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Degenerative diseases of the central nervous system included a number of neurodegenerative disease. Genetic studies of common complex neurodegenerative diseases, such as Alzheimer's disease, have focused on the identification of risk genes as targets for development of new treatments and improved diagnoses. This approach has identified the amyloid precursor protein (APP) (Goate et al., Nature 349:704-706 (1991)), presenilin 1 (PS1) (Sherrington et al., Nature 375:754-760 (1995)), presenilin 2 (PS2) (Levy-Lahad et al., Science 269:973-977 (1995); Rogaev et al., Nature 376:775-778 (1995)), and apolipoprotein E (APOE) (Corder et al., Science 261:921-923 (1993)) genes as contributing to risk in Alzheimer's disease. APP, PS1, and PS2 cause rare early-onset autosomal dominant Alzheimer's disease (5% of Alzheimer's disease cases), whereas APOE is associated with both risk and age at onset (AAO) in late-onset familial Alzheimer's disease, as well as in late- and early-onset sporadic Alzheimer's disease. Genomic screens in Alzheimer's disease (Kehoe et al., Hum Mol Genet 8:237-245 (1999); Pericak-Vance et al., Exp Gerontol 35:1343-1352 (2000) have recently localized additional but, as yet, unknown risk genes. Alzheimer's disease is a progressive neurodegenerative disorder which is the predominant cause of dementia in people over 65 years of age. Clinical symptoms of the disease generally begin with subtle short term memory problems and as the disease progresses, difficulties with memory, language and orientation occur more frequently. In late stage Alzheimer's disease, ventricular enlargement and shrinkage of the brain may be observed by magnetic resonance imaging. Some characteristic changes in the Alzheimer's disease brain include neuronal loss in selected regions; intracellular neurofibrillary tangles (NFTs) in the neurons of the cerebral cortex and hippocampus; and neuritic plaques containing amyloids that may be further surrounded by dystrophic neuriteism reactive astrocytes and microglia. See, e.g., Wisniewski et al., Biochem. Biophys. Res. Comm. 192:359 (1993). The NFTs characteristic of Alzheimer's disease consist of abnormal filaments bundled together in neuronal cell bodies. What are referred to as “Ghost” NFTs are also observed in Alzheimer's disease brains, presumably marking the location of dead neurons. Other neuropathical features of Alzheimer's disease include granulovacular changes, neural loss, gliosis and the variable presence of Lewy bodies. The identification between genetic loci and neurodegenerative changes or associations between genetic loci and the risk of developing a neurodegenerative disease may be useful in methods of diagnosing, screening and prognosing patients. They may also be used in therapeutic development methods. Identification of further genes would open new avenues
of research with the potential to delay onset beyond the natural life span.
Present knowledge about genes contributing to AAO in neurodegenerative
diseases clearly lags behind the understanding of genes contributing to
risk. Recently, there has been growing interest in using AAO information
as a quantitative trait, to identify genes that influence onset of disease
(Daw et al., Am J Hum Genet 64:839-851 (1999), Daw et al., Am J Hum Genet
66:196-204 (2000); Duggirala et al. Am J Hum Genet 64:1127-1140 (1999)).
Rapid development of methods of mapping quantitative trait loci (QTLs)
for general pedigrees (Goldgar, Am J Hum Genet 47:957-967 (1990); Amos,
Am J Hum Genet 54:535-543 (1994); Blangero et al. Genet Epidemiol 14:959-964
(1997)) has now made the search for novel genes affecting AAO feasible.
Nevertheless, the genetic basis for Alzheimer's disease is not well understood,
and there is a continued need to develop new genetic linkages and markers
as well as identifying new functional polymorphisms that are associated
with Alzheimer's disease. It may be advantageous to locate a gene or genes
common to the disorder.
The present invention demonstrates the identification of risk genes associated with Alzheimer's disease. These at risk linkage regions also indicate that LRP1 is a candidate gene for Alzheimer's disease. The present invention further discloses methods of screening a subject for Alzheimer's disease. The method comprises the steps of: detecting the presence or absence of a marker for Alzheimer's disease, or a functional polymorphism associated with a gene linked to Alzheimer's disease, with the presence of such a marker or functional polymorphism indicating that subject is afflicted with or at risk of developing Alzheimer's disease. The detecting step may include detecting whether the subject is heterozygous or homozygous for the marker and/or functional polymorphism, with subjects who are at least heterozygous for the functional polymorphism being at increased risk for Alzheimer's disease. The step of detecting the presence or absence of the marker or functional polymorphism may include the step of detecting the presence or absence of the marker or functional polymorphism in both chromosomes of the subject (i.e., detecting the presence or absence of one or two alleles containing the marker or functional polymorphism). More than one copy of a marker or functional polymorphism (i.e., subjects homozygous for the functional polymorphism) may indicate greater risk of Alzheimer's disease as compared to heterozygous subjects. A further aspect of the present invention is the use of
a means of detecting a marker, functional polymorphism or mutation as described
herein in screening a subject for Alzheimer's disease as described herein.
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