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Authors: Roses, Allen D.

Article Type: Research Article

Abstract: The association of Apolipoprotein E-4 with the age of onset of common late-onset Alzheimer's disease (AD) was originally reported in three 1993 papers from the Duke ADRC (Alzheimer's Disease Research Center) group [1--3]. The Center was investigating two diverse experimental streams that led to this discovery. The first being a genetic linkage study performed in multiplex familial late-onset AD in which a linkage was discovered at chromosome 19q13 [4,5]. The 1991 multilocus analysis of linkage had been considered very controversial [6]. The second stream came from a series of amyloid-β binding studies in which a consistent protein “impurity” was present …on gel separation analyses [1]. After sequencing this “impurity” band, several tryptic peptide sequences were found to be identical for apoE which, at that time, had no known association with Alzheimer's disease. The flash of recognition was the knowledge that APOE was one of the first genes localized to chromosome 19 in the mid-1980's. Within a three week period in late 1992, a highly significant association was identified in clinical patients from multiplex families, in sporadic clinical patients, and in autopsy diagnosed series [1,2]. Within the first two months of 1993, it was possible to clearly demonstrate that the APOE isoforms were associated with differing ages of onset, but the course of illness following diagnosis was related more to age than APOE genotype [3]. The earliest submitted paper reported the familial association and amyloid-β binding [1]. The second reported the association with common sporadic late-onset, [not-known to be familial] AD patients [2]. The third reported that APOE4 carriers had earlier rates of onset of clinical disease than APOE2 or APOE3 carriers [3]. Subsequently, over more than a decade, the biological expression of apoE in human neurons was confirmed as distinct from rodent brain [7,8] Proteomic experiments and positron emission tomography data have led to a series of clinical trials with agents selected to increase glucose utilization. These agents also regulate inflammatory responses of neural cells. Rosiglitazone, a PPARγ agonist which also leads to mitochondrial proliferation shown efficacy as a monotherapy in a Phase IIB clinical trial of 511 patients in an APOE allele-specific analysis. Show more

DOI: 10.3233/JAD-2006-9S340

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 361-366, 2006

Authors: Lutz, Michael W. | Crenshaw, Donna G. | Saunders, Ann M. | Roses, Allen D.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-101765

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 247-251, 2011

Authors: Heinzen, Erin L. | Need, Anna C. | Hayden, Kathleen M. | Chiba-Falek, Ornit | Roses, Allen D. | Strittmatter, Warren J. | Burke, James R. | Hulette, Christine M. | Welsh-Bohmer, Kathleen A. | Goldstein, David B.

Article Type: Research Article

Abstract: 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 ε4 risk allele, identified a novel variant that influences disease risk within the APOE ε4 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. Show more

Keywords: Alzheimer's disease, copy number variation, dementia, genome-wide association study

DOI: 10.3233/JAD-2010-1212

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 69-77, 2010

Authors: Cogswell, John P. | Ward, James | Taylor, Ian A. | Waters, Michelle | Shi, Yunling | Cannon, Brian | Kelnar, Kevin | Kemppainen, Jon | Brown, David | Chen, Caifu | Prinjha, Rab K. | Richardson, Jill C. | Saunders, Ann M. | Roses, Allen D. | Richards, Cynthia A.

Article Type: Research Article

Abstract: MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.

Keywords: Alzheimer's disease, inflammation, insulin signaling, microRNA, neurogenesis

DOI: 10.3233/JAD-2008-14103

Citation: Journal of Alzheimer's Disease, vol. 14, no. 1, pp. 27-41, 2008