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Principal Investigator  
Principal Investigator's Name: Bess Frost
Institution: UT Health San Antonio
Department: Barshop Institute
Proposed Analysis: Based on nanopore DNA long read sequencing of a small set of control and Alzheimer’s disease patient brains, we have identified novel candidate Alzheimer’s disease susceptibility genes harboring non-reference mobile element insertions. Our second objective is to utilize the ADSP umbrella whole genome sequencing dataset (NG00067) to determine if our findings are conserved in a larger cohort of patients with Alzheimer’s disease. We are also performing nanopore DNA sequencing of a small set of patients with progressive supranuclear palsy versus controls. Using this data, we will identify retrotransposon-associated PSP susceptibility genes. We will then determine if our findings are conserved in a larger cohort of patients using NIAGADS PSP datasets. Study Design: CRAM alignment files aligned to the GRCh38 reference genome from the ADSP discovery (snd10000) and PSP-UCLA (snd10017) WGS data sets will be analyzed with xTea (Chu et al. 2021) to identify the presence of mobile element insertions previously identified via nanopore. To facilitate the analysis, only genomic regions containing insertions of interest will be analyzed. xTea takes alignment files and outputs a genomic variant call file (gVCF) containing the genotype of the non-reference mobile element insertions. Mobile element insertion calls will then be quality filtered with the following criteria: minimum genotype score of 20, DP of 10 and variant level filter of variant quality score log-odds > -3. Sex and familial relationships will also be considered. Analysis Plan: We have identified multiple candidate non-reference mobile element insertion variants using nanopore long read sequencing of DNA extracted from frontal cortex of patients at Braak 0, III, and V/VI. Non-reference mobile insertions identified via nanopore will be compared in control, Alzheimer’s disease, and PSP NIAGADS datasets. Insertions meeting the designated criteria will be considered for a replication analysis using cohorts from the ADSP umbrella dataset. We will determine whether these variants can predict the longitudinal clinical rate of disease progression and correlate with other features such as tau PET positivity, CSF tau, and cognitive testing. We will also consider sex, age, and high-risk genotypes.
Additional Investigators