Abstract
Altered glucose metabolism has been described in Alzheimer's disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p=0.04), but not in Northern Spanish (p=0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p=0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia world-wide
The controls were consistently in HW equilibrium, e.g. overall p = 0.61; North Europe p = 0.92; North Spain p = 0.37. Since this pattern suggested heterosis, we looked for an association of LV heterozygotes with AD
This we found in our whole dataset [odds ratio (OR) = 0.78 (95% confidence interval: 0.64 - 0.95, p = 0.01)] and in North Europe [OR = 0.76 (0.60 - 0.97, 0.03)], which was consistent in all five Northern European centres
Summary
Glucose is one of the major sources of energy for brain neurons. It is essential for the proper functions of memory and cognition. Majores et al (2002) reported on the association between a VNTR polymorphism in the 50 regulatory region of the insulin (INS) gene and the onset of AD. Those data suggested that the INS polymorphism might act as a modifier of AD progression; the risk of AD itself was not associated with this polymorphism (Majores et al 2002)
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