The effort to identify genes with alleles that influence susceptibility to late onset AD (LOAD) proceeds logically from linkage to association and then to identification of specific susceptibility alleles. Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for LOAD, we obtained linkage at approximately 80 centimorgans (cM) on chromosome 10 (Ch10). Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Pursuing these findings, we have now identified three Ch10 genes (VR22, PLAU, and IDE) with variants that show strong association with LOAD and/or plasma Abeta42. The proposed study focuses exclusively on IDE. There is compelling biological evidence from IDE knockout mice that the insulin degrading enzyme is normally involved in Abeta degradation, so IDE is clearly an excellent candidate gene. In our MCJ series, LOAD showed highly significant (p<10[-7]) association with the same IDE haplotypes that the Brookes group showed to be significantly (p<0.01) or highly significantly (p<10[-9]) associated with AD in multiple case-control series from Scotland and Sweden. These same haplotypes showed significant association with plasma Abeta42 in our extended LOAD series. The goal of this study is to identify the LOAD susceptibility alleles in the IDE region. In all LOAD patients from the MCJ series, we will thoroughly screen the coding and putative regulatory regions of the IDE gene and, if necessary, adjacent genes. The SNPs that we find (approximately 60 are expected from our initial screen of IDE) will be analyzed using a two stage statistical approach to identify the set of putative susceptibility alleles that show strongest, most reproducible association with LOAD and with plasma Abeta42. Strongly associating SNPs will then be evaluated for biological effects relevant to LOAD. To facilitate analysis of variants in putative regulatory regions and to increase the size of our case-control cohort, we will prepare cDNA and genomic DNA from the large number of frozen LOAD brains available through the Neuropathology Core.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG016574-08
Application #
7256285
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
8
Fiscal Year
2006
Total Cost
$186,628
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Baker, Darren J; Petersen, Ronald C (2018) Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J Clin Invest 128:1208-1216
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Tse, Kai-Hei; Cheng, Aifang; Ma, Fulin et al. (2018) DNA damage-associated oligodendrocyte degeneration precedes amyloid pathology and contributes to Alzheimer's disease and dementia. Alzheimers Dement 14:664-679
Ramanan, Vijay K; Przybelski, Scott A; Graff-Radford, Jonathan et al. (2018) Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. J Alzheimers Dis 65:1345-1352
Knopman, David S; Lundt, Emily S; Therneau, Terry M et al. (2018) Joint associations of ?-amyloidosis and cortical thickness with cognition. Neurobiol Aging 65:121-131
Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600
Ferman, Tanis J; Aoki, Naoya; Crook, Julia E et al. (2018) The limbic and neocortical contribution of ?-synuclein, tau, and amyloid ? to disease duration in dementia with Lewy bodies. Alzheimers Dement 14:330-339
Hanfelt, John J; Peng, Limin; Goldstein, Felicia C et al. (2018) Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center. Neurobiol Dis 117:62-71
Schaffert, Jeff; LoBue, Christian; White, Charles L et al. (2018) Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease. Neuropsychology 32:410-416
Besser, Lilah; Kukull, Walter; Knopman, David S et al. (2018) Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord 32:351-358

Showing the most recent 10 out of 1014 publications