title: APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease.
abstract: Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (β=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10(-8), PFDR=2.48 × 10(-3)). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95% CI: 4.45-12.01, P=3.84 × 10(-5)). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: J I
authors.initials: JI
authors.lastname: Vélez
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: F
authors.initials: F
authors.lastname: Lopera
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.|Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Sepulveda-Falla
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: H R
authors.initials: HR
authors.lastname: Patel
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: A S
authors.initials: AS
authors.lastname: Johar
authors.affiliation: Genome Discovery Unit, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Chuah
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: C
authors.initials: C
authors.lastname: Tobón
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: D
authors.initials: D
authors.lastname: Rivera
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: A
authors.initials: A
authors.lastname: Villegas
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Biomolecular Resource Facility, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Peng
authors.affiliation: Early Mammalian Development Laboratory, Research School of Biology, The Australian National University, Canberra, ACT, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Arkell
authors.affiliation: NYU Child Study Center, NYU Langone Medical Center, New York, NY, USA.|Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: F X
authors.initials: FX
authors.lastname: Castellanos
authors.affiliation: Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Andrews
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: M F
authors.initials: MF
authors.lastname: Silva Lara
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: P K
authors.initials: PK
authors.lastname: Creagh
authors.affiliation: Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Easteal
authors.affiliation: Mental Health Research Center at Eastern State Hospital, University of Kentucky, Lexington, KY, USA.
authors.forename: J
authors.initials: J
authors.lastname: de Leon
authors.affiliation: South Australian Health and Medical Research Institute and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Wong
authors.affiliation: South Australian Health and Medical Research Institute and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Licinio
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|South Australian Health and Medical Research Institute and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia.
authors.forename: C A
authors.initials: CA
authors.lastname: Mastronardi
authors.affiliation: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.|Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: M
authors.initials: M
authors.lastname: Arcos-Burgos
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053329:Apolipoprotein E2 / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053329:Apolipoprotein E2; D001057:Apolipoproteins E; C508853:PSEN1 protein, human; D053764:Presenilin-1