title: Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease.
abstract: We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Crook
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Otto
authors.initials: O
authors.lastname: Pedraza
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Colleen S
authors.initials: CS
authors.lastname: Thomas
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Malphrus
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Gina D
authors.initials: GD
authors.lastname: Bisceglio
authors.affiliation: Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rosebud O
authors.initials: RO
authors.lastname: Roberts
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Lucas
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Smith
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ivnik
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Machulda
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. Electronic address: taner.nilufer@mayo.edu.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000523:psychology*; D053327:Apolipoprotein E4 / Q000235:genetics; D051152:Clusterin / Q000235:genetics; D060825:Cognitive Dysfunction / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology*; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008568:Memory; D008875:Middle Aged; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics; D036082:Receptor, EphA1 / Q000235:genetics; D012306:Risk; D044465:White People
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; D053327:Apolipoprotein E4; C495242:CLU protein, human; D051152:Clusterin; C574492:MS4A6A protein, human; D008565:Membrane Proteins; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D036082:Receptor, EphA1
keywords: Alzheimer's disease; Association; Cognitive decline; Genetic risk; Memory; Mild cognitive impairment