Genetics of Young Onset Alzheimer's Disease

Historically, young onset Alzheimer’s disease (YOAD) is defined as onset of clinical symptoms before the age of 65, and 90% of such patients are not associated with mutations in the main 3 Ab related genes (APP, PSEN1 and PSEN2). The objective of this project is to deeply characterize known and new genetic components of YOAD in the largest pathologically confirmed cohort in the world and to evaluate the impact of SNVs, SVs and repeat expansions. Due to their earlier onset age, and strong heritability, we hypothesize that YOAD patients are enriched in rare pathogenic variants within the Ab and Tau pathways. In addition, patients with YOAD are often misdiagnosed for frontotemporal dementia due to clinical symptom overlap. In that context, we also hypothesize that there is genetic overlap between both diseases.
We generate whole-genome sequencing data from over 900 YOAD patients, including more than 400 autopsy confirmed YOAD cases, over 1000 FTD patients and 800 controls.
We are requesting access to the ADSP whole-genome sequencing data (raw and VCF) to i) to perform gene-based, single variant and pathway association analyses in ADSP YOAD and late onset data to replicate our findings, ii) increase our YOAD cohort size for assessing the overlap and differences between FTD and YOAD patients. Single nucleotide variants, as well as structural variants, will be assessed. To do so, we will use already generated SNVs VCF but also generate structural variant calling using our Mayo pipeline.
We will utilize several commonly used software programs, such as Plink-seq and SKAT package, to perform our association analyses. All analyses will be done at the single variant, gene, structural variant, and pathway levels. Using these approaches, we hope to identify novel mutations/genes/pathways that are related to both AD and FTD and will benefit the larger scientific community working on neurodegenerative disorders.

We aim at identifying new risk factors for young onset Alzheimer’s disease (age at onset before 65). To do so we use deep phenotyping and genetic approaches. Upon completion of our work, we will obtain a comprehensive understanding of young onset Alzheimer’s disease genetics. Altogether our project will identify potential new therapeutic targets for young onset Alzheimer’s disease and will pave the way for individualized therapy development not only for young onset Alzheimer’s disease, but also for the more common late onset AD.