title: Genomics of Alzheimer Disease: A Review.
abstract: OBJECTIVE
  To provide a comprehensive review of knowledge of the genomics of Alzheimer disease (AD) and DNA amyloid β 42 (Aβ42) vaccination as a potential therapy.
  
  
  METHODS
  Genotype-phenotype correlations of AD are presented to provide a comprehensive appreciation of the spectrum of disease causation. Alzheimer disease is caused in part by the overproduction and lack of clearance of Aβ protein. Oligomer Aβ, the most toxic species of Aβ, causes direct injury to neurons, accompanied by enhanced neuroinflammation, astrocytosis and gliosis, and eventually neuronal loss. The strongest genetic evidence supporting this hypothesis derives from mutations in the amyloid precursor protein (APP) gene. A detrimental APP mutation at the β-secretase cleavage site linked to early-onset AD found in a Swedish pedigree enhances Aβ production, in contrast to a beneficial mutation 2 residues away in APP that reduces Aβ production and protects against the onset of sporadic AD. A number of common variants associated with late-onset AD have been identified including apolipoprotein E, BIN1, ABC7, PICALM, MS4A4E/MS4A6A, CD2Ap, CD33, EPHA1, CLU, CR1, and SORL1. One or 2 copies of the apolipoprotein E ε4 allele are a major risk factor for late-onset AD. With DNA Aβ42 vaccination, a Th2-type noninflammatory immune response was achieved with a downregulation of Aβ42-specific effector (Th1, Th17, and Th2) cell responses at later immunization times. DNA Aβ42 vaccination upregulated T regulator cells (CD4+, CD25+, and FoxP3+) and its cytokine interleukin 10, resulting in downregulation of T effectors.
  
  
  CONCLUSIONS
  Mutations in APP and PS-1 and PS-2 genes that are associated with early-onset, autosomal, dominantly inherited AD, in addition to the at-risk gene polymorphisms responsible for late-onset AD, all indicate a direct and early role of Aβ in the pathogenesis of AD. A translational result of genomic research has been Aβ-reducing therapies including DNA Aβ42 vaccination as a promising approach to delay or prevent this disease.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas2Editor, JAMA Neurology.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Rosenberg
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Doris
authors.initials: D
authors.lastname: Lambracht-Washington
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Geriatric Research, Education and Clinical Center, Bedford Veterans Hospital, Bedford, Massachusetts5Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Weiming
authors.initials: W
authors.lastname: Xia
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42)