Evidence for genetic linkage of Alzheimer's disease to chromosome 10q.

Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Science (Impact Factor: 31.03). 01/2001; 290(5500):2302-3. DOI: 10.1126/science.290.5500.2302
Source: PubMed

ABSTRACT Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades Abeta, the principal component of beta-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD). We performed parametric and nonparametric linkage analyses of seven genetic markers on chromosome 10q, six of which map near the IDE gene, in 435 multiplex AD families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset families. Furthermore, we found evidence for allele-specific association between the putative disease locus and marker D10S583, which has recently been located within 195 kilobases of the IDE gene.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is the most common type of dementia in the elderly population. Three genes have been identified as responsible for the rare early-onset familial form of the disease: the amyloid precursor protein (APP) gene, the presenilin 1 (PSEN1) gene and the presenilin 2 (PSEN2) gene. Mutations in these genes, however, account for less than 5% of the total number of AD cases. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. In this paper, we review the most important genes supposed to be involved in the pathogenesis of AD, known as susceptibility genes, in an attempt to provide a comprehensive picture of what is known about the genetic mechanisms underlying the onset and progression of AD. Hypotheses about the role of each gene in the pathogenic pathway are discussed, taking into account the functions and molecular features, if known, of the coded protein. A major susceptibility gene, the apolipoprotein E (APOE) gene, found to be associated with sporadic late-onset AD cases and the only one, whose role in AD has been confirmed in numerous studies, will be included in a specific chapter. As the results reported by association studies are conflicting, we conclude that a better understanding of the complex aetiology that underlies AD may be achieved likely through a multidisciplinary approach that combines clinical and neurophysiological characterization of AD subtypes and in vivo functional brain imaging studies with molecular investigations of genetic components.
    Brain Research Bulletin 07/2003; 61(1):1-24. · 2.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene.European Journal of Human Genetics advance online publication, 5 December 2012; doi:10.1038/ejhg.2012.263.
    European journal of human genetics: EJHG 12/2012; · 3.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Deposition of amyloid-β peptide (Aβ), a pathological hallmark of Alzheimer's disease (AD), locates upstream of the AD cascade. Aβ is constantly anabolized and catabolized in the brain, and the steady-state Aβ level is physiologically determined by the metabolic balance between the anabolic and catabolic activities. Even subtle alterations in this metabolic balance over a long period of time could turn Aβ into a pathogenic agent that influences both the pathological progression and incidence of the disease. Therefore, AD may be a consequence of proteolytic disorder. In order to overcome AD, lowering the Aβ levels in the brain is necessary. There are many strategies to address this, such as β-, γ-secretase inhibitors or Aβ vaccination. Recently, we demonstrated that neprilysin is the most potent Aβ-degrading enzyme in vivo and hypothesized that neprilysin deficiency would influence the steady-state Aβ levels in the brain by alternating the Aβ metabolism. Therefore, to maintain or upregulate neprilysin activity in the brain will be a relevant strategy for prevention and therapy of AD through reduction of the Aβ levels. In this review, we describe several therapeutic strategies for manipulating the Aβ level and our current understanding of Aβ metabolism, focusing on the Aβ-degrading enzyme, neprilysin. Drug Dev. Res. 56:171–183, 2002. © 2002 Wiley-Liss, Inc.
    Drug Development Research 08/2002; 56(2):171 - 183. · 0.87 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014