Dementia of the Alzheimer's type (DAT) is the most common form of dementia in the elderly. The etiology of DAT is a combination of genetic and environmental factors. Forty-five to fifty-five per cent of the total genetic risk. in DAT has been pegged to four genes (APP, PS1, PS2, APOE) with by far the greatest proportion explained by the APOE-4 allele. However, additional novel genes remain to be identified and would be most easily identified in large families having a low frequency of the APOE-4 allele. Large families are extremely valuable because they can provide identity-by-descent data across many affected individuals. Unfortunately the late-onset nature of DAT makes family histories difficult to trace and the geographic dispersion of families in the United States often results in lost contact between distant familial branches. While pervasive these problems are not universal, with certain cultural and religious isolates, such as the Amish, having large and stable families. The Amish present numerous advantages for study, including recent derivation from a small number of founder couples, large family size, extensive genealogical records, few marriages outside the Amish communities, and stable social and environmental influences. Over the past six years, we have successfully approached and studied several Amish families with DAT in Indiana/Michigan and Ohio. Our initial studies of the Indiana/Michigan Amish have shown a lower frequency of the APOE-4 allele yet strong clustering of DAT cases in families, suggesting that genetic factors other than APOE are at work. At the same time, progress in completing the human genome sequence and in developing molecular and statistical tools has opened many new avenues for gene identification. We wish to avail ourselves of these strengths to map the DAT genes in the Amish families.
Our specific aims are to: 1). Ascertain every Amish DAT family in Adams and surrounding counties of Indiana/Michigan and Holmes and surrounding counties of Ohio with the goal of identifying all DAT cases; 2). Screen the Amish pedigrees for genetic linkage to known loci and perform a genomic screen; 3). Perform fine mapping to identify the minimal candidate region and use SNPs to identify the underlying genes; and 4). Develop new methods to examine gene-gene interactions in large and complex pedigrees such as those found in the Amish.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-EDC-2 (04))
Program Officer
Miller, Marilyn
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
Cukier, H N; Kunkle, B K; Hamilton, K L et al. (2017) Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function. J Alzheimers Dis Parkinsonism 7:
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
Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah et al. (2017) Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement 13:119-129
Hou, Liping; Kember, Rachel L; Roach, Jared C et al. (2017) A population-specific reference panel empowers genetic studies of Anabaptist populations. Sci Rep 7:6079
Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-121
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-200.e20
Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-150

Showing the most recent 10 out of 69 publications