SUMMARY Alzheimer’s Disease (AD) is projected to affect 13 million people in the US by 2050 and remains neither curable nor preventable. Following remarkable recent progress, the genomic architecture of AD and related dementias (ADRD) is coming into focus. Similar to other common and genetically complex disorders, AD is characterized by substantial locus heterogeneity and polygenic susceptibility: risk or protective alleles are being identified in many distinct genes, and in most individuals, a subset of common and rare variants likely interact to trigger neurodegeneration. The critical next steps include confirmation of the responsible genes, understanding the functional impact of disease-associated variants, elaboration of the relevant cell types and pathways, and determining how polygenic interactions mediate disease risk. We propose an integrated computational and tiered experimental validation strategy to accelerate AD functional genomics, building on advances from the AD Sequencing Project (ADSP) and leveraging powerful technologies available in the fruit fly, Drosophila melanogaster. First (AIM 1), leveraging infrastructure developed for the Clinical Genome Resource and ENCODE projects, we will integrate ADSP results with other human data, including brain transcriptome and epigenome profiles, prioritizing genes and variants for experimental follow-up. Next (AIM 2), using high-throughput Drosophila screening, we will systematically manipulate 2,000 conserved, candidate AD genes in vivo to pinpoint causal modulators of age-dependent neurodegeneration, including interactions with Tau, Aß, and other pathologic triggers. Third (AIM 3), for a subset of 200 prioritized gene candidates, we will generate customized Drosophila strains and characterize cell-type expression and loss-of-function phenotypes. Lastly (AIM 4), for 50 high-priority targets, we will experimentally probe mechanisms in-depth, including testing of cell-type specific requirements (neurons vs. glia) and examining gene-gene interactions that define relevant pathways. We will broadly share all project data and resources with the research community (AIM 5). Our integrative, tiered, cross-species strategy promises rapid functional annotation of ADSP targets using powerful, in vivo assays in the aging nervous system of Drosophila, and is ideally suited for reciprocal cross-validation in complementary mammalian preclinical models. On a scale and timeframe not currently possible in other model systems, our innovative experimental strategy will transcend barriers to translation of human genetic discoveries and catalyze breakthroughs in our understanding AD pathobiology.

NARRATIVE Alzheimer's disease is a devastating and incurable neurodegenerative disorder projected to affect 13 million individuals in the US by 2050. Integrating results from human genetic studies with innovative model organism investigations, we will discover the mechanisms responsible for risk of Alzheimer's disease and related dementias. Improved functional understanding of Alzheimer's disease susceptibility, including disease amplifying and protective factors, holds enormous potential for therapeutic breakthroughs.