Lack of Association of a Polymorphism in the Low-density Lipoprotein Receptor-Related Protein Gene With Alzheimer Disease

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Abstract
Background: The apolipoprotein E ε4 (ApoE ε4) allele is associated with an increased risk for development of Alzheimer disease (AD). We hypothesized that polymorphisms in proteins that interact with ApoE also might have an impact on the likelihood of AD developing. We examined a polymorphism in the gene for the low-density lipoprotein receptor-related protein (LRP), because LRP is a major ApoE receptor in the brain that also mediates binding and degradation of secreted Kunitz protease inhibitor forms of amyloid precursor protein. Subjects and Design: The LRP genotypes in 2 groups were studied. The first group consisted of 130 patients with probable or definite AD (mean±SD age, 78.2±8.9 years) and 64 nondemented, control subjects (mean±SD age, 81.7±12.3 years) who were primarily the spouses of the patients. The second group consisted of individuals from a population-based, epidemiologic study, including 38 cognitively impaired individuals (mean±SD age, 79.9±4.1 years) and 93 nondemented controls (mean±SD age, 78.7±4.4 years). Finally, 22 brains with a neuropathological diagnosis of AD were evaluated for neuronal loss, β-amyloid deposition, and neurofibrillary tangle number and compared with the LRP genotype. Results: No genetic disequilibrium in LRP allele frequencies between controls and patients with AD or cognitive impairment was observed. No interaction between the ApoE ε4 and LRP genotypes was observed in patients with AD. Moreover, the LRP genotype did not correlate with degree of neuronal loss, β-amyloid deposition, or neurofibrillary tangle number in individuals examined using quantitative neuropathological techniques. Conclusion: This LRP gene polymorphism is not linked with the pathophysiological changes of AD.