Abstract Details

Title In Vivo Functional Dissection of Alzheimer's Disease Genetic Risk

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P3 - Poster Session 3 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-001

Objective To pinpoint causal genes in Alzheimer’s risk loci and define their requirements in the aging brain.

Background Hundreds of candidate Alzheimer’s disease (AD) susceptibility genes have been nominated based on genome-wide association studies (GWAS). However, most of these genes have poorly understood roles in the nervous system. GWAS is also limited because it typically does not narrow down which genes mediate association with AD risk. Further studies are needed to resolve which genes are causal.

Design/Methods We considered over 500 candidate AD risk genes. We prioritized 53 according to human functional genomic evidence, 24 according to in vivo evidence for interactions with tau/Aβ-induced neurotoxicity, 14 because of AD-associated rare variants, and 15 based on published evidence for modifying AD-related pathology. In total we prioritized 106 AD risk genes. We created loss-of-function Drosophila mutants and characterized the consequences of gene loss using brain histology to reveal structural changes, electroretinograms to quantify neurophysiological function, and recovery from traumatic or thermal stressors to measure resilience. We also characterized cell type-specific expression patterns of these genes in the brain.

Results

Loss of approximately half of the genes tested produces a defect in at least one assay. Our results suggest that multiple genes within a locus are important for neuronal health. We unexpectedly found that loss of 7 genes involved in lipid biology (e.g. APOE, ABCA7, DOC2A) enhances neuronal function as measured by electroretinograms. In addition, hierarchical clustering by phenotypes identifies 5 groups that may represent distinct pathways of biological disruption, e.g. endocytic defects and immune dysfunction, that contribute to AD risk.

Conclusions Our cross-species functional genomic approach pinpoints genes at AD risk loci with requirements for brain structure and function in aging. Beyond advancing our understanding of genetic mechanisms in neurodegeneration, our results reveal novel requirements for dozens of genes in neuronal homeostasis.

Authors/Disclosures
Jennifer M. Deger, BSA PRESENTER	Miss Deger has nothing to disclose.
Shabab Hannan, PhD	Dr. Hannan has nothing to disclose.
Mingxue Gu, PhD	Ms. Gu has nothing to disclose.
Colleen Strohlein	Miss Strohlein has nothing to disclose.
Oguz Kanca, PhD	The institution of Dr. Kanca has received research support from NIH.
Lindsey D. Goodman, PhD (Baylor College of Medicine)	Dr. Goodman has nothing to disclose.
liwen Ma, Research Technician	Ms. Ma has nothing to disclose.
Megan A. Cooper	Miss Cooper has nothing to disclose.
Catherine Grace Burns	Ms. Burns has nothing to disclose.
Mohammed Hamdan, MD	Dr. Hamdan has nothing to disclose.
Ismael Al-Ramahi, PhD	Dr. Al-Ramahi has nothing to disclose.
Hugo J. Bellen, PhD (BAYLOR COLLEGE OF MEDICINE)	The institution of Dr. Bellen has received research support from CASMA.
Joshua M. Shulman, MD, PhD, FAAN (Duncan Neurological Research Institute)	Dr. Shulman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Helis Medical Foudation. The institution of Dr. Shulman has received research support from National Institutes of Health.

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