The implication of dynamic repetitive DNA in Alzheimer’s disease

Alzheimer's disease (AD) is the most common cause of dementia, and although genome-wide association studies have identified numerous risk loci, a large part of its heritability remains unexplained. This thesis investigates whether structural variation in repetitive DNA, particularly tandem repeats (TR) and transposable elements (TE), contributes to this missing heritability and to the gene-regulatory mechanisms underlying AD risk. We integrate structural variation into fine-mapping analyses of well-established AD-associated loci, revealing that TRs and TEs, particularly SVA elements, are enriched in these regions and may act as genetic modifiers where causal SNPs have not been identified. We show that structurally variable SVA elements (SV-SVAs) become transcriptionally active in cortical organoids and function as enhancers whose strength depends on the length of their internal VNTR. Using CRISPR-engineered human embryonic stem cells and cortical organoid models, we demonstrate that deletion of SV-SVAs in AD-associated loci can cause epigenomic and transcriptomic changes, supporting a functional link between these elements and nearby disease-associated genes. Finally, we carry out a preliminary genetic association analysis of tandem repeats across an AD cohort and cognitively health centenarians which identifies a VNTR within RTEL1 gene as a candidate disease risk modifier. Together, this work identifies repetitive DNA as an underexplored but functionally relevant layer of AD genetic risk, and provides a foundation for future studies aiming to resolve the genetic architecture of Alzheimer's disease beyond conventional variant analysis. Show more