Genome-wide scan of copy number variation in late-onset Alzheimer's disease.


Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE epsilon4 risk allele, identified a novel variant that influences disease risk within the APOE epsilon4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.





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Publication Info

Heinzen, EL, AC Need, KM Hayden, O Chiba Falek, AD Roses, WJ Strittmatter, JR Burke, CM Hulette, et al. (2010). Genome-wide scan of copy number variation in late-onset Alzheimer's disease. J Alzheimers Dis, 19(1). pp. 69–77. 10.3233/JAD-2010-1212 Retrieved from

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Warren James Strittmatter

Professor Emeritus of Neurology

Apolipoprotein (apoE) has been recently implicated in the pathogenesis of Alzheimer's disease (A.D.). One of the apoE alleles, e4, behaves as an autosomal co-dominant trait in the majority of late-onset and sporadic A.D.. The aopE4 gene dose is a major risk-factor susceptibility gene for A.D. with homozygosity for this allele virtually sufficient to cause disease by age 80, and with 50% of homozygous patients developing disease by age 68. Incontrast, the e2 and e3 alleles decrease the probability of disease, and increase the age of onset. Thus the inherited apoE allele determines in part, the risk of developing A.D., and determines the rate of disease progression. Interactions of apoE protein with other molecules is therefore critical in the disease process, with isoforms-specific interactions of apoE determining th eprobability, and rate, of disease expression.
The three common protein isoforms of apoE; E2, E3, E4, differ from each other by one amino acid, which determines their profoundly differing interactions with other proteins. In vitro, apoE4 binds BA peptide faster, and with a different pH dependence, than does apoE3. This isoform-specific difference observed in vitro correlates with the greater BA peptide amyloid burden deposited in situ in homozygous e4 A.D. patients, compared with homozygous e3 A.D. patients. Paired-helical filaments of the neurofibrillary tangle are composed of tau protein. ApoE3 avidly binds tau in vitro, forming a complex not disociated by boiling in SDS. In contrast, apoE4 does not form such a complex. Isoform-specific interactions of apoE with tau could alter tau function or metabolism.


James Robert Burke

Professor of Neurology

My research focuses on the characterization of cognitive change with age.  I am specifically interested in delineating the change between normal and pathologic changes associated with aging and developing therapies to delay decline.  

My area of expertise is neurodegenerative diseases and dementia with an emphasis on Alzheimer's disease.

Keywords: Alzheimer's disease.

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