title: Vascular factors and markers of inflammation in offspring with a parental history of late-onset Alzheimer disease.
abstract: BACKGROUND
  Alzheimer disease (AD) is a complex disorder with a strong heritable component. Amyloid pathology, vascular factors, and inflammation are postulated to be involved in its pathogenesis, but causality has not been established unequivocally.
  
  
  OBJECTIVE
  To identify heritable traits in middle age that contribute to AD.
  
  
  METHODS
  We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. In such a design, the offspring under study are enriched for risk factors of AD but do not yet have the disease.
  
  
  METHODS
  The Netherlands.
  
  
  METHODS
  Two hundred six offspring of 92 families with a parental history of late-onset AD and 200 offspring of 97 families without a parental history of AD.
  
  
  METHODS
  The APOE epsilon4 genotype, vascular factors, production capacity of pro- and anti-inflammatory cytokines upon stimulation with lipopolysaccharide, and circulating markers of inflammation. All outcome measures were assessed in the offspring only and not in the parental generation.
  
  
  RESULTS
  More offspring with a parental history of AD carried APOE epsilon4 than those without a parental history of the disease (47% vs 21%, P < .001). Those with a parental history of AD also had higher systolic blood pressures (P = .006), higher diastolic blood pressures (P < .001), and lower ankle brachial indices (P = .005) when compared with offspring without a family history of dementia. Production capacity of pro-inflammatory cytokines in offspring with a parental history of AD was also different, with higher levels of IL-1beta (interleukin 1beta) (P < .001), IL-1beta to IL-1ra ratio (P < .001), tumor necrosis factor alpha (P = .008), IL-6 (P = .04), and interferon gamma (P = .01). All of these positive associations were independent of APOE epsilon4 genotype.
  
  
  CONCLUSIONS
  Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies, of which blood pressure control can be implemented directly.
authors.affiliation: Department of Psychiatry, VU University Medical Center/GGZ-inGeest, Osdorpplein 880, 1068 TD, Amsterdam, the Netherlands. e.vexel@vumc.nl
authors.forename: Eric
authors.initials: E
authors.lastname: van Exel
authors.forename: Piet
authors.initials: P
authors.lastname: Eikelenboom
authors.forename: Hannie
authors.initials: H
authors.lastname: Comijs
authors.forename: Marijke
authors.initials: M
authors.lastname: Frölich
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Smit
authors.forename: Max L
authors.initials: ML
authors.lastname: Stek
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.forename: Jan E
authors.initials: JE
authors.lastname: Eefsting
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002648:Child; D016241:Child of Impaired Parents / Q000523:psychology / Q000706:statistics & numerical data*; D016207:Cytokines / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000235:genetics / Q000517:prevention & control; D007249:Inflammation / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010375:Pedigree; D010455:Peptides / Q000235:genetics*; D012307:Risk Factors
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D016207:Cytokines; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C021266:vascular factor