheimer's disease. , 2013, The New England journal of medicine.

[90]  U. Schreiter-Gasser,et al.  Identification and differential expression of a novel alternative splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells. , 1992, The Journal of biological chemistry.

[91]  Cornelia M van Duijn,et al.  Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric. , 2002, The American journal of pathology.

[92]  C. Ki,et al.  Presenilin 1 gene mutation (M139I) in a patient with an early-onset Alzheimer’s disease: clinical characteristics and genetic identification , 2010, Neurological Sciences.

[93]  W. März,et al.  Evaluation of the apo E genotyping kit on the LightCycler. , 2000, Clinical chemistry.

[94]  G. Schellenberg,et al.  The Clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients , 1996, Annals of neurology.

[95]  R. Tanzi.  The genetics of Alzheimer disease. , 2012, Cold Spring Harbor perspectives in medicine.

[96]  B. Ghetti,et al.  A novel mutation (G217D) in the Presenilin 1 gene (PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum , 2002, Acta Neuropathologica.

[97]  G. Small,et al.  Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation , 2011, Neuroscience Letters.

[98]  S. Younkin,et al.  Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. , 2003, Human molecular genetics.

[99]  D. Y. Lee,et al.  Association between apolipoprotein E polymorphism and Alzheimer's disease in Koreans , 1999, Neuroscience Letters.

[100]  Robert Cook-Deegan,et al.  Disclosure of APOE genotype for risk of Alzheimer's disease. , 2009, The New England journal of medicine.

[101]  B. Strooper,et al.  Pathogenic APP mutations near the γ-secretase cleavage site differentially affect Aβ secretion and APP C-terminal fragment stability , 2001 .

[102]  J. Hauw,et al.  Very early onset AD with a de novo mutation in the presenilin 1 gene (Met 233 Leu) , 2003, Neurology.

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

[104]  A. Miyashita,et al.  Mutational Analysis in Early-Onset Familial Dementia in the Japanese Population , 2008, Dementia and Geriatric Cognitive Disorders.

[105]  J. Growdon,et al.  Familial Alzheimer's chromosome 14 mutations , 1995, Nature Medicine.

[106]  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.

[107]  G. Lenzi,et al.  A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[108]  Christine Van Broeckhoven,et al.  Molecular genetics of Alzheimer's disease: An update , 2008, Annals of medicine.

[109]  M. Yamada,et al.  Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile) , 2001, Journal of neurology, neurosurgery, and psychiatry.

[110]  A. Goate,et al.  PRESENILIN1 G217R MUTATION LINKED TO ALZHEIMER DISEASE WITH COTTON WOOL PLAQUES , 2009, Neurology.

[111]  R. Mahley,et al.  Apolipoprotein E: far more than a lipid transport protein. , 2000, Annual review of genomics and human genetics.

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

[113]  K. Nakashima,et al.  A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis , 2004, Neuroscience Letters.

[114]  I. Andrulis,et al.  Functional characterization of novel presenilin-2 variants identified in human breast cancers , 2006, Oncogene.

[115]  J. Hardy,et al.  A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis , 2007, Neuropathology : official journal of the Japanese Society of Neuropathology.

[116]  Roger N Rosenberg,et al.  Genome-wide association studies in Alzheimer disease. , 2008, Archives of neurology.

[117]  Nick C Fox,et al.  A presenilin 1 R278I mutation presenting with language impairment , 2004, Neurology.

[118]  Keith A. Johnson,et al.  CD33 Alzheimer’s disease locus: Altered monocyte function and amyloid biology , 2013, Nature Neuroscience.

[119]  Kyoko Suzuki,et al.  A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease , 1999, Human mutation.

[120]  A. Miyashita,et al.  Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation , 2009, Journal of Neurology.

[121]  J. Hardy,et al.  A presenilin-1 mutation (T245P) in transmembrane domain 6 causes early onset Alzheimer's disease , 2006, Neuroscience Letters.

[122]  B. de Strooper,et al.  Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. , 2001, Human molecular genetics.

[123]  A. Miyashita,et al.  A mutant PSEN1 causes dementia with lewy bodies and variant Alzheimer's disease , 2005, Annals of neurology.

[124]  K. Hayashi,et al.  PCR-SSCP: a simple and sensitive method for detection of mutations in the genomic DNA. , 1991, PCR methods and applications.

[125]  D. Campion,et al.  Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation , 2000, Neurology.

[126]  A. Hofman,et al.  Variant of TREM2 associated with the risk of Alzheimer's disease. , 2013, The New England journal of medicine.

[127]  J. Hardy,et al.  A new presenilin Alzheimer’s disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5 , 2004, Neuroscience Letters.

[128]  K. Elliott,et al.  Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity. , 2009, Human molecular genetics.

[129]  R. Mahley,et al.  Apolipoprotein (apo) E4 and Alzheimer's disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology , 2006, Acta neurologica Scandinavica. Supplementum.

[130]  Shinobu Tanaka,et al.  Surveyor nuclease-based genotyping of SNPs. , 2006, Clinical laboratory.

[131]  C. van Broeckhoven,et al.  Genetics of Early-Onset Alzheimer Dementia , 2003, TheScientificWorldJournal.

[132]  M. Rossor,et al.  A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer's disease , 2007, European journal of neurology.

[133]  B. Dubois,et al.  Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. , 1995, Human molecular genetics.

[134]  R. Tanzi,et al.  The genetic epidemiology of neurodegenerative disease. , 2005, The Journal of clinical investigation.

[135]  T. Iwatsubo,et al.  Clinical and biomarker investigation of a patient with a novel presenilin-1 mutation (A431V) in the mild cognitive impairment stage of Alzheimer’s Disease , 2002, Biological Psychiatry.

[136]  C. van Broeckhoven,et al.  Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. , 2001, American journal of medical genetics.

[137]  B. Strooper,et al.  Alzheimer dementia caused by a novel mutation located in the APP C‐terminal intracytosolic fragment , 2006, Human mutation.

[138]  Jungeun Kim,et al.  A novel PSEN1 H163P mutation in a patient with early-onset Alzheimer's disease: Clinical, neuroimaging, and neuropathological findings , 2012, Neuroscience Letters.

[139]  G. Damonte,et al.  Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. , 2007, Archives of neurology.

[140]  Guojun Bu,et al.  Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy , 2009, Nature Reviews Neuroscience.

[141]  F. Tagliavini,et al.  A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features. , 2011, Journal of Alzheimer's disease : JAD.

[142]  R. Mahley,et al.  Alzheimer disease: Multiple causes, multiple effects of apolipoprotein E4, and multiple therapeutic approaches , 2009, Annals of neurology.

[143]  L. Fernández-Novoa,et al.  A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease , 1998, Neurogenetics.

[144]  A Rostagno,et al.  Apolipoprotein J (clusterin) and Alzheimer's disease , 2000, Microscopy research and technique.

[145]  B. Ghetti,et al.  Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. , 2000, Archives of neurology.

[146]  J. Kril,et al.  Understanding the pathogenesis of Alzheimer’s disease: will RNA‐Seq realize the promise of transcriptomics? , 2011, Journal of neurochemistry.

[147]  T. Sekiya,et al.  Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[148]  Winnie S. Liang,et al.  GAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers , 2007, Neuron.

[149]  M. Wilkins,et al.  Whole Transcriptome Sequencing Reveals Gene Expression and Splicing Differences in Brain Regions Affected by Alzheimer's Disease , 2011, PloS one.

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

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

[152]  A. Paetau,et al.  Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS‐1 mutations that lead to exceptionally high amyloid‐β concentrations , 2000, Annals of neurology.

[153]  T. Iwatsubo,et al.  Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer’s disease , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[154]  J. Molinuevo,et al.  Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. , 2002, Archives of neurology.

[155]  M. Cruts,et al.  Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. , 2001, Brain : a journal of neurology.

[156]  C. Masters,et al.  Novel Leu723Pro amyloid precursor protein mutation increases amyloid β42(43) peptide levels and induces apoptosis , 2000, Annals of neurology.

[157]  D. Munoz,et al.  Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. , 2010, Journal of Alzheimer's disease : JAD.

[158]  Rebecca F. Halperin,et al.  A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. , 2007, The Journal of clinical psychiatry.

[159]  Marc Cruts,et al.  Locus-Specific Mutation Databases for Neurodegenerative Brain Diseases , 2012, Human mutation.

[160]  You-Qiang Song,et al.  Screening for PS1 mutations in a referral-based series of AD cases , 2001, Neurology.

[161]  M. Anagnostouli,et al.  Novel mutations and repeated findings of mutations in familial Alzheimer disease , 2005, Neurogenetics.

[162]  V. Procaccio,et al.  Surveyor™ Nuclease: A new strategy for a rapid identification of heteroplasmic mitochondrial DNA mutations in patients with respiratory chain defects , 2005, Human mutation.

[163]  P. Pástor,et al.  A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer’s disease , 2001, Neurology.

[164]  R. Mahley,et al.  Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[165]  G. Schellenberg,et al.  Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene , 1998, Human mutation.

[166]  R. Dukoff,et al.  Quantitative assessment of apolipoprotein E genotypes by image analysis of PCR-RFLP fragments. , 2000, Clinica chimica acta; international journal of clinical chemistry.

[167]  M. Adams,et al.  Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease , 1996, Neuroreport.

[168]  Takashi Asada,et al.  Familial Alzheimer's disease genes in Japanese , 1998, Journal of the Neurological Sciences.

[169]  M. Barcikowska,et al.  Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: Genetic and bioinformatic assessment , 2006, Experimental Neurology.

[170]  R. Guerreiro,et al.  Complement receptor 1 (CR1) and Alzheimer's disease. , 2012, Immunobiology.

[171]  R. Mayeux,et al.  Use of Genetic Variation as Biomarkers for Alzheimer's Disease , 2009, Annals of the New York Academy of Sciences.

[172]  A. Singleton,et al.  TREM2 Variants in Alz hei mer's Disease , 2012 .

[173]  W. Kozubski,et al.  Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. , 2003, Journal of applied genetics.

[174]  C. van Broeckhoven,et al.  The presenilin genes: a new gene family involved in Alzheimer disease pathology. , 1996, Human molecular genetics.

[175]  M. Tabaton,et al.  Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation , 2003, Neurology.

[176]  R. Kuwano,et al.  A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease , 2009, Journal of Neurology.

[177]  R. J. Dolan,et al.  A novel presenilin mutation (M233V) causing very early onset Alzheimer's disease with Lewy bodies , 2001, Neuroscience Letters.

[178]  A. Hofman,et al.  Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). , 2000, Brain : a journal of neurology.

[179]  A. Pfeffer,et al.  Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland , 2003, Experimental Neurology.

[180]  B. Ghetti,et al.  Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[181]  Winnie S. Liang,et al.  GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. , 2007, Neuron.

[182]  C. Chien,et al.  Novel polymorphisms of the amyloid precursor protein (APP) gene in Chinese/Taiwanese patients with Alzheimer’s disease , 2009, Journal of Clinical Neuroscience.

[183]  J. Hardy,et al.  Variant Alzheimer’s disease with spastic paraparesis , 2000, Neurology.

[184]  K S Kosik,et al.  Public attitudes about genetic testing for Alzheimer's disease. , 2001, Health affairs.

[185]  M. Farrer,et al.  Molecular mapping of alzheimer‐type dementia in Down's syndrome , 1998, Annals of neurology.

[186]  M. Tabaton,et al.  A novel presenilin 1 L166H mutation in a pseudo-sporadic case of early-onset Alzheimer’s disease , 2005, Neurological Sciences.

[187]  R. Martins,et al.  Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer’s disease , 2003, Neurobiology of Aging.

[188]  Christine Van Broeckhoven,et al.  Genetic insights in Alzheimer's disease , 2013, The Lancet Neurology.

[189]  Nilüfer Ertekin-Taner,et al.  Genetics of Alzheimer's disease: a centennial review. , 2007, Neurologic clinics.

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

[191]  A. Goate,et al.  Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort , 2012, Alzheimer's Research & Therapy.

[192]  Qingli Xiao,et al.  Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis* , 2012, The Journal of Biological Chemistry.

[193]  T. Ogihara,et al.  The 717Val----Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. , 1991, Biochemical and biophysical research communications.

[194]  J. Meyer,et al.  Multiple threshold model for the onset of Alzheimer's disease in the NAS-NRC twin panel. , 1998, American journal of medical genetics.

[195]  J. Bähler,et al.  Next-generation sequencing: applications beyond genomes , 2008, Biochemical Society transactions.

[196]  I. Kanazawa,et al.  Genetic association of CTNNA3 with late-onset Alzheimer's disease in females. , 2007, Human molecular genetics.

[197]  R. Blesa,et al.  A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances , 2002, Journal of neurology, neurosurgery, and psychiatry.

[198]  M. Bullido,et al.  DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin‐1 gene: Two novel mutations , 1999, Human mutation.

[199]  Y. Ikejiri,et al.  A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy , 1997, Neuroscience Letters.