Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer’s disease

A specific isoform of apolipoprotein E has been associated with the accelerated rate of disease expression of sporadic Alzheimer’s disease (AD) and late-onset familial AD (FAD)^1–12. An earlier age at onset has also been demonstrated in familial AD patients with mutations in the amyloid precursor protein (APR) gene (APP717 and APP670/671)13 carrying the APOEɛ-4 allele compared to those who do not, but not in familial AD patients with APP692 or 693 mutations¹⁴, or in chromosome 14-linked familial AD patients¹⁵.Hypothesizing that receptors for apoE-containing lipoprotein^16–22 act as a potential risk factor for AD, we performed an association study using a polymorphic triplet (CGG) repeat^21,23 in the gene for the VLDL receptor (VLDL-R), a receptor for apoE-containing lipoproteins.The frequency of the 5-repeat allele was significantly higher in all of the Japanese sporadic AD patients (P<0.02) than in the Japanese controls. Moreover, the odds ratio was significantly increased in the AD patients homozygous for the 5-repeat allele (OR=2.1,95% Cl=[1.1–4.2]). Multiple logistic regression analysis reveals that the relative risk conferred by the presence of two copies of the 5-repeat allele and at least one copy of the APOEɛ-4 allele is 8.7 (95% Cl=[2.9–25.8]). Our results suggest that the VLDL-R gene is a susceptibility gene for AD.