The identification of mutations in the APP, PS1, and PS2 genes that cause early-onset familial Alzheimer's disease (AD), the demonstration that these mutations all increase Abeta42, and the discovery of an association between Apolipoprotein E4 and late-onset Alzheimer's disease have dramatically improved our understanding of Alzheimer's disease. It is clear, however, that much of the genetic risk in late onset Alzheimer's disease remains unexplained. Current strategies to identify other genes that affect late-onset Alzheimer's disease have met with limited success often because of the difficulty associated with obtaining late-onset families with sufficient power for reliable linkage analysis. Genetic studies using large numbers of small families or sib-pairs, to increase the power of the analysis, are also currently being performed by several groups however difficulties with the non-replication of positive loci, identified by different studies, has continued. It will also be difficult to identify the biologically relevant genetic variability using loci identified by this type of small family/sib pair analysis, as candidate regions tend to be large and poorly defined. In this proposal we describe how high plasma ABeta levels can be used as a surrogate phenotype to increase the power of late-onset AD families allowing not only the reliable linkage of a specific chromosomal region with disease but also facilitating the identification of the genetic variability that is responsible for the increased plasma Abeta42 and for the increased risk of developing Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018023-03
Application #
6631473
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Miller, Marilyn
Project Start
2001-03-15
Project End
2006-02-28
Budget Start
2003-05-15
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$348,075
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
De Jager, Philip L; Ma, Yiyi; McCabe, Cristin et al. (2018) A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research. Sci Data 5:180142
Kidana, Kiwami; Tatebe, Takuya; Ito, Kaori et al. (2018) Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice. EMBO Mol Med 10:
Sassi, Celeste; Nalls, Michael A; Ridge, Perry G et al. (2018) Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3. Neurobiol Aging 66:179.e17-179.e29
Li, Zeran; Del-Aguila, Jorge L; Dube, Umber et al. (2018) Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure. Genome Med 10:43
Sun, Wenyan; Samimi, Hanie; Gamez, Maria et al. (2018) Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci 21:1038-1048
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Patrick, Ellis; Rajagopal, Sathyapriya; Wong, Hon-Kit Andus et al. (2017) Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer's disease. Mol Neurodegener 12:51
Carrasquillo, Minerva M; Allen, Mariet; Burgess, Jeremy D et al. (2017) A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimers Dement 13:663-673
Miller, Jeremy A; Guillozet-Bongaarts, Angela; Gibbons, Laura E et al. (2017) Neuropathological and transcriptomic characteristics of the aged brain. Elife 6:
Carrasquillo, Minerva M; Barber, Imelda; Lincoln, Sarah J et al. (2016) Evaluating pathogenic dementia variants in posterior cortical atrophy. Neurobiol Aging 37:38-44

Showing the most recent 10 out of 54 publications