Vascular factors and markers of inflammation in offspring with a parental history of late-onset Alzheimer disease.
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.
van Exel
Eric
E
Department of Psychiatry, VU University Medical Center/GGZ-inGeest, Osdorpplein 880, 1068 TD, Amsterdam, the Netherlands. e.vexel@vumc.nl
Eikelenboom
Piet
P
Comijs
Hannie
H
Frölich
Marijke
M
Smit
Johannes H
JH
Stek
Max L
ML
Scheltens
Philip
P
Eefsting
Jan E
JE
Westendorp
Rudi G J
RG
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
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D016207:Cytokines; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C021266:vascular factor