title: Executive function changes before memory in preclinical Alzheimer's pathology: a prospective, cross-sectional, case control study.
abstract: BACKGROUND
  Early treatment of Alzheimer's disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer's disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology.
  
  
  RESULTS
  We recruited adults with probable Alzheimer's disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer's disease. We separated the asymptomatic group into those with (n = 34; preclinical Alzheimer's disease) and without (n = 36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-ε genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR = 0.13, 95% CI = 0.04-0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study.
  
  
  CONCLUSIONS
  Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer's disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach.
authors.affiliation: Molecular Neurology Program, Huntington Medical Research Institutes, Pasadena, California, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Harrington
authors.forename: Jiarong
authors.initials: J
authors.lastname: Chiang
authors.forename: Janice M
authors.initials: JM
authors.lastname: Pogoda
authors.forename: Megan
authors.initials: M
authors.lastname: Gomez
authors.forename: Kris
authors.initials: K
authors.lastname: Thomas
authors.forename: Sarah Deboard
authors.initials: SD
authors.lastname: Marion
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Miller
authors.forename: Prabha
authors.initials: P
authors.lastname: Siddarth
authors.forename: Xinyao
authors.initials: X
authors.lastname: Yi
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
authors.forename: Sherri
authors.initials: S
authors.lastname: Lee
authors.forename: Xianghong
authors.initials: X
authors.lastname: Arakaki
authors.forename: Robert P
authors.initials: RP
authors.lastname: Cowan
authors.forename: Thao
authors.initials: T
authors.lastname: Tran
authors.forename: Cherise
authors.initials: C
authors.lastname: Charleswell
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Alfred N
authors.initials: AN
authors.lastname: Fonteh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D056344:Executive Function / Q000502:physiology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D015233:Models, Statistical; D011446:Prospective Studies
chemical_list: D016229:Amyloid beta-Peptides