Alzheimer's disease is known to have a strong genetic basis, but it is not well understood. Prior work on families with dominantly inherited Alzheimer's disease significantly advanced our understanding of the role of beta-amyloid in the disease. This paved the way to a broader understanding of how Alzheimer's disease develops not only in individuals from these rare families but in those with common forms of the disease. Ultimately, these insights have guided the development of new therapies to halt or slow the progression of this devastating and relentless disease, which are ongoing. Our study seeks to find additional therapeutic targets by identifying new genetic mechanisms of disease.
We aim to identify new genetic causes of Alzheimer's disease in a large family with highly penetrant, dominantly inherited late-onset Alzheimer's disease. This family has been recruited over the last 11 years by researchers at the NIA-funded Emory Alzheimer's Disease Research Center. We currently have recruited 143 individuals, including 112 who have donated biological specimens, who span 10 generations from the original founders in 3 major branches. Genetic screening revealed no family member with an AD-causing mutation. In our proposal, we marry cutting-edge technology and classical genetic techniques to discover the AD-causing gene in a large multi-generational family. Because individuals in this pedigree are distantly related but continue to transmit AD as a dominantly inherited trait, we hypothesize that they share a rare or previously described AD-causing mutation. To test this hypothesis, we propose to identify all rare or previously described genetic variants among 12 distantly related affected members of this kindred using whole-exome sequencing. Next, we will test whether variants that are shared among the 12 affected individuals co-segregate with AD in the entire pedigree. Because there are approximately 10 generations separating affected individuals any variant that co-segregates with AD in the entire pedigree is likely causal since it is highly unlikely that a variant would co-segregate with AD ove that many generations by chance alone. To better understand the role of the gene containing the co-segregating variant in AD, we will examine the (1) expression of the gene in post- mortem tissue and (2) determine the genetic contribution of the gene to AD using an independent cohort.

Public Health Relevance

Alzheimer's disease and other neurodegenerative illnesses are highly relevant to the veteran population and the VA research mission. This is foremost due to the general aging of the veteran population since advanced age is the most important risk factor for these illnesses. Secondarily, because head injury in early adulthood is associated with higher odds of developing Alzheimer's disease and other dementias later in life, many aged veterans are at even higher risk for these devastating illnesses. The goal of this proposal is to identify a new genetic cause of Alzheimer's disease using a combination of cutting-edge and classical genetic techniques in large kindred with autosomal dominant AD not explained by a known cause. Discovery of new genetic causes of Alzheimer's disease will 1) shed light on new causes of the Alzheimer's disease, 2) aid development of new diagnostic tests, and 3) provide new targets for desperately needed treatments to slow or halt the relentless progression of this disease.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
1IK2BX001820-01A2
Application #
8541314
Study Section
Special Emphasis - Research on Clinical Application of Genetics (SPLC)
Project Start
2013-10-01
Project End
2018-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
824835805
City
Decatur
State
GA
Country
United States
Zip Code
30033
Wingo, Thomas S; Kotlar, Alex; Cutler, David J (2017) MPD: multiplex primer design for next-generation targeted sequencing. BMC Bioinformatics 18:14
Pan, Feng; Wingo, Thomas S; Zhao, Zhigang et al. (2017) Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells. Nat Commun 8:15102
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
Howell, Jennifer C; Watts, Kelly D; Parker, Monica W et al. (2017) Race modifies the relationship between cognition and Alzheimer's disease cerebrospinal fluid biomarkers. Alzheimers Res Ther 9:88
Seyfried, Nicholas T; Dammer, Eric B; Swarup, Vivek et al. (2017) A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease. Cell Syst 4:60-72.e4
Johnston, H Richard; Chopra, Pankaj; Wingo, Thomas S et al. (2017) PEMapper and PECaller provide a simplified approach to whole-genome sequencing. Proc Natl Acad Sci U S A 114:E1923-E1932
Wingo, Thomas S; Duong, Duc M; Zhou, Maotian et al. (2017) Integrating Next-Generation Genomic Sequencing and Mass Spectrometry To Estimate Allele-Specific Protein Abundance in Human Brain. J Proteome Res 16:3336-3347
Goodman, Richard A; Lochner, Kimberly A; Thambisetty, Madhav et al. (2017) Prevalence of dementia subtypes in United States Medicare fee-for-service beneficiaries, 2011-2013. Alzheimers Dement 13:28-37
Wingo, A P; Almli, L M; Stevens, J S et al. (2017) Genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs. Mol Psychiatry 22:774-783
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

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