Lack of association of a polymorphism in the low-density lipoprotein receptor-related protein gene with Alzheimer disease
A. E. Clatworthy, T. Gomez-Isla, G. W. Rebeck, R. B. Wallace and B. T. Hyman
Department of Neurology-Alzheimer Unit, Massachusetts General Hospital, Charlestown, USA.
BACKGROUND: The apolipoprotein E epsilon 4 (ApoE epsilon 4) 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, beta-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
epsilon 4 and LRP genotypes was observed in patients with AD. Moreover, the
LRP genotype did not correlate with degree of neuronal loss, beta-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.
